Clinical cancer immunotherapies are usually impeded by tumor immunosuppression driven by tumor associated macrophages (TAMs). Thus, TAMs can be considered as a promising therapeutic target for improved immunotherapy, and TAMs-focused molecular targeting agents have made ideal progress in clinical practice. Even so, most TAMs-targeting agents still cannot cover up their own shortcomings as free drugs. The emergence of multifunctional nanomaterials can expectedly endow these therapeutic cargoes with high solubility, favorable pharmacokinetic distribution, cell-specific delivery, and controlled release. Here, the underlying mechanisms of tumor immunosuppression caused by TAMs are first emphatically elucidated, and then the basic design of TAMs-focused immune-nanomedicines are discussed, mainly including diverse categories of nanomaterials, targeted and stimulus-responsive modifications, and TAM imaging in nanomedicines. A summary of current TAMs-targeting immunotherapeutic mechanisms based on functional nanomedicines for TAMs elimination and/or repolarization is further presented. Lastly, some severe challenges related to functional nanomedicines for TAMs-focused cancer immunotherapy are proposed, and some feasible perspectives on clinical translation of TAMs-associated anticancer immunonanomedicines are provided. It is hoped that, with rapid development of nanomedicine in cancer immunotherapy, TAMs-focused therapeutic strategies may be anticipated to become an emerging immunotherapeutic modality for future clinical cancer treatment. Immunotherapy is currently considered as a promising next-generation therapeutic strategy for various cancers thanks to its ability to modulate cell-specific immune responses toward tumors Among most immunosuppressive cells, TAMs, as crucial drivers of immunosuppressive TME, account for the largest proportion of immune cells in the TME (approximately 50% of tumor mass) 2), iron oxide (Fe3O4) or polysaccharides, have been identified as promising immunoregulatory adjuvants that can directly provoke adaptive immune responses against tumors Although those therapeutic agents based on TAMs have achieved some expected progress in basic and even clinical studies, they still cannot cover up their shortcomings as free drug molecules, namely low solubility, fast metabolism, nonspecific tissue distribution, off-target toxicity and side effects, poor cellular uptake, etc. Figure 1). Other studies in TAMs-targeting therapeutic strategies without the involvement of immune are not included. Collectively, there are three main types of TAMs-centered immunotherapies, including (1) blockage of bone-marrow-derived TAMs recruitment, (2) depletion of tumor-resident TAMs population, and (3) reprogramming of TAMs phenotype. We first detailedly explain the molecular mechanisms by which TAMs induce tumor immunosuppression, and then focus on the rational design of TAMs-centered functional nanomedicines, which involves multiple categories of nanomaterials with different physicochemical characteristics, and diverse functional modifications including targeting capacity, stimulus-responsive function and TAM imaging. Furthermore, we present an overview of current functional nanomedicines for different TAMs-targeting immunotherapeutic mechanisms. Finally, we mainly discuss some severe challenges in this research field, and provide some feasible perspectives on nanomedicines mediated TAMs regulation to alleviate the tumoral immunosuppressive microenvironment for effective cancer immunotherapy.In this review, we outline the current advances of functional nanomedicines mediated strategies in TAMs-focused cancer immunotherapy (2 (PGE2) by tumor cells In general, TAMs in TME are largely constituted by myeloid-derived and tissue-resident macrophages, both of which can elicit the undesirable tumor immunosuppression Figure ). First, TAMs can directly weaken the activities of T cells and NK cells, mainly including (i) TAMs often release IL-10 and TGF-β cytokines to suppress the immune function of T cells or NK cells The underlying mechanisms of tumor immune suppression driven by TAMs may be classified into two pathways . One such major mechanism is that, tumor-secreted macrophage colony stimulating factor (MCSF) can bind to colony stimulating factor 1 receptor (CSF1R) on TAMs, thus initiating the MCSF-CSF1R signaling pathway to recruit and polarize TAMs into immunosuppressive M2-like phenotypes In addition, tumor cells can directly evade the innate immune system through the crosstalk with TAMs  can be designed to avoid invading capillaries, while small enough NPs can be used to avoid phagocytosis by the reticuloendothelial system (RES) Table 1.The following is the main discussions of many types of NPs with different physicochemical properties and multifunctional modifications of nanoplatforms for TAMs-focused tumor immunotherapy. Based on recent studies in this field, various TAMs-focused functional nanomedicines for cancer immunotherapy are also summarized in Figure 3). As mentioned above, NPs are more readily internalized by TAMs during their delivery of targeted drugs to tumor cells, implying that they are latent drug carriers for macrophages. Furthermore, their physical characteristics such as size, charge or morphology may impact the phagocytosis effect of TAMs while NPs are constructed to target and modulate TAMs There are currently a variety of NPs based on different material categories, including organic nanomaterials , inorganic nanomaterials ), and biological/natural carrier-based nanomaterials, which can be considered for the effective load and delivery of drugs in TAMs-centered cancer immunotherapy ) responsible for their natural phospholipid bilayer structure Among most polymers, amphiphilic polymers, that can self-assemble into core-shell micellar NPs in aqueous solution, are mostly used as nanocarrier materials for the drug delivery in cancer therapy, which is beneficial to increase solubility and bioavailability of therapeutic agents 2) for initiating reactive oxygen species (ROS) photogeneration in endosome/lysosome or cytoplasm of TAMs Polymeric NPs also hold great promise as drug delivery systems for improved cancer immunotherapy by immunomodulating TAMs and directing the changeover of immunosuppressive TME, which can encapsulate drug molecules through hydrophobic or electrostatic interactions along with a high drug-loading efficiency 2 particles and small molecular IPI549, which remodeled TAMs-mediated immunosuppressive TME and liberated the immune system against tumors in vivo delivery barriers and the tumor penetration of NPs after intravenous injection. For polysaccharide NPs, Huang et al. employed PEG-histamine-modified alginate (PHA) to combine the galactosylated cationic dextran loaded with three types of ODNs  to form a nano-complex, which directed the reversion of TAMs phenotype and activated their antitumor immunity Several types of biomacromolecules like proteins  and human ferritin) in vivo delivery barriers, along with an ideal particle size of almost 100 nm that was a key determinant of physiological stability during blood circulation Besides, poly(amino acid) can be considered as a latent carrier framework. Liu et al. fabricated mixed polypeptide NPs based on n-butylamine-poly(L-lysine)-b-poly(L-cysteine) (PLL-PLC) polypeptides coated with sheddable PEG-PLL Inorganic materials, including carbon (C), silicon (Si), phosphorus (P), metal, etc., also have the tremendous potential as drug delivery NPs on account of their small sizes, large surface areas, ease of surface modifications, and facile synthesis, which have attracted extensive attention for TAMs-focused cancer immunotherapy.82(OH)22) and fullerene (C82) have been well validated as latent immunoregulatory NPs to target TAMs for priming T cell-mediated anticancer immunotherapy by reversing the immunosuppressive TME In terms of C-based nanomaterials, fullerenol , as a typical two-dimensional layered inorganic material, has been served as desirable antitumor NPs responsible for its biosecurity and photothermal conversion capacity 3O4 NPs 2) NPs 3) NPs 3O4 NPs and ZnO NPs have become the U.S. Food and Drug Administration (FDA)-approved nanoproducts owning to their structure stability, biocompatibility and biosafety 3O4 NPs can stimulate and reverse TAMs phenotype from immunosuppressive M2 type to immune-activated M1 type 2/g and pore size of 3.8 nm, which further favored the physical loading of another chemotherapeutic doxorubicin (DOX) for combination immunotherapy.Metal-based nanomaterials, like gold nanorods/NPs (AuNRs/AuNPs) At present, considerable evidences have proved that biomimetic natural nanocarriers derived from diverse biological membrane are emerged as immunotherapeutic systems for enhanced antitumor immunity. Among of them is natural killer (NK) cell membranes, which can play a role of immune-inducer in inherently promoting tumoricidal pro-inflammatory M1-type polarization and activating adaptive immune response for cancer immunotherapy Cell membranes-derived exosomes  can also be used as nanomaterials for immunotherapy. Dario et al. have indicated that these exosomes can be significantly uptaken by macrophages, which means that this class of nanocarrier has a certain potential for TAMs targeting In addition to biological membranes as natural vectors, it has been verified that the ink ejected from cuttlefish, composed of melanin, polysaccharides, oligopeptides, metals, etc. in vivo biological barriers Although a variety of nanomaterials are available for TAMs-centered immunotherapeutic strategies, there are still severe challenges in the effective delivery of immunomodulatory drugs to target tissues and cells using nanoplatforms due to inherent As is well known, the aforementioned NPs possess the ability of passive targeted delivery resulted from the enhanced permeability and retention (EPR) effect, which enables the increased tumor accumulation of NPs on account of leaky tumor vasculature specific TAMs-targeting ligands for the surface modification of nanocarriers are mainly classified as follows: first, for carbohydrates-associated ligands, both mannose Bletilla Striata polysaccharide (BSP)) During the past decades, great efforts have been devoted to actively targeting M2-like TAMs using above-mentioned nanoplatforms surface-modified with diverse macrophage-affinity ligands. In general, To ensure the therapeutic efficacy of immune-stimulating drugs after targeting the tumor immune microenvironment, stimulus-responsive groups can be reasonably introduced into NPs to trigger drug release in a spatiotemporal controlled manner, which is conducive to further promoting specific immune activation to enhance the efficacy of immunotherapy. Accordingly, in TAMs-centered immunotherapeutic strategies, such drug delivery nanoplatform should be intelligently designed to respond to common environmental stimuli mainly including internal response , protease) and external response (heat and light), thereby facilitating drug delivery and timely exerting immunotherapeutic effect of the released drug within the targeted sites of TME.4HCO3) to respond to endosome/lysosome acidification (pH ~5-6), which could generate abundant CO2 and NH3 to facilitate the disassociation of NPs and disruption of endosome/lysosome membrane, thus effectively released phototherapeutic agents to cytoplasm of TAMs 2 is capable of inevitable degradation in acidic TME with sufficient H2O22O2 based on MnO2 NPs have been used for on-demand drug release in TAMs-associated cancer immunotherapy Among internal stimuli, acidic pH is a commonly used responsive condition, which mainly involves in weak acid in TME and low-pH within endosome/lysosome. Generally, tumor acidic microenvironment-responsive NPs, that consisted of pH-sensitive material such as O-carboxymethyl-chitosan 3O4 NPs, BP NPs, etc. As expected, these photo-responsive nanomaterials can achieve specific drug release in a spatiotemporal manner when exposed to specific light wavelengths For external stimuli, hyperthermia can be utilized as a physical stimulus for antitumor therapeutic response of NPs. There was a study about magnetic hyperthermia, namely that a liposome loaded with superparamagnetic NPs and CSF1R inhibitor BLZ945 were constructed for antitumor immune response under magnetic hyperthermia responses 3O4 nanomaterials have great application prospects for MRI imaging of macrophages 3O4 NPs to predict patient treatment response by imaging TAMs using MRI technique is currently in clinical trials and is believed to be put into clinical practice in the near future in vivo imaging under 980 nm laser excitation and was verified that their targeted imaging capacity could be achieved by their up-conversion fluorescence (540 nm) and downshifting fluorescence (1525 nm). From this study, such NPs have the potential to be used as a biocompatible diagnostic material for monitoring the tumor progression and assessing prognosis. In addition, He et al. developed a precise and deep-tissue multi-scale imaging technology with a surface-enhanced Raman scattering (SERS)/NIR-II optical AuDAg2S nanoprobe, which integrated SERS imaging and NIR-II in-depth biological fluorescence imaging, and eventually could achieve multidimensional tumor imaging in levels of single cell The imaging of TAMs, particularly the M2-type TAMs is very important for guiding tumor therapy and assessing therapeutic efficacy. In clinic, it can help extract prognostic data, delineate tumor boundaries, direct tumor biopsies, etc. Table 2.As previously mentioned, an ideal nanomedicine for TAMs-focused cancer immunotherapy is mainly composed of suitable nanomaterials with specific functional modifications, and targeted therapeutics encapsulated. In addition, TAMs play a key role in immune regulation by directly or indirectly promoting tumor cells to evade immune supervision. Moreover, considerable studies have revealed TAMs can trigger immunotherapy resistance, including checkpoint inhibitor therapy, adoptive cell transfusion, and tumor vaccines therapy +CCR2+ monocytes Figure ) TAMs in tumor tissue are partially derived from circulating Ly6CFigure ). These nanocomplexes possessed high loading capacity, increased half-life and small particle diameter (about 30 nm), which effectively delivered IBR to the tumor site and actively internalized by TAMs via SA-targeting. Then tumor immunosuppression caused by M2-TAMs was successfully blocked by inhibition of myeloid-cell recruitment responsible for IBR-induced BTK downregulation in TAMs, thus remarkably inhibiting tumor growth with negligible systemic toxicity.It has been found that the generation of protumoral TAMs is closely associated with Bruton's tyrosine kinase (BTK) overexpressed in TAMs Tissue-resident TAMs tend to polarize to an immune-deactivated M2 phenotype that can elicit tumor immune suppression in many malignancies + T cells-based immune response against tumor progression Figure ). Meanwhile, small Pt prodrug particles were released to penetrate into deep tumor region for further tumor eradication. As shown in Figure , this BLZ-945-loaded NP significantly reduced the population of TAMs (nearly 47.6%) in tumor tissues and obviously increased the abundance of activated CD8+ T cells along with sharp decrease of Treg cells in CD4+ T cells, indicating that inhibition of TAMs survival successfully enhanced the activation of CD8+ T cells-mediated immune response. In a recent report, Xie et al. introduced CSF1R blocker BLZ-945 into the bioactive nanovaccines, which effectively inhibited M2-like TAMs in tumor tissues through a series of pH/size/charge transitions, and finally remodeled the immunosuppressive TME for potentiating immunotherapeutic efficacy Figure ). By analysis of tumor immune environment, it was found that dual-targeting lipid NPs carrying siCD115 remarkably decreased the number of TAMs population accounting for about 52% in tumor tissues, along with a 60% decrease of CD206 (M2-type marker) and a 59% decline of PD-L1 on M2-TAMs . Moreover, these targeted nanomedicines resulted in an obvious inhibition of immunosuppressive IL-10 and TGF-β and a dramatic increase of immunostimulatory IL-12 and IFN-γ, and a 2.9-fold augment of CD8+ T cell infiltration in TME.CSF1-CSF1R chemokine axis has been viewed as the crucial signaling pathway responsible for polarization of TAMs to immunosuppressive M2 phenotype in vivo experiments, these ALN-containing targeted NPs preferentially accumulated in TAMs and effectively deleted TAMs by ALN-triggered apoptosis, eventually recovering local immune surveillance for suppressing tumor growth. In their follow-up study Several bisphosphonates, like clodronate (CLO) and alendronate (ALN), have been formulated into appropriate immunostimulatory nanomedicines for targeted depletion of M2-type macrophages. Sousa et al. used liposomal-encapsulated CLO to produce high cytotoxity toward macrophages for significant elimination of TAMs Figure ). In vivo outcomes during 21d tumor treatment showed that VEGF silencing by siVEGF-encapsulated M2pep-AuNPs observably decreased the number of macrophages in lung tissues, and resulted in an about 95% reduction of M2-like TAMs in tumor tissues .The vascular endothelial growth factor (VEGF) highly expressed in M2 TAMs can promote tumor progression and metastasis Figure ) Figure ) 2 release also decreased M2-macrophages recruitment by alleviating tumor hypoxia. Finally, both strategies synergistically augmented CTLs-based antitumor immunity and significantly suppressed tumor metastasis and recurrence. To fulfill the depletion of M2 macrophages within tumors, Sun and his colleagues reported HA-PDA@Fe3O4 NPs were developed for remodeling the immune “cold” of TME through regulation of the ratio of M1/M2 subpopulations  3O4 NPs, followed by mass production of different chemokines that could transformed tumor immune suppression through cascading amplification effects. More specifically, these HA-modified magnetite NPs simultaneously decreased relatively the populations of tumor-resident M2-TAMs by maintaining M2 macrophages, thus synergistically potentiating TAMs-focused tumor immunotherapy.In addition to above mechanisms, it has been reported that doxorubicin chloride (DOX·HCl) can effectively kill TAMs Figure ) 3 NPs loaded with anti-CD47 antibody for polarization of TAMs to M1-type through targeted inhibition of CD47-SIRPα pathway, thereby enhancing phagocytosis of cancer cells by M1-TAMs and initiating T cell-mediated antitumor immune responses Figure ), namely that hybrid polymeric NPs, composed of fluorinated-PEI (PF), HA and TME-sensitive peptides (TMSP), could highly effectively deliver Cas9/sgRNA and pIL-12 plasmids for promoting M1-polarized TAMs by the blockade of CD47 and IL-12-mediated immune-activation in melanoma Repolarizing M2-subtype using immune-nanomedicines is also a widely used strategy for TAMs-focused cancer immunotherapy nowadays. Accumulating studies have attested the M2 reprogramming is related to the regulation of different signaling pathways by nanomaterials carrying molecular targeted agents. For instance, TAMs can promote the evasion of tumor cells from immune surveillance through both typical mechanisms of MCSF-CSF1R and CD47-SIRPα. It has been reported that dual blockages of the CD47-SIRPα and MCSF-CSF1R signaling axes by liposomes-encapsulated SHP2 and CSF1R inhibitors show great potential for TAMs-based cancer immunotherapy, which resulted in sufficient re-education of M2-TAMs to an active M1 subpopulation  2 NPs for specific suppression of PI3K-γ pathway on MDSCs Figure ).The gamma isoform of phosphoinositide 3-kinase (PI3K-γ) highly expressed in myeloid cells (MDSCs or macrophages) holds a central switch between immune response and suppression, and regulates macrophages programming Figure ). However, some studies proposed the opposite view that inactivating NF-κB pathway could dominate the reprogramming of M2-like TAMs Figure ) As previously reported, the activation of NF-κB pathway may regulate the transformation of M2-to-M1 phenotype via some critical mechanisms in macrophages Other than NF-κB signaling-based mechanisms, some evidences have also testified that the M1-type polarization may be associated with expression regulation of the signal transducer and activator of transcription (STAT) Figure ) mTOR signaling, a typical cellular metabolic pathway, plays an essential regulation in M2 macrophage polarization, mainly resulting from up-regulating the expression of p-STAT3 and IL-10 Figure ) + T cells-mediated tumor cytotoxicity. Meanwhile, another targeted micelles-formulated DOX directly exerted chemotherapeutic activity against tumor cells, which was synergized with R837-induced immunotherapy for enhanced breast cancer therapy. Furthermore, Wei et al. applied R848-loaded PLGA NPs coated with nonpathogenic bacterium E.coli to realize the re-polarization of M2-type macrophages  E.coli could separately activate TLR4/5 related pathways for the conversion of M2 to M1 Figure ).Activation of TLRs-mediated signaling in macrophages by using some agonists, including CpG in vitroCurrent studies have proved that miR may play an important role in regulating macrophage polarization and activation. Among most miRs, miR155 has been used as a modulator for effectively restraining the TAMs-associated cytokine production via targeting C/EBPβ According to previous researches, spleen tyrosine kinase (SYK) plays a key role in the induction of the macrophage-mediated immune response after macrophages engulf crystals or NPs 3O4 NPs 3+-chelated NPs 3O4 NPs mainly activate the IRF5 signaling via generated Fe3+ instead of the ROS-induced NF-κB signaling  3O4 NPs may stimulate inflammatory responses by initiating the TLR4 signaling on surface of macrophages 3+ inside the macrophages can promote the phenotypic switching of macrophages by activation of NF-κB signaling pathway 2-xSe (CS NPs) to realize the repolarization of M1-like macrophages in melanoma Increasing evidences have demonstrated that FDA-approved Fe+ T cells + T cells  To the best knowledge of another reprogramming mechanism, aerobic glycolysis-produced lactate in the TME dominates phenotype conversion of M1-to-M2 TAMs and inactivation of CD8in situ gene editing of local macrophages in postoperative GBM lumen, to form CAR-M that could target the removal of glioma stem cells (GSCs). On the other hand, co-delivered CD47 antibody blocked the tumor "don't eat me" signal, synergistically enhancing the phagocytosis efficiency of CAR-M on GSCs, and facilitating its antigen presentation of CAR-M to activate the specific T cell immune response, which cleared the residual GSCs after surgery, formed immune memory, and avoided GBM recurrence. Overall, we believe that this novel immunotherapeutic strategy based on CAR-M should be paid more attention and actively studied by researchers, and we hope that more research reports on this topic will emerge in the future.In addition to those three main strategies, a novel TAMs-focused immunotherapy approach, CAR-macrophage (CAR-M) therapy, has been reported recently. Chen et al. developed an injectable hydrogel co-loaded with macrophage-targeted genetic engineering nanoparticles (pCAR-NPs) and CD47 antibody for immunotherapy of GBM to prevent postoperative recurrence of GBM TAMs, as the major immune cell types in TME, usually interact with other immune cells or tumor cells to create a tumor immunosuppressive microenvironment. TAMs thereby can be seen as an appealing therapeutic target for combination cancer immunotherapy. Recent advances in TAMs-focused cancer immunotherapy with multifunctional nanomedicines have highlighted three common therapeutic strategies aimed at targeting TAMs: blockage of bone-marrow-derived TAMs recruitment, depletion of tumor-resident TAMs population, and reprogramming of TAMs phenotype. With the unique advantages of functional nanocarriers in tumor-targeted drug delivery, they can effectively accumulate at tumor sites, and then selectively deliver immunomodulatory reagents to TAMs or indirectly affect the functional regulation of TAMs, thus creating an effector T cells favorable environment, often accompanied by increased infiltration, activation, maturation, and proliferation of immune-effector cells , and decreases in the number of immunosuppressive cells  and secretion of immunosuppressive factors.Although these three TAMs-focused nano-immunotherapies have shown good application progress in preclinical basic research, they still have their own potential side effects or limitations. For blockage of myeloid cell recruitment, some targeted therapeutic agents are used to interfere with the entry of exogenous macrophages into the tumor site, which may lead to a relative reduction in the population of M2 TAMs. Nonetheless, its essence is that the naturally existing resident macrophages in TME have not been effectively inhibited or eliminated, which makes the cunning tumors continue to employ these resident TAMs to perform tumor progression by the expression of biological proteins, cytokines or chemokines. Likewise, if tumor-resident TAMs are eliminated only by targeted drugs without simultaneously preventing the recruitment of bone marrow cell-derived macrophages, which is still possible to lead to accumulation of M2 macrophages in TME, further resulting in tumor development. Therefore, the clever integration of these two strategies into a nanosystem may not only avoid the occurrence of the above problems, but also achieve better therapeutic effects.In terms of the strategy of TAMs repolarization, whether bone marrow-derived or tumor-resident macrophages, the adoption of repolarization inducers  can contribute to the polarization of macrophages from M2 to M1. However, some of these polarization inducers may lead to abundant M1 macrophages in other normal tissues besides tumors, resulting in unanticipated proinflammatory or even excessive immune responses, which reflects the potential side effects of this class of treatment. Altogether it is important to understand and overcome these issues in TAM-based tumor immunotherapy before entering clinical trials.Additionally, for the development of pluripotent nanomedicines, their properties such as category, size, charge, shape, functional modification and optimal selection of therapeutic agents based on TAMs-associated molecular mechanisms need to be judiciously considered, which will enable increased solubility, improved pharmacokinetics, enhanced delivery stability, effective tumor accumulation, precise delivery and minimal systemic toxicity. In general, TAMs-targeted cancer immunotherapies usually use intelligent nanomedicines to fulfill preferential drug delivery to M2-like TAMs at tumor site. However, M2-type macrophages with specific receptor expression may be distributed in other normal tissues throughout the body, and some M2 phenotype receptors like mannose receptor and Siglecs are also overexpressed in DCs or other cell types, which significantly restricts the delivery efficacy of nanomedicines, and results in an inability to accurately target TAMs for stimulating potent antitumor immune response. The comprehension of complexity and heterogeneity of macrophage phenotype will facilitate the development of precise TAMs-targeting immunotherapeutic nanomedicines. Else, it has been reported that TAMs are surrounded by a dense network of extracellular matrix, which may severely impede the intratumoral delivery of nanomedicines and their accessibility to TAMs In clinic, the presence of unacceptable serious toxicity from immunotherapies, as well as the low response rate, are two troublesome problems to consider in the preclinical and clinical development of cancer immune nanomedicines Hitherto, very few of these therapies has been approved for clinical use. Even though FDA-approved ferumoxytol have been evidenced with macrophage reprogramming ability to promote TAMs repolarization to M1 phenotypes for cancer therapy, and these findings have not yet been further translated into clinical trials. Furthermore, because of the complex preparation procedure, stability of manufacture process and product, and rigorous quality control, great efforts should be devoted in the translational research of macrophage-centred immune-type nanomedicines for separate or combinational cancer therapy. Clearly, extensive validation in preclinical research is still required for accelerating clinical translation of TAMs-focused anticancer immune-nanomedicines.


In this era of competition, branding is an essential marketing tool for organizations to compete in today's dynamic markets. Organizations should realize the importance of employee-based brand equity from the perspectives of customer branding and financial performance. Employee-based brand equity plays a crucial role in building organizational brand equity. This study conceptualized a model that helps the practitioners to build employee-based brand equity and organizational brand equity. This study examines the role of organizational brand-building strategies and brand-oriented leadership in promoting employee-based brand equity and organizational brand equity. This study collected data from the employees of various beverage companies in China. This study analyzed data through partial least square structural equation modeling using Smart PLS 3. This study found a positive direct association between organizational brand-building strategies and employee-based brand equity. However, according to the results, no direct association was found between organizational brand-building strategies and organizational brand equity. This study also confirms that organizational brand-building strategies indirectly promote organizational brand equity through employee-based brand equity. Moreover, this study demonstrates that brand-oriented leadership directly influences employee-based brand equity and organizational brand equity but negatively moderates the relationship between organizational brand-building strategies and employee-based brand equity. No moderation was found in the relationship between organizational brand-building strategies and organizational brand equity. Finally, the practical and theoretical implications of this study are discussed. Branding is one of the powerful tools for organizations to compete in today's competitive market  were distributed among these 789 employees. Out of 789, 565 respondents filled the questionnaire in the second wave. Moreover, after a further one-month gap, the author distributed moderator variable (brand-oriented leadership) questionnaires among 565 respondents. Out of 565, 488 respondents completed questionnaires. Based on the key questions, the author identified the same respondents in all turns and finalized questionnaires that were complete in all respect. In this way, the author found 488 complete questionnaires.Participants' responses were measured through five-point Likert scale ranging from 1 (strongly disagree) to 5 (strongly agree). This study measured variables from previously used items. Organizational brand strategies were measured with the five-item scales. The five items were adapted from a previous study by Coleman, Chernatony, and Christodoulides , and for this purpose, partial least square (PLS) SEM was used instead of covariance-based techniques such as AMOS . Hair et al.  acknowleR2 value above 0.25 and up to 0.5 shows a moderate model strength in primary data. This study models DVs such as employee-based brand equity (R2 = 0.593) and organizational brand equity (R2 = 0.382) R2 values showed moderate strength in the model  . Thus, the H1 is accepted. Moreover, the beta value of this hypothesis showed that one unit change in organizational brand-building strategies would bring a 0.598 change in employee-based brand equity. Second, H2 predicted the positive impact of organizational brand-building strategies on employee-based brand equity. The t and p values  of H2 showed insignificant outcomes. Hence, H2 is rejected. It confirmed that organizational brand-building strategies do not positively influence the employee-based brand equity. Third, the H3 proposed that the employee-based brand equity positively impacted on organizational brand equity and t and p values showed acceptability . Thus, H3 is accepted. The beta value of H3 revealed that one unit change in employee-based brand equity would bring 0.409 unit changes in organizational-based equity. H5 proposed the positive influence of brand-oriented leadership on employee-based brand equity. The acceptable range for this proposition's t and p values is . Thus, H5 is accepted. The beta value showed that one unit change in brand-oriented leadership would hold 0.171 employee-based brand equity changes. H6 also proposed the direct impact of brand-oriented leadership on organizational equity. The t and p values of H6 showed significant outcomes . Hence, H6 is also accepted. According to the path coefficient value of H6, the one unit change in brand-oriented leadership will lead to 0.303 unit changes in organizational brand equity.This study applied a bootstrapping method with 5,000 samples for statistical verification of the model hypotheses . As predicted, organizational brand-building strategies positively influence the employee-based brand-building equity, and in turn, employee-based brand building positively influences the organizational brand equity. It shows that employee-based brand equity positively mediates the relationship between organizational brand-building strategies and organizational brand equity. Thus, H4 is accepted.t and p values of H7 , brand-oriented leadership has negatively moderated the relationship between brand-oriented leadership and employee-based brand equity. It shows that brand-oriented leadership weakens the relationship between organizational brand-building strategies and employee-based brand equity. Thus, H7 is accepted. Similarly, H8 also predicted a moderation effect of brand-oriented leadership between the association of organizational-based brand strategies and organizational brand equity but t and p values  showed insignificant outcomes. It shows that brand-oriented leadership did not moderate the relationship between organizational brand-building strategies and organizational brand equity. Thus, H8 is rejected.Moreover, H7 predicted the moderation effect of brand-oriented leadership between organizational brand-building strategies and employee-based brand equity. According to the Branding is considered an essential tool to compete in today's dynamic market (Huang and Tsai, Moreover, this study also checked the direct effect of brand-oriented leadership on employee-based brand equity. The outcomes show that brand-oriented leadership positively influences employee-based brand equity. Second, this study examined brand-oriented leadership's direct effect on organizational brand equity. The results revealed that brand-oriented leadership positively influences organizational brand equity. Hence, through brand-oriented leadership, organizations can apply internal brand management and brand communications that enhance employee brand commitment and engagement (Afshardoost et al., Furthermore, this study also assessed brand-oriented leadership as a moderator in the relationship between organizational brand-building strategies and employee-based brand equity. The outcomes showed that brand-oriented leadership reduces the strength of organizational brand-building strategies and employee-based brand equity relationships. Second, this study assessed the moderator role of brand-oriented leadership in the relationship between organizational brand-building strategies and organizational brand equity. This study results showed that brand-oriented leadership does not moderate the relationship between organizational brand-building strategies and organizational brand equity.The moderating effects of brand-oriented leadership on the relationship between organizational brand-building strategies and employee-based brand equity are unexpected. Brand-oriented leadership should positively impact as a moderator between organizational brand-oriented leadership and employee-based brand equity (Maleki Minbashrazgah et al., This study has many theoretical and practical implications. First, theoretically, this study extends the literature on organizational brand-building strategies. Previous studies did not consider organizational brand-building strategies to build employee and organizational brand equity (Järventie-Thesleff et al., Moreover, brand-oriented leadership plays a crucial role in positively impacting employee-based brand equity and organizational brand equity. This study suggests that top management must coordinate with brand-oriented leadership while building organizational brand strategies for smooth functioning in organizations.This study serves the literature in many different ways, but this study also has some limitations. First, this study collected data from different employees working in beverage companies in China in three waves. Future research can conduct a longitudinal study by enlarging the sample size to verify our study results. Second, future research may collect data from other industries by adopting this study model to strengthen the results of this study. Third, this study examined brand-oriented leadership as moderating construct between organizational brand-building strategies and employee-based and organizational brand equity. Future research may consider other moderators like the organizational culture. This study did not check the mediating effect between organizational brand-building strategies and employee-based brand equity relationships. Future research can also propose this relationship with the support of mediators. Moreover, this examined brand-oriented leadership's direct effect on employee-based brand equity and organizational brand equity and found positive outcomes. Future research can confirm this relationship with the support of mediators and moderators. Finally, this study was conducted in China. A similar study could be conducted in other developing countries or developed countries to strengthen and ensure the results.In this era of competition, organizations are now well aware of brand equity importance from the organizational and employees' perspectives. Firms are serving their efforts and resources to maintain their sustainability by creating brand equity. This study attempts to examine the role of organizational brand-building strategies on employee-based brand equity and organizational brand equity. The role of leadership in creating brand equity is also worthwhile because frontline employees are considered in the literature as ambassadors of the brand. This study also considers the role of brand-oriented leadership in the theoretical model for empirical investigation. This study's findings depict that organizational brand-building strategies positively influence employee-based brand equity, but their significant influence on organizational brand equity was not found. This study also examined the mediating role of employee-based brand equity in the relationship between organizational brand-building strategies and organizational brand equity and found that employee-based brand equity positively mediates this relationship. This study also assessed brand-oriented leadership's direct relationship with employee-based brand equity and organizational brand equity and discovered its positive effects. Moreover, this study also evaluated brand-oriented leadership as a moderator between organizational brand-building strategies and employee-based brand equity and found that brand-oriented leadership negatively moderates this relationship. Second, this study also considered brand-oriented leadership as a moderator between the association of organizational brand-building strategies and organizational brand equity; however, outcomes revealed that brand-oriented leadership does not moderate this relationship.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by Tianjin Vocational Institute, China. The patients/participants provided their written informed consent to participate in this study. The study was conducted in accordance with the Declaration of Helsinki.ZW has conceptualized the concept, collected data, and wrote the draft.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The rapid dissemination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), remains a global public health emergency. The host immune response to SARS-CoV-2 plays a key role in COVID-19 pathogenesis. SARS-CoV-2 can induce aberrant and excessive immune responses, leading to cytokine storm syndrome, autoimmunity, lymphopenia, neutrophilia and dysfunction of monocytes and macrophages. Pyroptosis, a proinflammatory form of programmed cell death, acts as a host defense mechanism against infections. Pyroptosis deprives the replicative niche of SARS-CoV-2 by inducing the lysis of infected cells and exposing the virus to extracellular immune attack. Notably, SARS-CoV-2 has evolved sophisticated mechanisms to hijack this cell death mode for its own survival, propagation and shedding. SARS-CoV-2-encoded viral products act to modulate various key components in the pyroptosis pathways, including inflammasomes, caspases and gasdermins. SARS-CoV-2-induced pyroptosis contriubtes to the development of COVID-19-associated immunopathologies through leakage of intracellular contents, disruption of immune system homeostasis or exacerbation of inflammation. Therefore, pyroptosis has emerged as an important mechanism involved in COVID-19 immunopathogenesis. However, the entangled links between pyroptosis and SARS-CoV-2 pathogenesis lack systematic clarification. In this review, we briefly summarize the characteristics of SARS-CoV-2 and COVID-19-related immunopathologies. Moreover, we present an overview of the interplay between SARS-CoV-2 infection and pyroptosis and highlight recent research advances in the understanding of the mechanisms responsible for the implication of the pyroptosis pathways in COVID-19 pathogenesis, which will provide informative inspirations and new directions for further investigation and clinical practice. Finally, we discuss the potential value of pyroptosis as a therapeutic target in COVID-19. An in-depth discussion of the underlying mechanisms of COVID-19 pathogenesis will be conducive to the identification of potential therapeutic targets and the exploration of effective treatment measures aimed at conquering SARS-CoV-2-induced COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an outbreak of global viral pneumonia, named coronavirus disease 2019 (COVID-19), which poses an extraordinary threat to human health and public safety A multitude of literature has manifested the implication of SARS-CoV-2 infection in regulation of inflammasome-dependent pyroptosis Pyroptosis has emerged as a host innate immune effector mechanism against infections. Pyroptosis impedes the production of infectious viruses and facilitates the release of proinflammatory contents that recruit immune cells to combat invading pathogens  Betacoronavirus in the family CoronaviridaeSARS-CoV-2 is a member of the genusCOVID-19 is a highly contagious disease caused by SARS-CoV-2 The outbreak of COVID-19 has pushed the world to the center of a new pandemic. Considerable research effort has been invested in seeking means to restrict SARS-CoV-2 spread and to treat COVID-19 through vaccines and therapies. Increasing knowledge of the pathogenicity, epidemiology and clinical features of SARS-CoV-2, along with organization and function of viral genome, will provide the basis for the development of new preventive and treatment approaches against COVID-19. Although experimental studies have made a breakthrough, there are significant gaps in the available evidence on SARS-CoV-2 biology. Like other RNA viruses, SARS-CoV-2 is prone to develop mutations, hence facilitating rapid virus evolution. Some variants such as B.1.351 (Beta), B.1.617.2 (Delta) and B.1.1.529 (Omicron) harbor mutations that make them more insusceptible to host immunity 9-bradykinin (DABK) mediated by SARS-CoV-2-induced ACE2 inhibition, cytokine storm syndrome, autoimmunity and coagulopathy ), proinflammatory cytokines  and interferon-γ (IFN-γ)) and free radicals, culminating in the development of cytokine storm syndrome The cytokine storm is implicated in the pathogenesis of COVID-19 and has a close relationship with disease deterioration in COVID-19 patients ACE plays an important role in the RAAS system. There are two distinct isoforms of ACE, ACE1 and ACE2. ACE1 is abundantly expressed in vasculature and renal proximal tubules Autoimmunity may be formed by a wide range of factors through establishment of a hyper-stimulated state of the immune system Reportedly, COVID-19 patients tended to have an increased incidence of coagulation disorders + and CD8+ T cells + and CD8+ T cells might be good biomarkers of COVID-19. The serum levels of proinflammatory cytokines (IL-6 and TNF-α) were intimately linked with lymphopenia Lymphopenia, also known as lymphocytopenia, refers to a dramatic decrease in the number of lymphocytes in the blood Neutrophils are the most eminent innate cells in viral defense. Neutrophilia is a condition defined by an increased count of neutrophils in the peripheral blood Monocytes and macrophages are important innate immune cells with prominent defensive activities against invading microbes + T cells may play dual roles in COVID-19 progression Pathogen infection can stimulate host innate immune system that recognizes pathogens and induces the release of proinflammatory cytokines that recruit immune cells to the infection site to trigger an inflammatory response Pyroptosis is a highly inflammatory form of programmed cell death that is manifested by GSDM-mediated membrane pore formation, cell swelling, cell membrane rupture, and release of cytoplasmic contents Inflammasomes are multimeric protein complexes that recognize danger signals and induce caspase-1-mediated pyroptotic cell death The plasma levels of GSDMD, proinflammatory cytokines (IL-1β and IL-18) and LDH were increased in COVID-19 patients versus healthy controls +) channels to activate NLRP3 inflammasome In vivo experiment showed that SARS-CoV-2 infection could trigger the NLRP3 inflammasome signaling and pyroptosis in the lungs of the transgenic K18-human ACE2 (hACE2) mice. IL-1β interrupted lung endothelial barrier through downregulation of cAMP response element-binding protein (CREB)-mediated vascular endothelial (VE)-cadherin expression and induced gathering of neutrophils, leading to the exaggerated inflammation state Similarly, another study also verified that SARS-CoV-2 ignited the activation of NLRP3 inflammasome and caspase-1, enhanced the generation of cleaved GSDMD, and promoted the release of LDH and IL-1β, thereby triggering lytic cell death in human primary monocytes SARS-CoV-2 S protein is a trimeric class I fusion protein consisting of S1 and S2 subunits and plays a crucial role in SARS-CoV-2 pathogenesis Mesenchymal stem cells (MSCs) exhibit anti-inflammatory activities and can be genetically engineered to carry mediations or target genes. MSC-based treatment may be an effective, tailored cell therapy suited to COVID-19-associated ARDS and acute lung injury SARS-CoV-2 S1 induced pyroptotic cell death in human visceral adipocytes through activation of the NLRP3 inflammasome signaling, induction of GSDMD cleavage and IL-1β release + Transporting Accessory Protein 1 (ATP6AP1). This event resulted in termination of the autophagic flux and induction of NLRP3 inflammasome-dependent pyroptosis. Conversely, pharmacological restoration of the autophagic flux abrogated NSP6-induced pyroptosis. Downregulation of caspase-1, NLRP3, ASC or caspase-1 could not completely dampen NSP-6-induced pyroptosis, implying that other pyroptosis-related pathways also operated. Autophagy serves as a critical host defense mechanism to resist microbial invasion. It not only has the ability to degrade invading pathogens, but also favors antigen presentation and augments adaptive immune responses Interruption of the autophagic flux is capable of inducing NLRP3 inflammasome activation SARS-CoV-2 has evolved to counteract the pyroptosis pathway in infected cells. It was reported that SARS-CoV-2 N protein could directly bind to NLRP3 and facilitated its interaction with ASC NLRP1 was shown to act as a sensor of SARS-CoV-2 in human lung epithelial cells NSP1 and NSP13 were reported to antagonize the NLRP3/caspase-1 pathway-mediated IL-1β maturation Compelling evidence has identified that the pyroptosis pathway plays a momentous role in COVID-19 immunopathogenesis. The ACE2 receptor is present on various types of cells, such as respiratory epithelial cells and tissue-resident macrophages, which allows SARS-CoV-2 to infect these cells Pyroptotic macrophages that have phagocytosed viruses can cause the liberation of multitudinous alarmins, such as cytokines, chemokines, LDH and reactive oxygen species (ROS), eliciting an expeditious reaction from proximate immune cells and a pyroptosis chain reaction. Pyroptosis could permit viral components  to be released in the circulation, which possibly results in the genesis of immune complex and accumulation of immune cells in target tissues to actuate critical inflammatory cascade. Pyroptosis in alveolar macrophage causes acute lung injury by fostering infiltration of neutrophils and monocyte-derived macrophages into the lung tissues and increasing alveolar contents of proinflammatory cytokines  in vitro studies or correlative datasets derived from patient samples. Moreover, it is obscure whether pyroptosis affects COVID-19 pathogenesis independent of cytokine release. Therefore, continued studies are needed to determine the role of pyroptosis in COVID-19 immunopathology. The engagement of other cell death pathways such as apoptosis and necroptosis has also been proposed. Different cell death modes may act synergistically in COVID-19. Whether pharmaceutical targeting of the pyroptosis pathway is sufficient to achieve successful management of COVID-19 is an important future question to pursue.Collectively, hyper-activation of the pyroptosis pathways leads to the cytokine storm and severe injury to host. Pyroptosis has thus been the focus of extensive study. Studying pyroptotic cell death during SARS-CoV-2 infection could provide a better comprehension of COVID-19 pathophysiology and will contribute to the development of better therapeutic approaches that can alleviate the damage caused by SARS-CoV-2-associated immune responses. Significant reduction of certain types of immune cells, including lymphocytes and monocytes, is the major driver of COVID-19 severity. The accurate mechanisms underlying lymphopenia and monocytopenia are yet to be elucidated. Currently, most COVID-19 studies mainly rely on NLRP3 inflammasome activation is involved in the development of various disorders, including cardiovascular diseases, chronic obstructive pulmonary disease, hypertension and type 2 diabetes + T cells from COVID-19 patients versus healthy controls In vitro experimental studies showed that pan-caspase inhibitor emricasan (EMR) could reduce active caspase-1 in CD4+ T cells from COVID-19 patients. A phase I clinical trial is under way to determine the safety and tolerability of EMR in COVID-19 patients. Inflammasome activation serves as an important innate immune defense against invading pathogens. Nevertheless, inflammasome-mediated pyroptosis in immune cells causes massive release of inflammatory and danger signals, which could be detrimental to the host. The exuberant caspase response might cause immune-relevant pathological process in COVID-19. Blockade of the pyroptosis pathway in immune cells by using caspase inhibitors would represent an effective treatment approach. However, it remains to verify whether pan-caspase inhibition can suppress inflammasome activation and prevent disease progression in COVID-19 patients. Disulfiram is an approved drug used to treat alcohol addiction Suppression of downstream pathways of inflammasome activation also represents an appealing therapeutic option. Caspase-1 was found to be upregulated in CD4Pyroptosis acts as a critical mechanism of cytokine release resulting from cell membrane disruption Hyper-inflammation and lung dysfunction are key pathophysiological hallmarks of COVID-19. The equilibrium between viral pathogenicity and host immunity has a significant impact on COVID-19 severity. Inflammasome assembly is provoked in response to a variety of PAMPs that emerge during pathogen infections, followed up by the production of proinflammatory cytokines and chemokines including IL-1β, IL-6, IL-18 and TNF-α. Generally, a sound immune system can efficiently eradicate the infection, whereas a compromised immune system causes excessive accumulation of active immune cells in the lungs, contributing to a cytokine storm and multiorgan failure via circulation. Harnessing the extravagant inflammation may be a potential therapeutic strategy for COVID-19 treatment. Pyroptosis-associated inflammation has a close relationship with COVID-19 immunopathogenesis. A growing body of evidence has manifested the therapeutic potential of pyroptosis regulators in the management of COVID-19. Further clinical trials aimed at controlling immune-related damages in COVID-19 are under way. It is of great necessity to corroborate the therapeutic benefits, determine the optimal dose, route, frequency and timing of administration, and investigate the safety, tolerability and pharmacokinetics of drug candidates, all of which may make it feasible for pyroptosis-targeting therapies to cope with COVID-19.Pyroptosis is a pivotal cell response to microbial infections and non-infectious stimuli, which has been implicated in the pathogenic mechanisms of various diseases. The crosstalk between SARS-CoV-2 and the pyroptosis pathway has been preliminarily unveiled. SARS-CoV-2 infection can induce pyroptosis in host cells, and the propagation and spread of this virus are prevented owing to the removal of infected cells via pyroptosis. However, SARS-CoV-2 infection causes uncontrolled cell death, leading to extensive cell damage and unfavorable immune responses. Meanwhile, the virus can delicately coordinate this inflammatory cell death pathway to drive its replication and pathogenesis. The mechanisms exploited by the virus to regulate pyroptosis are worthy of further investigations. More studies are required to figure out the contribution of pyroptosis to SARS-CoV-2 infection and COVID-19 development. The cytokine storm is a main promotor of COVID19 progression, while the production and release of cytokines are closely associated with pyroptosis. It is arduous to illuminate the separate role of pyroptosis in COVID-19. Furthermore, the causal relationship between pyroptosis and cytokine release should also be determined. There are few studies using preclinical animal models  to elucidate the role of pyroptosis during SARS-CoV-2 infection. Most studies have revealed the effects of canonical inflammasome pathways on SARS-CoV-2 pathogenicity, yet it is unclear whether other pyroptosis pathways such as apoptotic caspase-mediated pathway and non-canonical inflammasome pathways are engaged in the pathological process of SARS-CoV-2. In-depth investigations of pyroptosis and its implication in COVID-19 immunopathology would provide new insights into the pathogenic mechanisms of SARS-CoV-2 and help to design efficacious therapeutic approaches for COVID-19 treatment.Pharmacological regulation of the pyroptosis pathway could be a promising intervention to combat COVID-19. Importantly, curtailing this cell death process may lessen the effect of counterproductive inflammatory factors. At present, many therapeutic measures targeting inflammasomes, caspases, GSDMD or cytokines are entering clinical trials to evaluate efficacy in mitigating COVID-19. Considering the double-edged roles of pyroptosis in SARS-CoV-2 pathogenesis, it is indeed essential to decide whether and when this cell death process should be induced or impeded. Several key components of the pyroptosis pathway, such as inflammasomes and caspases, function to regulate cytokine maturation and release, rendering them to be ideal targets for COVID-19 therapy. Overall, the clinical benefits of therapeutic manipulation of the pyroptosis pathway are multifaceted and the screen for available or new targeting agents may represent a particularly worthwhile effort. However, the safety and effectiveness of such agents must be carefully evaluated through clinical trials. In addition, the specific mechanisms responsible for their therapeutic activities also need further research before clinical translation.


Cancer is a complex pathological disease and the existing strategies for introducing chemotherapeutic agents have restricted potential due to a lack of cancer cell targeting specificity, cytotoxicity, bioavailability, and induction of multi-drug resistance. As a prospective strategy in tackling cancer, regulating the inflammatory pyroptosis cell death pathway has been shown to successfully inhibit the proliferation and metastasis of various cancer cell types. Activation of inflammasomes such as the NLRP3 results in pyroptosis through cleavage of gasdermins, which forms pores in the cell membranes, inducing membrane breakage, cell rupture, and death. Furthermore, pyroptotic cells release pro-inflammatory cytokines such as IL-1β and IL-18 along with various DAMPs that prime an auxiliary anti-tumor immune response. Thus, regulation of pyroptosis in cancer cells is a way to enhance their immunogenicity. However, immune escape involving myeloid-derived suppressor cells has limited the efficacy of most pyroptosis-based immunotherapy strategies. In this review, we comprehensively summarize the cellular and molecular mechanisms involved in the inflammasome-mediated pyroptosis pathways in cancer cells, exploring how it could modulate the tumor microenvironment and be beneficial in anti-cancer treatments. We discuss various existing therapeutic strategies against cancer, including immunotherapy, oncolytic virus therapy, and nanoparticle-based therapies that could be guided to trigger and regulate pyroptosis cell death in cancer cells, and reduce tumor growth and spread. These pyroptosis-based cancer therapies may open up fresh avenues for targeted cancer therapy approaches in the future and their translation into the clinic. Our innate immune system detects and engages with pathogen-associated molecular patterns (PAMPs) using pattern-recognition receptors (PRRs) expressed either on the surface or intracellularly, to remove the invading pathogens . PRRs inIn particular, NLRs and ALRs have distinct domain architectures and functions . Upon ac+ T cells, thereby enhancing antitumor immunity , gasdermin B [GSDMB], gasdermin C [GSDMC], gasdermin D [GSDMD], gasdermin E [GSDME], also known as DFNA5) and pejvakin (PJVK) [Pyroptotic cell death takes the form of regulated necrosis, however, in some instances, the pathway can also engage apoptosis. Pyroptosis is the result of GSDMD being cleaved into its N-terminal fragment, which can then oligomerize to form pores in the cell membrane aiding the release of pro-inflammatory cytokines , 18. To n (PJVK) . Among tn (PJVK) , 21. GSDn (PJVK) . In cancn (PJVK) .L [Gasdermins can also be cleaved by apoptotic caspases such as caspase-3, caspase-6, caspase-8, granzymes, death-related proteases in natural killer cells (NK cells), and cytotoxic T lymphocytes (CTLs) –26. In tL . FurtherL .During canonical pyroptotic pathway activation, the GSDMD-NT fragment moves toward the plasma membrane to form pores, resulting in cell depolarization and cytokine secretion . GSDMD c2+ influx from the extracellular environment, which can direct calpain activation and ESCRT  assembly. Membrane repair mediated via ESCRT downstream of activated GSDMD can negatively regulate inflammasome-induced pyroptosis [GSDMD pore formation in the plasma membrane also allows Caroptosis . FailureDuring infection, cytosolic lipopolysaccharides (LPS) are detected by human caspases 4 and 5 and murine caspase-11, to induce non-canonical activation of the NLRP3 inflammasome pathway , 37. BefAs mentioned earlier, the GSDMD amino-terminal fragment can locate the mitochondria to result in mitochondrial outer membrane permeabilization, thus promoting caspase-3 activation . This is+ T cells, resulting in a positive feedback loop in a caspase-independent manner [Gsdme gene silencing in melanoma cells has been shown to reduce pyroptotic cell death and resulting immune infiltrate [Through this mechanism, the expression of GSDME increases phagocytosis of cancer cells and recruitment of CD8t manner . Gsdme gfiltrate , thus bofiltrate . TogetheInflammasomes are multimeric protein complexes that are formed within the cytoplasm of cells and they regulate inflammatory responses and pyroptosis , 51. TheA range of stimuli, detected by the innate immune system receptors and sensors have been identified for NLRP3 activation. Under specific conditions, DNA-dependent activators of IRF/Z-DNA binding protein 1 (DAI/ZBP1), DEAD-box polypeptide (DDX), cGAS can mediate NLRP3 inflammasome activation , 56. A rDuring pyroptotic cell lysis, the release of pro-inflammatory cytokines, IL-1β, and IL-18 trigger a robust immune response within the TME , 62. ApaTo this end, Zhivaki et al. have shown that IL-1β was produced by hyperactive dendritic cells in a pyroptosis-independent manner, thereby enabling a durable anti-tumor response. Interestingly, by neutralizing the activity of IL-1β, the antitumor response mediated by hyperactive type 1 DCs (DCs1) can be completely abrogated .+ T cell recruitment via CXCL10 production [In some tumors, the inflammasome effector cytokine activation enhances the production of proangiogenic factors like vascular endothelial growth factor (VEGF) . This isoduction .Immunotherapeutic approaches, including antibody-mediated therapy (anti-CTLA-4 and anti-PD-1/PD-L1), and chimeric antigen receptor (CAR) T-cell therapy, have improved clinical outcomes following cancer treatment , 73. PD-+ T cells activate the NLRP3 inflammasomes in DCs, promoting IL-1β maturation and thereby contributing to anti-tumor immunity [+ T cell frequency along with activated memory CD4+ T cells positively correlated with NLRP3 expression [Following antigen presentation, the CD8immunity . In patipression . Considepression .+ and Treg (regulatory T-cell) cell populations in pancreatic carcinoma, indicating the possibility of targeting NLRP3 for reprogramming the TME towards an immunogenic phenotype [+ T cells [Inflammasome signaling in macrophages drives differentiation of CD4henotype . Tumor-a T cells . These r T cells , signify+ T cell activity and increasing the Treg population [+ T and NK- cells following inflammasome activation and pyroptosis [In melanoma cells, NLRP3/IL-1β activation contributes to the expansion of MDSCs in the TME, thus reducing NK- and CD8pulation . These dpulation  in a negpulation , which rroptosis .+ cytotoxic T lymphocytes (CTLs) may also result in pyroptosis, facilitating antigen release during the local immune response [Attacking cancer cells using CD8response . Howeverresponse . For insresponse . In cytoresponse . In the response .+ TILs, potentiating antigen-specific immunity. However, it has been shown that TIM-3 negatively regulates signaling through IL-1 and IL-18 [Next-generation immune checkpoint inhibitor (ICI) targets such as T cell immunoglobulin and mucin domain-containing (TIM) − 3, is co-expressed with PD-1 on exhausted T cells . Specifind IL-18 , highlignd IL-18 .Although immunotherapy techniques have shown great promise in targeting tumors, they can enhance the systemic immune response against normal healthy cells leading to unwanted tissue damage. This has led to the development of more targeted therapies such as nanoparticle therapy which allows synthesized nano-range (1-100 nm) particles to specifically target tumor cells and TME, enhance pyroptosis and initiate tumor cell-specific adaptive immune responses .in-vitro and in-vivo, inducing cancer cell pyroptosis using both photo-treatment and chemotherapy drugs, resulting in the release of pro-inflammatory mediators that activate BMDCs [Nanotherapy uses nanoparticles, mainly biomimetic, together with photodynamic therapy and chemotherapy to activate the pyroptotic cell death pathway and boost the anti-tumor response by overcoming toxicity and increasing bioavailability and drug capacity. Cancer cell membrane-based biomimetic nanoparticles  target solid tumors both te BMDCs .Several pyroptosis pathways related to mitochondrial modulation can induce PD-L1 secretion , throughTo address tumor cell selectivity, Wang and colleagues have utilized a near-infrared (NIR) fluorophore that responds to and induces selective cell pyroptosis in cancer cells overexpressing quinone oxidoreductase isozyme 1 (NQO1). This strategy further boosted antitumor immunity which prolonged survival in a mouse breast cancer model, with the synergizing of the nanocarrier with ɑPD1 .Since mitochondrial stress leads to ROS production which then activates NLRP3 inflammasomes, TME-responsive nanoparticles loaded with chemotherapy drugs followed by laser treatment target mitochondria and activate pyroptosis mediated by GSDME in colon cancer cells . The effSome chemotherapy drugs can initiate apoptosis in cancer cells by activating caspase-3. However, gasdermin-E, encoded by the DFNA5  gene and cleaved by caspase-3 and granzyme B is silenced in some tumors by DNA methylation. This allows tumor cells to escape the local immune response and increase resistance to anticancer therapy. Inhalable nanospheres which incorporate DNA methyltransferases like Decitabine were successfully used to treat lung tumors and reduce metastasis by DFNA-5 gene hypomethylation and gene activation, leading to pyroptosis . InteresGasdermins induce pyroptosis by forming pores (ca. 10 nm) in the lipid bilayer. Mimicking this process, Chen et al., have produced vesicular DNA nanopores that fuse with the cell membrane in the presence of an acidic TME. Following fusion, these nanopores promote water influx into the cancer cells to induce pyroptosis-like cell lysis which was therapeutically effective in A549 tumor spheroids and hepatoma tumor-bearing mice . This stDespite emerging progress in nanoparticle therapy to induce pyroptotic cell death, very limited strategies have succeeded in anti-cancer therapeutic efficiency. Several challenges need to be overcome before the potential clinical transformation of these studies. As an initial prospect, the mechanisms by which these nanoparticles result in pyroptosis-induced tumor cell death using real-time imaging studies can be utilized . FurtherOncolytic viruses (OVs) contain the ability to modulate the TME, thus influencing the anti-tumoral immune response . MechaniNT infect tumor cells to induce pyroptosis. In addition, the immune checkpoint (PD1/PD-L1) increased the oncolytic effect of rAAV-GSDMDNT, stimulating antitumor immunity [Even more interestingly, in preclinical cancer models, recombinant adeno-associated viruses (rAAVs) expressing GSDMimmunity . In a meimmunity  Fig. 3)NT infectVal-boroPro (VbP) non-selectively inhibits post-proline cleavage serine proteases, being active against the dipeptidyl peptidases DPP4,7, 8, and 9 . Inhibit+ T cells and activated the intrahepatic inflammasome as seen in a mouse model of human hepatocellular carcinoma [In mouse models of pancreatic cancer, inhibition of DPP9 enhanced NK and T cell infiltration and caused a reduction in tumor growth through inflammasome activation and pyroptosis . Consistarcinoma . ClinicaRecent work has begun to clarify the complex roles of pyroptosis in different aspects of immune function. Regarding the immunomodulatory effects of pyroptosis on tumorigenesis, there are still several unresolved questions. In certain contexts, induction of pyroptosis mediated by DAMPs or by inflammasome agonists can enhance immune cell responses and hinder tumor development, once cytokines, chemokines, cleaved GSDMs, and caspases are released at the same time to respond to tissue damage. On the other hand, pyroptosis through inflammasome-driven secretion of inflammatory mediators could support tumorigenesis , through+ cytotoxic T-lymphocytes (CTLs) in the TME [Mediators released during pyroptosis may stimulate M1-polarization of macrophages, promotes maturation of DCs, and activation of CD8 the TME , for exa the TME  suggestiListeria monocytogenes (Lmo) induced GSDMC-dependent pyroptosis modulating intratumoral or systemic T cell responses. Intravenous living bacterial therapy (Lmo@RBC) is also a favored anaerobic colonization strategy that potentiates tumor immune therapy [Recently, it has been shown that GSDMC may influence the effects of gut-derived microorganisms on anticancer therapy. For example, selective virulence factor deletions in  therapy .3 probe, a biorthogonal system that released gasdermins from nanoparticles in tumor cells. Less than 15% of cells undergoing pyroptosis was sufficient to result in T-cell-mediated tumor regression. This evidence further supports the anti-tumor potential of pyroptosis [In general, therapeutic targeting of tumors can be challenging and complex due to tumor heterogeneity and treatment resistance. Modulation of cell death is an avenue that has been explored over the years in cancer therapy where several types of immunogenic cell death (ICD) pathways such as pyroptosis, necroptosis, and ferroptosis (regulated necroptosis) have been researched. Among the ICD forms targeted, pyroptosis has shown more promise in the clinic in comparison to ferroptosis and other ICDs for several reasons. The potential for translation of pyroptosis targeting is mainly due to the involvement of gasdermins which are present only in the pyroptotic cell death pathway . Recentlroptosis . HoweverFerroptosis is a distinct type ICD that is iron-dependent and is characterized by an imbalance of the redox state which leads to intracellular ROS production. GPX4 (glutathione peroxidase 4) has been identified by Yang et al., as a key regulator of ferroptosis which inhibited xenograft tumor growth in mice . HoweverEvidence also exists that tumor cells enhance oxidative stress as an immune evasion mechanism and therefore, suppress ferroptosis and enhance resistance to this form of cell death . AlthougOn the other hand, one of the challenges of the pyroptosis-based therapeutic approach to cancer is that, in different tumors, the expression and function of its activators can be altered by a variety of stimuli, and mutational and epigenetic mechanisms. Considering the number of therapeutic targets and strategies, as well as the different immunological landscapes, among patients, pre-clinical studies in organoid models  and humaIn addition, the different therapeutic strategies against cancer, including immunotherapy, oncolytic virus therapy, and nanoparticle-based therapies could be guided to trigger and regulate pyroptotic cell death in cancer cells, leading to tumor-shrinking or remission. These pyroptosis-based cancer therapies may open up fresh avenues for targeted cancer therapy approaches in the future and their translation into the clinic.


Potential clinical applications in wound repairAdipose-derived mesenchymal stem cells and wound healing. Almalki discusses and review the therapeutic potential of AMSCs for wound repair via acceleration of wound closure, re-epithelialization, enhancement of angiogenesis and immunomodulation of prolonged inflammatory responses, as well as the current challenges in clinical implementation. He concluded that AMSC-based therapy for non-healing or chronic cutaneous wounds in animal models has been shown to accelerate wound healing through different mechanisms. Therefore, the use of autologous AMSCs to promote cutaneous wound healing in patients appears to be a promising therapeutic strategy.see page 1075 Evaluation of diaphragm thickness to predict intubation requirement and mortality in critical COVID-19 patientsDal et al investigate the value of measuring the DT on thorax CT at ICU admission for predicting intubation requirement and mortality among COVID-19 patients. The patients’ demographic characteristics, laboratory parameters, DT measurements, MV requirements, and mortality statuses are retrospectively screened. The relationships between DT on initial CT, MV requirement, and mortality are investigated. They concluded that mortality and MV requirements can be predicted from DT measurements. Diaphragm thickness can facilitate the identification of high-risk patients on CT evaluation at ICU admission.see page 1120Self-esteem mediates the relationship perceived stigma with self-efficacy for diabetes management in individuals with type 2 diabetes mellitusOzturk et al determine the mediating effect of self-esteem in the relationship between the perceived stigmatization of individuals with T2DM and their self-efficacy regarding diabetes management. A descriptive information form, diabetes management self-efficacy scale, Rosenberg self-esteem scale, and type-2 diabetes stigma assessment scale are used in data collection. They concluded that minimizing the perceived stigmatization can improve patients’ diabetes management self-efficacy. With patient training programs and individualized nursing care plans prepared by psychiatric nurses to provide psychological support patients and through their interventions that increase self-esteem, self-stigmatization can be reduced.see page 1157 Case report and review of literaturesPost COVID-19 pulmonary mass. Hussen present an unusual and a rare pulmonary affection by COVID-19, in which only one lung is affected. Coronavirus disease-19 attacks the lungs and interferes seriously with their functions. The attack is usually bilaterally, while a uni lateral pulmonary affection is unusual. The presentation, both clinical and radiological findings, bronchoscopy appearance, the strange operative findings of the resected mass, the uneventful post-operative course, in addition to the histopathological report, is presented. He concluded that unilateral lung affection is unusual and post-viral pneumonia COVID-19 should be considered as a possible aftermath, which may not be uncommon in Iraq.see page 1165


Since the introduction of coronavirus disease 2019 (COVID-19) messenger ribonucleic acid (mRNA) vaccines, there have been multiple reports of post-vaccination myocarditis . We report on four patients with active autoimmune rheumatic diseases (ARDs) and probable or confirmed myocarditis following COVID-19 mRNA vaccination managed at a tertiary hospital in Singapore; we reviewed the literature on post-COVID-19 mRNA vaccination-related myocarditis and ARD flares. Three patients had existing ARD flares (two had systemic lupus erythematosus (SLE), one had eosinophilic granulomatosis polyangiitis (EGPA)), and one had new-onset EGPA. All patients recovered well after receiving immunosuppressants comprising high-dose glucocorticoids, cyclophosphamide, and rituximab. Thus far, only one case of active SLE with myocarditis has been reported post-COVID-19 mRNA vaccination in the literature. In contrast to isolated post-COVID-19 mRNA vaccination myocarditis, our older-aged patients had myocarditis associated with ARD flares post-COVID-19 vaccination (that occurred after one dose of an mRNA vaccine), associated with other features of ARD flares, and required increased immunosuppression to achieve myocarditis resolution. This case series serves to highlight the differences in clinical and therapeutic aspects in ARD patients, heighten the vigilance of rheumatologists for this development, and encourage the adoption of risk reduction strategies in this vulnerable population. No schistocytes were seen on the peripheral blood film. The direct Coombs test was positive. Her ECG showed a left bundle branch block and a prolonged QRS with no hyperacute ST-segment change. A chest X-ray (CXR) showed normal lung fields with mild cardiomegaly. The TTE revealed a reduced ejection fraction of 50% and global hypokinesia with no RWMA; findings were consistent with myocarditis.A 43-year-old Burmese female with a known history of SLE was admitted for investigation of a pre-syncopal event, which occurred three weeks after her second COVID-19 mRNA vaccination  followed by high-dose glucocorticoids, rituximab, and intravenous immunoglobulin (IVIg). Her effort tolerance improved and troponin I normalized with treatment. A repeat TTE three months later showed improvement in LVEF (to 55%) and a resolution of global hypokinesia. She did not receive further doses of the COVID-19 vaccine.During the clinical evaluations of these patients, infective etiologies for myocarditis were not detected. None of the cases tested positive for COVID with polymerase chain reaction (PCR) testing.A literature search performed up until 26 August 2022 yielded 27 articles, of which, only 1 case series of 3 patients described cardiac involvement associated with an ARD flare post-COVID-19 vaccination.Myocarditis involves the inflammation of the myocardium and can affect the adjacent epicardium and pericardium . PatientSince the introduction of mRNA COVID-19 vaccines, uncommon reports of post-vaccination myocarditis have surfaced, contributing to further concerns over their safety . As of MH1 immune responses after vaccination, molecular mimicry, PEG-facilitated immune responses, and allergies, as well as the interaction between the SAR-CoV-2 S protein and ACE2 [According to the VAERS databases established in 1990, myocarditis adverse events have also been reported mostly after receiving smallpox, anthrax, typhoid, hepatitis B, and influenza vaccines . Howeverand ACE2 .Myocarditis may be a manifestation of some autoimmune and auto-inflammatory diseases, such as sarcoidosis, Behçet’s disease, EGPA, idiopathic inflammatory myopathy, and SLE. The true incidence is not accurately known but is estimated to be 9–16% of all myocarditis cases, and their incidence and prognoses vary with different ARD diseases ,20. CardWatad A et al. reported that most patients in their study cohort (17 out of 20) experienced active ARD (both flare and de novo) symptoms after receiving the first dose of a COVID-19 vaccine . AlthougPatients with ARD have a higher risk of infection and are prone to develop severe infections due to underlying autoimmune dysregulation and treatment-induced immunosuppressive states . As suchThe main limitation of this case series is the small number of patients reported from a single tertiary center. This did not allow enough data to calculate the rate of such events within a vaccinated population. Nevertheless, the reported cases serve to highlight the rare occurrences of ARD flares with myocarditis after receiving COVID-19 mRNA vaccines, and alert ARD patients and rheumatologists to this potential adverse effect.This case series adds to the expanding knowledge about the complications that can ensue in ARD patients after receiving mRNA vaccines. While isolated post-vaccination myocarditis mainly affects younger males, typically occurring six weeks after two vaccination doses and is usually mild and self-limiting, the patients in our case series who had ARD flares with myocarditis were observed to be older, started experiencing symptoms suggestive of ARD flares/myocarditis after one dose of the vaccine, were more severe, and required aggressive immunosuppression for treatment. This highlights that compared to isolated post-mRNA vaccination myocarditis, post-mRNA vaccination active ARD with myocarditis has different management considerations, including prompt treatment with immunosuppressants for satisfactory outcomes. As knowledge of post-vaccination complications increases with the increasing use of mRNA vaccines, rheumatologists will gain insight and experience into their management, including vigilance for rare complications. Further understanding of the biomechanics of mRNA vaccines and data collected from vaccinated ARD patients would also improve vaccination strategies for this vulnerable population.


The severity of COVID-19 commonly depends on age-related tissue stiffness. The aim was to review publications that explain the effect of microenvironmental extracellular matrix stiffness on cellular processes. Platelets and endothelial cells are mechanosensitive. Increased tissue stiffness can trigger cytokine storm with the upregulated expression of pro-inflammatory cytokines, such as tumor necrosis factor alpha and interleukin IL-6, and tissue integrity disruption, leading to enhanced virus entry and disease severity. Increased tissue stiffness in critically ill COVID-19 patients triggers platelet activation and initiates plague formation and thrombosis development. Cholesterol content in cell membrane increases with aging and further enhances tissue stiffness. Membrane cholesterol depletion decreases virus entry to host cells. Membrane cholesterol lowering drugs, such as statins or novel chitosan derivatives, have to be further developed for application in COVID-19 treatment. Statins are also known to decrease arterial stiffness mitigating cardiovascular diseases. Sulfated chitosan derivatives can be further developed for potential use in future as anticoagulants in prevention of severe COVID-19. Anti-TNF-α therapies as well as destiffening therapies have been suggested to combat severe COVID-19. The inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells pathway must be considered as a therapeutic target in the treatment of severe COVID-19 patients. The activation of mechanosensitive platelets by higher matrix stiffness increases their adhesion and the risk of thrombus formation, thus enhancing the severity of COVID-19. COVID-19 has become a major global concern in the last two years . It has Arterial stiffness determined from carotid-femoral pulse wave velocity for mild, moderate, and severe COVID-19 patients has been found to be essentially higher for severe and moderate COVID-19 patients compared to mild COVID-19 patients .The elevated plasma levels of adhesion molecules, such as ICAM-1 and VCAM-1, vascular adhesion protein-1, and vascular endothelial growth factor, has been reported for severe and moderate COVID-19 patients ,6.The increased ICAM-1 expression may take place as a result ofthe increase of pro-inflammatory cytokines, such as TNF-α and/or cytoskeletal reorganization. Selenium can inhibit tumor necrosis factor alpha (TNF-α) induced ICAM-1, VCAM-1, and endothelial-leukocyte adhesion molecule-1 (E-selectin) expression . It has Platelet hyperactivity and thrombotic complications in severe COVID-19 patients with comorbidities such as hypertension, cardiovascular disease, and obesity, but not in mild COVID-19 patients, was reported. Thrombotic complications are a well-recognized hallmark of COVID-19. The role of the thrombotic complications in COVID-19 is not completely understood at present. Manne and coauthors consider that “pathological drivers of thrombosis in COVID-19 remain unclear” .Platelets play important role also in processes in lungs. It has been reported that higher numbers of platelets are associated with higher rates of venous thromboembolism, but higher mean platelet volume is associated with higher rates of arterial thrombotic events .The review will focus on the influence of micro-environmental stiffness on various mechanisms of cellular processes involved in COVID-19 that have been suggested by different authors. Essential improvement in mechanisms understanding can be achieved if increased arterial stiffness in critically ill COVID-19 patients is taken into account. This review will cover only publications devoted to the various aspects of extracelllular matrix (ECM) stiffness interrelated with oxidative stress and the inflammation that has been observed in the COVID-19 disease with the aim to provide a rational basis for the future development of novel therapies. Publications related to direct and indirect destiffening strategies and destiffening agents are of great interest. The effect of mechanical forces and extracellular matrix stiffness on biological cellular processes was the criterium for published data inclusion in this review.The effect of the combination of surface stiffness with surface hydration on the cellular processes has been reviewed  and it wDehydration also results in enhanced tissue stiffness and triggers NF-κB activation . HydratiPatients with severe COVID-19 admitted to the intensive care unit (ICU) are at especially high thrombotic risk . It was Platelets are mechanosensitive, and increasing substrate stiffness results in the increased platelet adhesion and spreading ,19. AdheIncreased arterial stiffness and the increased content of membrane cholesterol was observed in age-related diseases and in age-dependent COVID-19. The increase of membrane cholesterol content increases arterial stiffness. Increased arterial stiffness can be associated with increased platelet adhesion, platelet activation and thrombus formation. The increase of membrane cholesterol content enhances the probability of virus entry and severity of COVID-19. Heparin and chitosan sulfates have the potential to mitigate thrombus formation. Cytokine storm induced by increased vascular wall stiffness inputs both into tight junction integrity disruption and into platelets activation. The negative effect of increased tissue stiffness can be reversed by de-stiffening technologies .Various molecular mechanisms have been suggested to describe infection process. For example, Iwasaki and coworkers consider that the S spike protein of SARS-CoV-2 binds with angiotensin-converting enzyme 2 (ACE2) as a receptor and then enters into host cells. The hyper-proinflammatory cytokine storm, including interleukin-6, nuclear factor kappa B (NF-κB), and TNF-α released from SARS-CoV-2-infected macrophages and monocytes, results in multi-organ injury/failure and the development of severe COVID-19 . ACE2 anCorrelation between platelet activation and arterial stiffness was reported by Yamasaki and coauthors , althougThe hyperexpression of Factor VIII in COVID-19 subjects was observed. It was suggested that the thrombogenicity of SARS-CoV-2 infection might be linked to widespread endothelial damage and Factor VIII ,31,32,33Dehydration and glycation reactions during aging process leads to the increase of ECM density and stiffness. Changes in ECM stiffness result in cytoskeleton reorganization and concomitant transcription factor NF-κB activation. TNF-α is the inducer of the nuclear transcription factor NF-κB. TNF-α activation decreases tight junction integrity and leads to leukocytes extravasation and to related cardiovascular diseases. At the same time, tight junction integrity disruption leads to the increased virus entry and development of severe COVID-19 disease .The role of transcription factor NF-κB was demonstrated in The reorganization of the cytoskeleton induced by increased aging and increased density of ECM due to crosslinking, dehydration, and glycation reactions leads to the activation of transcription factor NF-κB. Both inflammation and thrombotic complications depend on the activation of transcription factor NF-κB. The expression of adhesion molecules leads to the binding and transmigration of leukocytes, but virus entry increases vascular wall stiffness and initiates in critical points with high stiffness platelet adhesion and thrombus formation .It has been reported that Ras homolog family member A (RhoA) activity increases with the increase of stiffness, but simvastatin treatment decreases active RhoA levels. Simvastatin decreases endothelium permeability is due to the decrease of ECM stiffness . The actSubstrate stiffness leads to Rho signaling. Rho signaling initiates NF-Kb signaling and increases EC permeability. NF-Kb signaling results in the expression of adhesion molecules and cytokines and leads to ECM synthesis, increasing substrate stiffness. Rho signaling increases cellular stiffness that leads to ICAM-1 clustering and leucocyte adhesion and extravasation. ECM synthesis, the expression of adhesion molecules and cytokines, the increase of EC permeability, and the increase of leukocyte adhesion and extravasation contribute to lung injury as a result of ICAM1 clustering . The ECMMicrovesicles play important role in the progression of various diseases, including COVID-19. Microvesicles are observed at elevated concentrations in diseased tissues . It has Weinbaum and co-authors recently concluded that arterial stiffness is associated with glycocalyx degradation, endothelial dysfunction, and vascular disease . IncreasIt is also known that associations exist between higher flavonoid consumption and a lower arterial stiffness . ResearcCholesterol content increases in the membranes of cells with aging. Oxidized low-density lipoprotein (LDL) cholesterol is vasoconstrictor and thrombogenic. The synthesis and release of nitric oxide is inhibited by LDL cholesterol . StatinsChitosan and chitosan oligosaccharides inhibit pro-inflammatory cytokines, adhesion molecules and nuclear factor NF-κB activation, and the translocation of NF-κB from cytoplasm to nucleus which has been associated with the development of age-related diseases ,86,87,88Researchers at the University of Cambridge, Addenbrooke’s Hospital, United Kingdom, demonstrated that arterial stiffness measured by pulse-wave velocity and related diseases can be treated and reduced using anti-TNF-α therapy . The proIt has been also reported in a number of publications that various polyphenol compounds inhibit TNF-α in vitro ,103,104.Statins, angiotensin II receptor 1 blockers, and ACE2 exert beneficial effects on endothelial progenitor cells . At the Aspirin decreases arterial stiffness . The enhIt has been suggested that SARS-CoV-2 and its Spike protein directly stimulated the release of coagulation and inflammatory factors and the formation of leukocyte-platelet aggregates .However, it was previously reported that platelets sense microenvironmental mechanical properties  and subsCardiovascular diseases are associated with increased oxidative stress , and carThis means that the evident relationship between oxidative stress and matrix stiffness must be expected. Reactive oxygen species (ROS) promote arterial stiffening  and chanP-selectin may be proposed as a marker of endothelial dysfunction and increased arterial stiffness in hypercholesterolemic patients. Oxidative processes leading to endothelial dysfunction and platelet activation result in increased soluble P-selectin levels . P-selecA correlation has been found between arterial stiffness determined by pulse wave velocity and platelet activation .It has been reported that oxidative stress by Nox2 activation is associated with severe disease and thrombotic events in COVID-19 patients .Reciprocal dependence between TNFα- and NOX2 has been reported , evidencHigh levels of 8-iso-PGF2α in COVID-19 have been reported , indicatOxidative stress activity based on the level of 8-iso-PgF2α; pro-inflammatory activity based on tumor necrosis factor-α, its type I soluble receptor; and C-reactive protein levels and the effects of antihypertensive treatment on systemic inflammation, oxidative stress, and pro-inflammatory cytokine levels in 186 hypertensive patients during a 2-month course of treatment have been reported with aim of identifying the possible role of oxidative stress in hypertension. It was found that the grade of hypertension influences the increase in the serum levels of TNF-α and 8-iso-PgF2α, and the duration of hypertension affects the activity of the TNF- α with no effect on the levels of 8-iso-PgF2α . The simIt has been stated that vitamins improve arterial stiffness due to destiffening . So, thePhysical activity decreases the risk for severe COVID-19 outcomes and alleviates post-acute COVID-19 syndrome . Such coExtracellular matrix stiffening, linked with inflammation and oxidative stress, is a driving factor of various age-related diseases, including cardiovascular pathologies and very likely COVID-19. Efforts to find effective drugs that are able to fight severe COVID-19 and post-COVID-19 complications are expected to remain to be a hot topic in the near future.This review was limited to the articles containing information about the matrix stiffness effect on cellular processes and age-related diseases. The increased tissue stiffness and related tissue integrity disruption and increased membrane cholesterol content in severe COVID-19 patients may be associated with increased virus entry into host cells and increased disease severity. Cholesterol content in cell membrane increases with aging and with ECM stiffening. Statins for cholesterol depletion and arterial stiffness reduction and anti-TNF-α therapies for cytokine storm prevention and arterial stiffness reduction in COVID-19 could be suggested for more detailed investigation. Local stiffness growth at the sites of rigid virus particle penetration into vascular walls can trigger mechanosensitive platelet activation and the initiation of thrombus formation in critically ill COVID-19 patients.Glycocalyx degradation in severe COVID-19 patients has been related with increased arterial stiffness. The inhibition of NF-κB and TNF-α can improve tissue integrity and biomechanical properties. Heparin and potentially sulfated chitosans can be used in the future for the treatment of stiffness-induced thrombotic complications in COVID-19. Aspirin prevents thrombus formation by decreasing platelet turnover and mitigates severe COVID-19 complications. Various diets can regulate stiffness and related health risks.The molecular mechanism is still poorly understood. Very different experimental results from various areas of research presented in this review taken together provide evidence that ECM stiffness plays an important and often decisive role in the cellular processes responsible for age-related and age-dependent diseases, including COVID-19. The association of arterial stiffness with inflammation and oxidative stress can give new insights into the mechanisms of thrombus formation. Prospective, randomized, and well-designed studies would be beneficial to develop a synergistic combination of natural and synthetic molecules for the potential treatment of COVID-19 and post-COVID-19 patients, provided that proper evidence of their efficacy and safety is established. Therefore, larger prospective studies on the assessment of arterial stiffness and tissue integrity should be performed in order to gain more breakthrough knowledge related to the prevention and treatment of severe COVID-19 infection.