II centers. Strong agostic interactions with the “C−H”‐groups of the cyclohexyl substituents result in an unusual low‐spin square planar CoII complex, which is unreactive towards external substrates. Such agostic interactions are absent in the complex with phenyl substituents on the borate backbone. This complex displays a high‐spin tetrahedral CoII center, which is reactive towards external substrates including dioxygen. To the best of our knowledge, this is also the first investigation of agostic interactions through single‐crystal EPR spectroscopy. We conclusively show here that the structure and properties of these CoII complexes can be strongly influenced through interactions in the secondary coordination sphere. Additionally, we unravel a unique ligand rearrangement for these classes of anionic mesoionic carbene‐based ligands.We present herein anionic borate‐based bi‐mesoionic carbene compounds of the 1,2,3‐triazol‐4‐ylidene type that undergo C−N isomerization reactions. The isomerized compounds are excellent ligands for Co II complexes with these ligands display geometries, spin states, and reactivities that are controlled by agostic interactions in the secondary coordination sphere.C−N isomerization reactions on borate‐based anionic bi‐mesoionic carbene ligands are reported. The Co Borate‐based anionic N‐heterocyclic carbenes (NHCs) are well‐established as an important class of ligand.21, 22LC,C OTf and (H2L2)OTf , and theoretical (wave‐function‐based methods) approach is used to investigate the compounds and their reactivity.In the past decade, metal complexes of MICs were shown to display excellent properties, e.g. in homogeneous catalysis,42, 43C Figure . In the 2L1)OTf was synthesized in good yield by reacting 1,5‐diphenyl‐1H‐1,2,3‐triazole with dicyclohexyl‐trifluoromethanesulfonate‐borane (Scheme 2L1)OTf, we reacted this borate salt with CoCl2 in the presence of LDA at room temperature for 12 hours 2] and [Co2], which unfortunately could not be separated. The identity of these complexes was established by single‐crystal X‐ray diffraction studies (see below).The triazolium‐substituted borate salt H2LOTf was s2L1)OTf was reacted with LiTMP  at −50 °C, and the mixture was slowly warmed up to room temperature over a period of 2 hours. A crystalline solid was obtained after purification in good yield. A 1H NMR spectrum of this compound did not display any signals corresponding to the C−H protons of the triazolium rings, indicating that the deprotonation was successful. The molecular structure in the crystal obtained through single‐crystal X‐ray diffraction studies shows the formation of a dilithium complex  from the second L1N,N ligand. A THF molecule is also coordinated to the lithium centers resulting in a pseudo tetrahedral geometry at the metal ion. The two lithium ions together with the nitrogen donors form a six‐membered ring. The core of this structure has a fused seven‐ring 5:6:5:6:5:6:5 system.The bond lengths within the ligands are all in the expected range. The lithium centers are chelated through the nitrogen donors of the 2L1)OTf was now reacted with LDA at 50 °C for 4 hours, cooled to room temperature, and the resulting mixture was stirred with CoCl2 for 12 hours. Work up of this mixture led to the isolation of only one type of complex, [Co2], as crystalline material. The molecular structure in the crystal of [Co2] shows that the cobalt center is coordinated by two nitrogen donors each from the two L1N,N ligands  is not necessary for the isomerization reaction at the ligand backbone. We next carried out a temperature‐dependent monitoring of the deprotonation and the isomerization reaction through multinuclear NMR spectroscopy. These results showed that with LiTMP, even at low temperatures, the deprotonation is almost instantaneous. Two different species are formed at low temperatures, which convert to one predominant species at room temperature, the signals of which display a good match with the signals of the isolated crystals . With the information obtained from these deprotonation studies, we set out to optimize the synthesis of the cobalt complex.  and 1.918(1) Å are short and in a range expected for a low‐spin cobalt(II) ion. Additionally, the angles around the cobalt center are 86.6(1) and 93.4(1)°, which is very close to angles for a perfect square planar coordination geometry. The CoII ion lies perfectly on the plane defined by the four N‐donor atoms. All these data point to a square planar, low‐spin CoII center, which is extremely rare for CoII complexes with non‐macrocyclic ligands. The complex [Co2] displays several irreversible oxidation steps as revealed by cyclic‐voltammetry experiments. Additionally, two irreversible reduction steps are observed as well, the first of which becomes more reversible at higher scan rates . Inspired by the similarity in the geometry of the first coordination sphere of [Co2] to square planar CoII–porphyrin complexes, we set out to investigate the reactivity of this complex with pyridine and dioxygen. To our surprise and disappointment, the complex [Co2] did not react with either of the external substrates. As the single crystals of [Co2] were relatively large (0.29×0.21×0.11 mm3) and of a well‐defined shape, we decided to perform single‐crystal EPR measurements on that complex.The C−C, C−N and B−C bond lengths within the xyz coordinate system. The KCl cube was placed on a flat surface on a special quartz rod, which was introduced in the EPR spectrometer cavity, attached to a home‐made goniometer. Placing the KCl cube on each of three orthogonal faces and rotating the quartz rod allowed as to acquire EPR spectra for multiple crystal orientations in three orthogonal planes. Further details are given in the SI and in selected references.I(59Co)=7/2) arising from a single cobalt(II) centre, which reveals the triclinic P1‾space group of the crystal. Selected single‐crystal spectra are shown in Figure S15 and the full set of spectra in the three experimental crystal planes is shown in Figure S16. The well‐resolved hyperfine splittings and low linewidths indicate that intermolecular magnetic dipolar and exchange interactions are negligible, in the crystal. We discovered that one “CH2‐group” each from the cyclohexyl substituents at the borate backbone of the L1N,N ligands is oriented exactly at the axial coordination sites of the CoII center 2] 2] 2] in the pure form as bulk material and hence this complex will not be discussed any further herein. The detailed analysis of the molecular structure in the crystal, the EPR parameters, and the reactivity studies  of [Co2] led us to hypothesize that the geometry, the spin state, and the reactivity of this metal complex are controlled by the strong non‐covalent (agostic) interactions in the secondary coordination sphere. Additionally, in the IR spectrum of the complex [Co2] a weak and broad signal is observed at 2620 cm−1, which is also an indication of the presence of an agostic interaction in this complex . Such a signal is absent from all the other compounds investigated here, lending credence to the assignment of this band to the presence of agostic interactions. Calculations reproduce this band with reasonable accuracy . In order to validate this hypothesis of the effect of agostic interactions on the properties of the cobalt complex, we decided to synthesize the ligand (H2L2)OTf, which has two phenyl substituents (instead of cyclohexyl) on the borate backbone of the ligand.To our surprise, the e Cop‐OCHTPP with e Cop‐OCHTPP with 2L2)OTf was synthesized by the reaction of 1,5‐diphenyl‐1H‐1,2,3‐triazole with diphenylchloro‐borane, followed by the addition of trimethylsilyl triflate, in good yield (Scheme 2L2)OTf with LDA and further reaction with CoCl2 delivered [Co2] in reasonable yield. Whereas the crystals of [Co2] are yellow in color, [Co2] is pink in the crystalline state. A look at the molecular structure of [Co2] in the crystal shows that the CoII center is coordinated by two N‐atoms each from both the ligands 2] are around 1.973(6) Å, and are thus substantially longer than the Co−N bond lengths in [Co2] (1.913(3) Å). Additionally, the N‐Co‐N bond angles around the metal center are 94.1(1), 115.9(1), 116.7(1), and 94.7(1)°. These values indicate a distorted tetrahedral geometry around the CoII center with the distortion being imposed by the chelating nature of the L2N,N ligand. Additionally, no agostic or other non‐covalent interactions are observed in the secondary coordination sphere of the cobalt center in this complex. All the above data point towards a high‐spin tetrahedral CoII center in [Co2]. Accordingly, no EPR signals were observed for this compound even at liquid nitrogen temperatures. Thus, it is seen that the phenyl substituents on the borate backbone of L2N,N do not display any agostic interactions with the CoII center. This result is strikingly different from what was shown above for the complex [Co2]. The agostic interactions on the secondary coordination sphere thus control the geometry , the spin state (low spin vs. high spin), and the EPR properties  of the complexes [Co2] and [Co2].Thus, as expected, two C−N isomerization reactions have taken place on the backbone of each of the ligands. All four Co−N bond lengths in [Co2] does not show any reactivity towards the tested external substrates despite possessing a formal square planar coordination geometry at the CoII center, and a low‐spin state. We attributed the absence of this reactivity to the blocking of the axial coordination sites through agostic interactions. Gratifyingly, complex [Co2], which does not display any agostic interactions, reacts spontaneously with pyridine . A proper reaction of [Co2] with pyridine led to the quantitative isolation of the complex [Co2py]. The CoII center in [Co2py] has a distorted square pyramidal geometry 2py] displays an EPR signal both in the solid state and in solution at 100 K  and 1.969(1) Å. The Co−N distance to the pyridine‐N atom is 2.138(1) Å. Complex [Co2py] was simulated with g‐values of 2.298, 2.290, and 2.028 and A‐values  of 17.5, 19.2, and 243 MHz. The observed bond lengths, the near axial g‐anisotropy, and a large hyperfine coupling to the cobalt nucleus along the z‐direction are all signs of a low‐spin CoII center in [Co2py]. The EPR spectrum recorded in frozen solution has similar g‐ and A‐values. Additionally, for the spectrum in frozen solution, the hyperfine coupling to the axial pyridine‐N nucleus is resolved as well 2] to low spin in [Co2py]. Prompted by the reactivity of [Co2] with pyridine, and its extremely air‐sensitive nature, we decided to react [Co2] with O2. The new compound formed delivered an EPR signal which was simulated with g‐values of 1.993, 2.024, and 2.040 and A‐values  of 9, 13, and 65 MHz  radical. appears to be able to activate and bind O2.The EPR spectrum obtained from a powder polycrystalline sample of [Co2]: [Co2]Tr, where the apical CH2 groups directly above and below the CoII atom were removed from the cyclohexyl substituents, we performed complete‐active space self‐consistent field (CASSCF) calculations, with multi‐reference perturbation theory (NEVPT2) to take into account dynamical correlation effects, using the ORCA program.L1N,N)2] and [Co2py] the low‐spin multiplicity configuration was the ground state. The CASSCF/NEVPT2 calculations show that the ground state configurations for [Co2], [Co2]Tr, and [Co2py] contain the unpaired electron mainly in the dz2orbital, with the first two excited configurations corresponding to excitations from the dz2to dxz and dyz orbitals, respectively 2] is in the 5400–5500 cm−1 range, while for the truncated form [Co2]Tr, it is in the 2800–3050 cm−1 range and for [Co2py] it is in the 9300–9560 cm−1 range. These calculations were able to reproduce the experimental g‐values with remarkable accuracy  should be addressed to the authors.SupplementaryClick here for additional data file.


The reaction of tris‐(2‐pyridinylene‐N‐oxide)triaminoguanidinium salts with zinc(II) formate leads to the formation of cyclic supramolecular coordination compounds which in solution bind fullerenes in their spherical cavities. The rapid encapsulation of C60 can be observed by NMR spectroscopy and single‐crystal X‐ray diffraction and is verified using computation.The synthesis of a new triaminoguanidinium‐based ligand with three  Cage bound: Synthesis of a new triaminoguanidinium‐based ligand with three tris‐chelating [NNO] binding pockets and C3‐symmetry is described. Reaction with zinc(II) formate leads to the formation of cyclic supramolecular coordination compounds that in solution are able to bind fullerenes in their spherical cavities. The rapid encapsulation of C60 is observed by NMR spectroscopy and X‐ray diffraction and is validated by DFT. Covalently bonded systems are quite common, for example, cyclodextrins, cucurbiturils and cryptands which bind cations,60 and C70 encapsulated supramolecular entity. We were able to compute spectroscopic properties and assign the C60 signals in both the free state and bound inside of the metallacycle  due to their large size. Herein we demonstrate not only that a geometry‐optimized structure of a large empty metallacycle can be obtained, but also the Ce Figure  C. ThereC3‐symmetric building blocks with three tris‐chelating binding pockets and suitable co‐ligands , TAG‐NCS (4‐NCS), or TAG‐BF4 (4‐BF4), respectively  requires standard protection and deprotection procedures for the aldehyde moiety. The oxidation of the pyridine nitrogen can be realized under mild conditions by using urea hydrogen peroxide with phthalic anhydride in acetonitrile.4‐X) are obtained by the amination of guanidinium salts with hydrazine hydrate.5‐X) serve as an excellent ligands for ZnII. The reaction of [H3(pyO)3L]Cl (5‐Cl) with Zn(O2CH)2 in N,N‐dimethylformamide results in the formation of a supramolecular coordination compound [Zn24Cl24{(pyO)3L}12] 3L}12] (7) can be crystallized from the reaction mixture containing [H3(pyO)3L]BF4, ZnBr2 and NaO2CH. DOSY‐NMR spectroscopy ([D6]DMSO) of 7 shows neither decomposition nor aggregation of the coordination complex in solution. Only one species is detected in addition to solvents and water. The diffusion coefficient of 7 is found to be D=(7.36±0.08)×107 cm2 s−1. The hydrodynamic diameter of 7 can be determined to be 29.9±1.2 Å using the Stokes–Einstein equation, which corresponds well with the observed diameter of the crystal structure .An isostructural cyclic coordination oligomer [Zn24(NCS)16(O2CH)8{(pyO)3L}12] (8) with a 59 % yield. The zinc(II) ions, which were formally occupied by the halides Cl− or Br−, share those sites with isothiocyanate and formate co‐ligands 16(O2CH)8{(pyO)3L}12] (8) with a toluene solution of C60, as there was no observed color change.Introduction of isothiocyanate leads to the formation of the analogous NCS‐metallacycle [Zn8) was added to a toluene solution of C60 or C70. Single crystals of the respective inclusion compounds were collected after a few days 20(O2CH)4{(pyO)3L}12] (9). The lattice parameters underwent a slight change compared to 8, whereas the space group was maintained. The periphery of the metallacycle was slightly perturbed, presumably due to the change in polarity of the solvent mixture.From these experimental results we decided to encapsulate the fullerenes into the metallacycles in solution. A solution of empty metallacycle  to 140.40 ppm (C60⊂9) clearly indicates the incorporation of C60 in the cavity of the metallacycle.The incorporation of C60 by the metallacycle (6) to be favorable . However, there is an additional local minimum (C) where the C60 interacts with the periphery of the metallacycle. This has also been observed crystallographically. An analogous binding plot is observed for the C70 case (see Supporting Information for details). The use of dispersion corrections in these calculations is critical in order to correctly model the attractive interaction. In addition to the entropy loss, there is an electronic energy barrier (B) that C60 (and C70) must overcome caused by steric interactions between the C60/70 and pyridinyl groups located at the entrance of the metallacycle. Due to the nature of these calculations, stepwise single‐point calculations from the fully optimized state (A) were applied. The binding energetics are only qualitative. The differences in electrostatic potentials for 6–8 are shown in Figure 2 moieties carry the negative potential. This is gradually attenuated in the series of 6>7>8 with 8 having the least positive inner core. These potentials might be useful in tuning the affinity and specificity for guest molecules.Calculations predicted the encapsulation of Ce Figure  c A. How60⊂9 species versus the free C60 (144.3 ppm vs. 142.2 ppm)  also match the computed IR spectrum and the fingerprint region contains several characteristic absorptions .In agreement with experimental data, spectroscopic assignments using computations  predict an approximately 2.0 ppm upfield shift for the encapsulated C) Figure  a. The Itris‐chelating pyridine‐N‐oxide based ligands [H3(pyO)3L]X. Coordination of zinc(II) ions leads to structurally interesting cyclic coordination oligomers which serve as hosts for fullerenes C60 and C70. The inclusion of fullerenes was observed by single‐crystal X‐ray diffractometry and NMR spectroscopy, and was validated using computations. These metallacycles are robust and show no sign of decomposition. Although computations on such large systems are challenging, we were able to model the C60/C70 encapsulated metallacycles and even predict spectroscopic data, which are in strong agreement with the experimental results. Electrostatic potential maps reveal that the positive charges of the cavity cores can be tuned by the peripheral halide co‐ligands. These computations help to provide a deeper understanding of host‐guest interaction in these metallacycles. Similar computations will no doubt be useful for the rational design of host molecules with other cargo. In the future, these complexes could serve as container molecules transporting important cargo.We report the synthesis of a new type of Experimental methods, synthesis, computational details and results can all be found in the Supporting Information.https://www.ccdc.cam.ac.uk/services/structures?id=doi:10.1002/chem.201905390 , contain the supplementary crystallographic data for this paper. These data are provided free of charge by http://www.ccdc.cam.ac.uk/.CCDC The authors declare no conflict of interest.As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.SupplementaryClick here for additional data file.


Tumor and regional lymph node formalin‐fixed paraffin‐embedded samples prepared from the surgical specimens were subjected to immunohistochemistry. We confirmed that the recurrence‐free survival of the high HER2‐AAb group was significantly longer than that of the low HER2‐AAb group (p = 0.015). The numbers of tumor‐infiltrating CD20+ immune cells (ICs) (p < 0.001), IGKC+ICs (p = 0.023), and CXCL13+ ICs (p = 0.044) were significantly higher in the high HER2‐AAb group than in the low HER2‐AAb group. The number of CD4+ ICs in the B‐cell follicles of the regional lymph nodes was also significantly greater in the high HER2‐AAb group than in the low HER2‐AAb group (p = 0.026). Our findings indicate that a high level of HER2‐AAb is associated with enhanced humoral immunity against breast cancer and thus may provide a rationale for the association of HER2‐AAb with favorable prognosis.Humoral immunity plays a substantial role in the suppression of breast cancer. We have revealed that a high serum concentration of anti‐HER2 autoantibody (HER2‐AAb) is associated with favorable outcomes in patients with invasive breast cancer. Thus, we aimed to clarify the association between high serum concentration of HER2‐AAb and humoral immune response in the tumor microenvironment. Out of 500 consecutive patients with invasive breast cancer, we selected those whose HER2‐AAb values were high ( Anti‐HER2 autoantibody in breast cancer patients is positively associated with their outcomes. Enhanced humoral immunity in the tumor microenvironment is associated with autoantibody, providing a rationale for favorable outcomes in such patients. Examples of this association are as follows: high levels of autoantibodies to MUC1 in patient sera are associated with favorable prognosis in a relatively small cohort of breast cancer patients.p = 1.8 × 10–7) than that in healthy subjects.p = 0.015). These findings suggest that a high level of HER2‐AAb is associated with antitumor immunity against breast cancer. Thus, we aimed to determine whether and how antitumor immunity was enhanced in breast cancer patients whose serum concentration of HER2‐AAb was high.Given the production of autoantibody to a TAA is associated with enhanced antitumor immunity, it is speculated that the level of autoantibodies in cancer patients is lower than that in healthy individuals because healthy individuals may be protected against cancer by the enhanced antitumor immunity. Thus, to identify an autoantibody associated with enhanced antitumor immunity, a highly sensitive quantitative assay that can determine low levels of autoantibody needs to be established. Using a highly sensitive ELISA assay, we found that the serum concentration of autoantibody to HER2 (HER2‐AAb) in patients with early stage breast cancer is significantly lower (22.1n = 20) or above 67.81 ng/ml .The distribution of the log‐transformed serum HER2‐AAb concentrations of 100 healthy women  recruited at a breast screening center reported previously,2.2n = 31, high HER2‐AAb group; n = 18, low HER2‐AAb group) and regional lymph node FFPE samples  prepared from the patients’ surgical specimens were subjected to immunohistochemistry. Several cases in the cohort were not used solely because the corresponding FFPE samples were missing. The FFPE blocks were sliced at a thickness of 4 μm, and the thin sections were de‐paraffinized with Hemo‐De  and ethanol followed by rehydration with 80% ethanol and tap water. For CD4 and CXCR5 double staining and for CXCL13 and PD‐L1 staining, the thin sections were fixed again with 10% buffered formaldehyde for 2 min and 10 mM glycine‐PBS for 10 min. Antigen retrieval was performed with Target Retrieval Solution pH 6 (Dako) at 98°C for 20 min for CD20 and IGKC, with Target Retrieval Solution pH 9 (Dako) at 98°C for 20 min for HLA‐A/B/C, with Target Retrieval Solution pH 9 at 98°C for 40 min for CD8 and FOXP3, with Target Retrieval Solution pH 9 at 121°C for 10 min for CXCL13 and CD4 plus CXCR5 double staining, and with Universal HIER Antigen Retrieval Reagent pH 6 (Abcam) at 125°C for 1 min for PD‐L1. Inactivation of endogenous peroxidase was performed with 2% H2O2/methanol for 10 min, and blocking was performed with an Avidin/Biotin Blocking Kit (Vector Laboratories) and/or Block ACE (KAC) for 30 min. The following primary antibodies were used: polyclonal anti‐Kappa Light Chain , anti‐CD20 , anti‐HLA Class 1 ABC , anti‐CD8 , anti‐FOXP3 , anti‐CXCR5 , anti‐CD4 , polyclonal anti‐CXCL13 , and SP142‐compatible anti‐PD‐L1 .Tumor formalin‐fixed paraffin‐embedded (FFPE) samples (2.3Tumor‐infiltrating immune cells (ICs) were separately counted in three regions: intratumoral (IT) ICs, defined as ICs present in tumor parenchyma, adjacent stromal (AS) ICs, defined as ICs present within a tumor cell (TC) diameter away from tumor parenchyma, and distant stromal ICs, defined as ICs present in a tumor stroma but outside of an AS compartment. A representative microphotograph of a breast tumor in which ICs were present in the IT, AS, and distal stromal area is shown in Figure Each cell count was a sum of the counts in five 40× fields selected randomly. Total cell count was defined as a sum of IT, AS, and distant stromal ICs. Follicular CD4‐positive cells were defined as CD4‐positive cells in CXCR5‐positive cell clusters/follicles in the axillary lymph nodes and demonstrated as a sum of five 40× fields selected randomly. Protein expression in TCs was evaluated as a percentage of TCs positive for the protein of interest except for HER2. HER2 expression was estimated in accordance with the recommendation by the American Society of Clinical Oncology and the College of American Pathologists.2.4Among patients whose frozen tumor samples obtained by surgical removal were available, the top 10 patients in the high HER2‐AAb group and top five patients in the low HER2‐AAb group—those with the highest numbers of CD20‐positive ICs infiltrating the tumors were selected. The frozen samples were immersed in RNAlater‐ICE (Invitrogen) and stored at –80°C until use. RNA extraction, unbiased amplification of BCR genes, next‐generation sequencing, and data analysis were performed by Repertoire Genesis Inc. as previously described.2.5HER2 gene amplification of TCs from surgically excised tumors in all selected cases was examined by SRL, Inc. Briefly, FFPE samples were sectioned at a thickness of 4 μm and stained with a PathVysion HER2 DNA Probe Kit (Abbott) in accordance with the manufacturer's instructions. Fluorescence was observed using Duet‐3 (BioView). HER2 amplification was evaluated in accordance with the recommendation by the American Society of Clinical Oncology and the College of American Pathologists.2.6HER2/ERBB2 gene (IDT), followed by next‐generation sequencing using MiSeq (Illumina). The obtained sequences were mapped to the hg19 human reference sequence to detect mutations. Among the detected mutations, synonymous mutations, single‐nucleotide polymorphisms described in the dbSNP Database, those with less than 10 mutant allele coverages, germline mutations with around 50% or 100% mutant allele frequencies, and mutations with fewer than 8% mutant allele frequencies were excluded.We selected patients whose frozen tumor samples were available for further analysis (23 patients in the high HER2‐AAb group and 15 patients in the low HER2‐AAb group). The frozen samples were subjected to genomic DNA extraction using the DNeasy Blood & Tissue Kit (Qiagen). One sample from the high HER2‐AAb group and one sample from the low HER2‐AAb group were not used for further analysis because of insufficient DNA content. The library was prepared using xGen custom probes for all exons of the 2.7p value of <0.05 was considered significant. All tests were described as two‐tailed.Statistical tests used are specified in the figures, figure legends, and table footnotes. Statistical analysis was performed using GraphPad Prism 6.0  and JMP Pro 11 (SAS Institute Inc.). A 2.8All procedures performed in this study were in accordance with the ethical standards of the institutional ethical committee  and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from all individual participants included in the study.2.9Consent for the publication of research data was included in the consent forms and approved by the institutional review board of Osaka University Hospital. Images from tissue specimens of patients are entirely unidentifiable.2.10All data generated or analyzed during this study are included in this article and its additional files.33.1n = 33) and the low HER2‐AAb group (n = 20) were selected for further analyses. The baseline patient characteristics of the two groups were similar in terms of menopausal status, histological type, tumor size, lymph node metastasis, histological grade, hormone receptor status, HER2 status, and adjuvant therapy  play a central role in antitumor immunity. Thus, we aimed to investigate the association between HER2‐AAb and the extent of TILs and to clarify the difference in various IC types infiltrating in the tumors between the high and low HER2‐AAb groups. The extent of TILs in the high HER2‐AAb group was similar to that in the low HER2‐AAb group  cells enable the maturation of B cells in the lymphoid follicles of SLOs, so they are essential for humoral immunity.3.4IgHV and IgHJ genes by the unbiased amplification of BCR genes followed by next‐generation sequencing.H, indicating the diversity of BCRs, were not significantly different between the high HER2‐AAb group and low HER2‐AAb group, the IgHVJ distributions were skewed in most of the cases of both groups (Figure The diversity of BCRs in TILs reflects the specificity of the humoral immune responses in the tumor microenvironment.s Figure , suggest3.5Tumors may shape their microenvironments by expressing a number of immune‐related cell surface molecules and by secreting cytokines and chemokines that recruit or repel specific types of stromal cells or ICs. A B‐cell‐specific chemokine CXCL13 was expressed in tumors of the high and low HER2‐AAb groups to the same extent (Figure HER2 gene to determine whether it was associated with HER2‐AAb. The amplification of the HER2/ERBB2 gene and the expression of HER2 protein, estimated by fluorescent in situ hybridization and immunohistochemistry, respectively, were not different between the high and low HER2‐AAb groups (Figure HER2 gene were observed in 3 out of 23 cases in the high HER2‐AAb group and in 2 out of 15 cases in the low HER2‐AAb group (Figure We explored the abnormality of the s Figure A and B. p Figure C.3.6Finally, we evaluated the association between the two factors in light of the various factors estimated in the present study Figure D and E. 4We found that the high concentration of serum HER2‐AAb was associated with the accumulation of B cells, plasma cells, and CXCL13‐positive ICs in breast tumors and of follicular CD4‐positive ICs, which presumably represented Tfh cells, in the axillary lymph nodes. The accumulation of these IC types in the high HER2‐AAb group was unlikely to be a coincidence because those cells are functionally relevant to each other in the context of the enhancement of humoral immunity; Tfh cells play a central role in enhancing humoral immunity by interacting with the B cells in the germinal center of B‐cell follicles in the SLOs.The association between favorable prognosis and a high level of serum HER2‐AAb has been demonstrated in a previous study,HER2 gene of invasive lobular carcinoma than in the HER2 gene of invasive ductal carcinoma.Notably, the rationale behind the immunogenicity of HER2 is still unclear. In this present study, we observed an increased number of patients with invasive lobular carcinoma in the high HER2‐AAb group, albeit not statistically significant. Missense mutations can be found more frequently in the For the theoretical understanding of the mechanisms underlying antitumor effects of HER2‐AAb, immunological and non‐immunological mechanisms can be proposed; HER2‐AAb may enhance natural killer cell‐mediated cytotoxicity, which is a major mode of action of trastuzumab. HER2‐AAb may also activate the complement system, resulting in tumor cell lysis.In conclusion, a high level of HER2‐AAb was associated with the systematic enhancement of humoral immunity in the breast cancer microenvironment. Consistent with the growing evidence that humoral immunity plays a crucial role in antitumor immunity in breast cancer, our findings may provide a rationale underlying the association of a high level of HER2‐AAb with favorable prognosis. Further studies investigating the reason underlying HER2‐AAb induction in a specific population of breast cancer patients are warranted.The authors declare that they have no conflict of interests.Figure S1Click here for additional data file.


Although there is a rapid development of photoelectronic applications in solar cells, photodetectors, light emitting diodes (LEDs), and lasers based on 2D RPPs, the state‐of‐the‐art performance is far inferior to that of the existing devices because of the limited understanding on fundamental physics, especially special photophysics in carrier dynamics, excitonic fine structures, excitonic quasiparticles, and spin‐related effect. Thus, there is still plenty of room to improve the performances of photoelectronic devices based on 2D RPPs by enhancing knowledge on fundamental photophysics. This review highlights the special photophysics of 2D RPPs that is fundamentally different from the conventional 3D congeners. It also provides the most recent progress, debates, challenges, prospects, and in‐depth understanding of photophysics in 2D perovskites, which is significant for not only boosting performance of solar cells, LEDs, photodetectors, but also future development of applications in lasers, spintronics, quantum information, and integrated photonic chips. This review highlights the special photophysics of 2D perovskites that is fundamentally different from the conventional 3D congeners, which is significant for not only boosting performance of solar cells, light emitting diodes, photodetectors, but also future development of applications in lasers, spintronics, quantum information, and integrated photonic chips. In the 1990s, Mitzi et al. originally introduced layered organic–inorganic hybrid perovskites (C4H9NH3)2(CH3NH2)n−1SnnI3n+1, which are analogous to the Ruddlesden–Popper phase of K2NiF4 material. For the 2D RPPs, inorganic perovskite layers are intercalated with bulky organic cations acting as the spacers. The general chemical formula of such 2D RPPs is (RNH3)2An−1MnX3n+1 , where RNH3 is a large bulky aliphatic or aromatic alkylammonium spacer cation, typically, n‐butylammonium (n‐BA) and 2‐phenylethylammonium (PEA), A is monovalent organic cation, such as CH3NH3+ (MA+) and HC(NH2)2+ (FA+), M is a divalent metal cation, such as Pb and Sn, X is a halide anion , and n represents the number of [MX6]4− octahedral layers within each period.Given the background that hybrid lead halide perovskites (LHPs) have become one of the most popular semiconductors in optoelectronics area over the past years,4, 5 Ion migration in a 3D perovskite is the source of many instabilities, such as photocurrent hysteresis and giant switchable photovoltaic effect, which can accelerate the degradation of perovskite‐based electronic devices. The intrinsically better stability of 2D RPPs is largely attributed to the absence of ion migration. Compared to 3D perovskites, the formation of an ion vacancy in 2D RPPs requires more energy, suppressing ion migration. Hydration of 3D perovskite surface induced by moisture can cause the poor contact, resulting in performance loss of optoelectronic devices. Since the organic spacers can suppress the penetration of moisture to the perovskites, the 2D layered LHPs are also expected to exhibit improved moisture stability. Thus, extremely smooth and clean surface can be acquired in 2D layered LHPs via mechanical exfoliation, which will significantly enhance the optoelectronic performance. It is reported that the smooth 2D perovskite less sensitive to ambient moisture exhibits a quite low dark current, outperforming the rough surface by 23.6 times in terms of photodetectivity. Consequently, the unencapsulated solar cells based on 2D RPPs retain over 60% of their maximum efficiency for over 2250 h under constant, standard illumination (AM1.5G), and the devices exhibit a greater tolerance to relative humidity of 65% than their 3D counterparts. Very recently, Ren et al. developed a new 2D RPPs by using 2‐(methylthio)ethylamine hydrochloride (MTEACl) as the bulky alkylammoniums spacer. The (MTEA)2(MA)4Pb5I16 (n = 5) RPPs showed enhanced charge transport and improved stabilization due to weakened van der Waals interactions. Significantly improved efficiency and stability were achieved in the solar cells based on this new type of 2D RPPs. A power conversion efficiency as high as 18.06% (17.8% certified) was acquired, where the solar cells showed excellent moisture tolerance for 1512 h (70% relative humidity), thermal stability for 375 h (85 °C), and photostability up to 1000 h (operation at the maximum power point).Compared to ordinary 3D organic–inorganic LHPs with inherent instabilities, the 2D layered RPPs have recently attracted significant attention owing to their improved environmental stability when subjected to light, humidity, and heat stress.8, 9n value) and the inserted long‐chain ligands, in addition to the halogen component. For example, the bandgap of PEA2(MA)n−1PbnI3n+1 changes from ≈2.6 eV for n = 4, to 2.7, 2.9, 3.1 eV for n = 3, 2, 1, respectively. Besides their superior stability and high degree of tunability, another intriguing property is the natural multiquantum‐well (MQW) structures of the 2D RPPs. The barrier of organic ligands and the quantum well (QW) of inorganic octahedral layers have very different dielectric constants. The Coulomb interaction in the QW is strictly screened by the presence of the organic barrier because of the well‐known dielectric confinement effect caused by the high contrast in dielectric constants. Therefore, the electron–hole interaction within the exciton is very strong, resulting in huge oscillator strengths, large exciton binding energies, and novel 2D quantum confinement effect. Moreover, the electronic, optical, and magnetic properties also can be tailored accordingly.In addition to the excellent stability, the electronic structures of 2D RPPs are more flexible, compared to their 3D counterparts. The band gaps of 2D RPPs can be tuned by the number of inorganic layers , lasers, laser cooling, and strong optical nonlinearities. The 2D RPPs generally exhibit high quantum efficiency (QE), for examples, respectable power conversion efficiency of 12.51% for solar cell and high external quantum efficiency (EQE) for LEDs. In particular for the LEDs, a maximum luminance of 2480 cd m−2 at 490 nm is achieved based on the 2D RPPs with record‐high photoluminescence (PL) quantum yield (QY) of 88%. By using quasi‐2D RPPs as the active layer, a LED with an EQE of 8.8% and radiance of 80 W sr−1 m−2 at the near‐infrared wavelengths has also been demonstrated. The EQE was rapidly improved to 11.7%. And a higher radiance of around 82 W sr−1 m−2 is achieved at 3.6 V. By applying triplet management strategies, Qin et al. achieved stable green lasers from quasi‐2D perovskite under continuous wave (CW) optical pumping in air at room temperature using a distributed‐feedback cavity with a high‐quality factor.On the basis of their excellent stability, flexible bandgap, and MQW effect, the 2D RPPs have exhibited abundant optoelectronic properties and promising applications in solar cells,27 pho Recently, 2D RPPs for optoelectronics have been reviewed by Chen et al. Summary on the structures, growths, and optoelectronic performances of 2D RPPs with different chemical components are outlined in their review. Up‐to‐date progress on optical and optoelectronic properties of 2D RPPs was reviewed by Gao et al. and Wang et al. Recently, a comprehensive review covering synthesis methods, optical properties, and device demonstrations with a focus on thickness and dimensionality controlled properties was presented by Leng et al. However current reviews mainly summarize common optical properties and their corresponding applications mainly limited to LEDs and PV in a general manner without a focus on the fundamental photophysics.Although there is a rapid development of photoelectronic applications based on 2D RPPs, the state‐of‐the‐art performance is far from mature due to the limited understanding on the fundamental physics, especially special photophysics in carrier dynamics, excitonic fine structures, excitonic quasiparticles, and spin‐related effect. Thus, there is a huge potential to improve the performance of solar cells and LEDs based on the 2D RPPs by enhancing the understanding on fundamental photophysics. Hitherto, there are only few review articles spotting light on photophysics of 2D perovskites. Pedesseau et al. discussed the excitonic properties and possible Rashba effect related to the loss of inversion symmetry.37 RecSince there are growing reports on the newly emerging novel photophysics, such as quasiparticle dynamics, transient photophysics, and spin‐related properties, the topic on 2D RPPs has drawn increasing research effort driven by the need to understand the fundamental physical process of light interaction with the materials, which is critical for significant improvement of device performance and will deserve much more attention in the future. This encourages us to review the recent progress on the novel photophysics of 2D RPPs in this work.Figure n > 1 is named as quasi‐2D RPPs. Here, for simplicity of description, all RPPs with different n values are called 2D without a distinction. The RPPs, especially solution‐processed films, usually contain grains with different layer number n, the average n is denoted as 〈n〉.As schemed in 22.1Eb, typically few hundreds of meV). The quantum confinement leads to strongly bound excitons with binding energy up to 300–400 meV for phenylethylammonium (PEA = C6H4CH2CH4NH3) lead iodide (PEA2PbI4) RPPs, which is evidently larger than that of 3D LHP. As a comparison, the reported exciton binding energy for iodine‐based 3D perovskites is in the range from 2 to 50 meV, and 67–150 meV for bromine‐based 3D perovskites. Furthermore, the divergence between excitonic binding energy of 2D and 3D is filled by quasi‐2D perovskites with n > 1. Excitons in 2D RPPs are anisotropic. For in‐plane directions along the inorganic perovskite layer, the excitons remain delocalized, exhibiting Wannier‐like behavior. However, along the direction perpendicular to the inorganic perovskite layer, excitons are localized as Frenkel‐like behavior, with high oscillator strengths that are suitable for the generation of high exciton densities.Due to the huge energy difference and high contrast in dielectric constants between the bandgap of the inorganic layer (QW) and the organic layer (barrier), the Coulomb interaction between photogenerated electron–hole is very strong, resulting in significant oscillator strengths and very large exciton binding energies 2[PbI4] and (C6H13NH3)2[PbI4]⋅2I2 resulting from calculations are 288 and 171 meV, respectively, which is consistent with the experimental results that Eb value of (C6H13NH3)2[PbI4] decreases from 230 to 180 meV after I2 intercalation. It should be noted that, for most 2D RPPs, the length of organic cation of the 2D RPPs is notably smaller than the barrier thickness of conventional artificial MQWs. In these 2D RPPs, the exciton Bohr radius has been estimated to be 1.7 nm in the plane of the layers, equal to 3 or 4 unit cells, thus the envelope functions of the neighbor inorganic layers are not strictly separated. Therefore, 2D RPPs should be regarded as MQWs with caution.However, on the other hand, for ideal solar‐cell absorbers, weak binding energy between electrons and holes is favorable for charge carriers to easily separate and transport toward their respective charge collectors. Therefore, control over the exciton binding energy in 2D RPPs is required to enable their applications in a broad range of optoelectronic technologies. Smith et al. demonstrated that 2D RPPs can be stabilized by inserting small molecules into the binding spacers,48 and2.2 In 3D LHPs, very long diffusion lengths, even exceeding microns have been reported. However, in 2D RPPs, the quantum confinement and dielectric confinement hinder the carrier mobility. The mobility of 2D RPPs substantially decreases as n value decreases due to the quantum confinement. For (BA)2(MA)n−1PbnI3n+1, the mobility values are 2 × 10−3, 8.3 × 10−2, and 1.25 cm2 V−1 s−1 at 77 K when n = 1, 2, and 3, respectively. Thereby, Milot et al. indicated that the increase of quantum confinement effects and exciton binding energy would lead to the decrease of charge carrier mobility and increase of bimolecular and Auger recombination rates. By balancing the trade‐off between trap reduction, quantum confinement, and layer orientation, highly effective carrier mobility of nearly 10 cm2 V−1 s−1 and long carrier diffusion lengths of 2.5 µm were reached. To improve mobility, Cheng et al. largely reduced the exciton binding energy by using high dielectric‐constant organic spacers. Time‐of‐flight measurements demonstrated that the electron and hole mobilities are ≈11.1 and 9.5 cm2 V−1 s−1, respectively. In addition to reducing quantum confinement, Zhao et al. demonstrated that the long‐distance carrier transport in 2D RPPs could be enabled by a trap‐mediated charge transport process. A long‐lived (hundreds of nanoseconds) and nonluminescent electron−hole separated state is produced by trap‐induced exciton dissociation. The carrier diffusion distances for n = 2–4 2D RPPs are as long as 2−5 µm.High mobility and long transport distance are crucial for better photoexcited carrier extraction efficiency.50 In  At room temperature, the diffusivity of exciton is 1 cm2 s−1, equivalent to a high exciton mobility of 40 cm2 V−1 s−1. At 50 K, the diffusivity and effective mobility of the free exciton transport are as high as 3 cm2 s−1 and 1000 cm2 V−1 s−1, respectively. When approaching liquid helium temperature in experiment, a nonlinear regime of anomalous diffusion showed a rapidly expanding exciton cloud and diffusivities up to 30 cm2 s−1.The temperature‐dependent mobility also has been reported. Ziegler et al. directly monitored the diffusion of excitons in hBN‐encapsulated 2D RPPs through ultrafast emission microscopy from liquid helium (5 K) to room temperature (290 K).59 At 2.3 is found to be more than one order of magnitude higher than that in GaAs QWs based on the temperature‐dependent PL measurements. The longitudinal optical (LO) phonon energy (ELO) was determined to be 14 meV and the exciton coupling with the optical phonon strength (ΓLO) was estimated to be on the order of 70 meV. The acoustic phonon scattering parameter (Γac) is equal to 0.03 ± 0.01 meV K−1. As a result, PL emission lines have to be interpreted in the framework of a polaron model. Similar conclusion was also achieved in other 2D LHP, such as BA lead iodide (BA)2PbI4 (BA = CH3(CH2)3NH3) and hexylammonium (HA) lead iodide (HA)2PbI4 (HA = CH3(CH2)5NH3). At low temperatures (<100 K), the PL linewidth broadening is due to acoustic phonon scattering at 0.026 meV K−1, whereas at high temperatures, LO phonon–exciton coupling is the dominant mechanism that broadens the PL. The phonon–exciton coupling parameters of three typical 2D RPPs are summarized in Table Another consequence from the large exciton binding energy and oscillator strength is the strong exciton–phonon interactions. The exciton–phonon interaction of 2D PEA lead iodide RPPs60 is 2)2PbI3 and HC(NH2)2PbBr3 are investigated by the temperature dependent PL line broadening. It was found that scattering from LO phonons via the Fröhlich interaction is the dominant source of electron–phonon coupling near the room temperature, with negligible scattering via acoustic phonons. The interacting energies of LO phonon modes are determined to be 11.5 and 15.3 meV, and Fröhlich coupling constants are about 40 and 60 meV for the lead iodide and bromide perovskites, respectively. Similarly, high electron–phonon coupling near the room temperature was also discovered to be dominated by LO phonons via the Fröhlich interaction in the (PA)2(MA)2Pb3Br10 2NH3+) hybrid perovskite. The strong exciton–phonon coupling in 2D RPPs can accelerate polariton relaxation, which is beneficial for realizing polariton lasing with very low threshold. It could add interesting opportunities for the development of broadband, short‐pulsed lasers.PL spectroscopy is a powerful tool to study the exciton–phonon interactions. For example, electron–phonon couplings of 2D RPPs HC2, which is an index of exciton–photon interaction strength, where g is the exciton–photon coupling strength, γcav and γexc are the half‐widths of uncoupled exciton and microcavity resonances.On the basis of the large exciton binding energy and oscillation strength, the confined 2D excitons are also intriguing for the study of excitonic quasiparticles, such as strong exciton–photon coupling, also called as exciton–polaritons. Exciton–polaritons are half‐light, half‐matter quasiparticles formed due to the coupling between excitons and microcavity photons. Thereby, a hybrid state behaving as two separated energy branches (upper polariton branch and lower polariton branch) is formed. The minimum energy difference between these two branches is defined as Rabi‐splitting, 2PbI4 RPP at room temperature. Due to the strong combination between 2D exciton with Fabry–Pérot cavity modes and Bragg modes of the distributed Bragg reflector (DBRs), the hybridized exciton–polariton states can act as an ultrafast and reversible energy oscillation. To date, the strong coupling between the exciton and the optical mode of a Fabry–Pérot microcavity has been demonstrated at room temperature in both UV and visible ranges. In particular, the demonstration of polariton–polariton interactions may lead to polariton scattering, which would be a fundamental breakthrough for the new devices in the context of the low threshold polariton lasers.As shown in Figure perature.70 Due2.52(MA)n−1PbnBr3n+1 RPPs by using the long ligand octylamine (OA = CH3(CH2)7NH2) as spacers between lead bromide octahedrons layers with OA/MA molar ratio of 1:4. The PL spectrum of the RPP layers contains one main peak located at about 530 nm along with several minor peaks at higher photon energies originating from RPPs of n = 2–6. Similar to other 2D RPPs, the acquired RPPs are composed of mixed dimensionalities with different n‐values. Interesting, the refractive indices of 2D RPPs change with n‐values. As calculated by static dielectric constant ε using density functional theory, the refractive indices for OA ligands, n = 2, and n = 3 2D RPPs are 1.01, 1.39, and 1.46, respectively. The refractive index of 2D RPPs based on OA was experimentally determined to be ≈1.43 while the refractive index of 3D MAPbBr3 is about 2.3. Thus, the refractive index is smaller for the lower‐dimensional perovskite layers. Therefore, in the microplatelets with mixed RPP layers of different n values, the lower‐dimensional region can act as cladding layers while the regions of higher‐dimensional RPPs play the role of waveguiding due to the larger refractive index, resulting in photon confinement 2(MA)n−1PbnBr3n+1 RPPs.Li et al. synthesized (OA)t Figure . The intt Figure . Li et a2.6 excitonic energy reservoir  via a reprecipitation method. The resulted Mn2+ doped EA2PbBr4 exhibited a high PL QY of 78% owing to the efficient exciton trapping induced by Mn2+ doping and small activation energy. As a result, an extremely long PL lifetime of ≈0.75 ms is observed due to the heavy atom effect.The long‐lived PL signal usually implies a long carrier lifetime and a long carrier diffusion length, which is crucial for high‐performance PV. Different photophysical effects, including, defect tolerance Section , reversi80 exc Section , may lea2.7 Intriguingly, highly efficient PV devices can be acquired based on polycrystalline LHPs films containing a considerable density of point defects, the so‐called defect tolerance. Trap states are caused by structural defects derived from impurities or interruptions in the crystal lattice. The shallow traps may have little influence on the photophysics. Whereas, the deep traps are considered to bring nonradiative recombination centers, deteriorating efficiency and open‐circuit voltage of PV devices. Pandey et al. investigated the effect of different defects on the band structure of atomically thin 2D perovskites. They found that the most common defects only induce shallow or no states in the band structure, suggesting the 2D perovskites exhibit high defect tolerance.Traditionally, the trap states are detrimental for the device performances due to their impact on the charge carrier lifetime and effective mobility. Thereby, PV‐grade film and wafers based on conventional semiconductors require ultralow concentrations of impurities and crystalline defects at ppb levels.87 Int33.1n > 2 is dominated by lower energy edges states (LES), which dissociates excitons into longer‐lived free‐carriers. In their study, the 2D layered (BA)2(MA)n−1PbnI3n+1 RPP with n from 1 to 5 were investigated by confocal spatial PL mapping with ≈1 µm resolution. As shown in Figure n = 4 and 5. However, the LES emission was absent in the cases of n = 1 or 2.Exciton dissociation is crucial for charge carriers to be harvested by the current collectors of photoelectronic devices, such as solar cells and photodetectors. Interestingly, there is a special internal exciton dissociation through edge states in 2D RPPs. Blancon et al. discovered that the photophysics of 2D RPPs with carriers.89 In n > 2, a part of the photogenerated excitons transport to the edges of the crystal within its diffusion time and convert to LES and then efficiently emits photons at a lower energy level than that of the main exciton. Once the excitons are trapped in these LES, they will be dissociated into longer‐lived free‐carriers with the assistance from the edge state, although the average exciton binding energy is as large as 220 meV. The LES is protected from nonradiative processes, which can significantly boost the efficiency of optoelectronic devices. Therefore, these findings pave the way toward the rational design of high‐performance optoelectronic devices based on 2D RPPs. However, the nature of the edge state is still unclear. In the 2D materials, edge as termination of their 2D expansion is analogous to the surface of 3D bulk materials, which normally induces detrimental or unwanted effects. The unexpected edge state of 2D RPPs requires further research. Zhao et al. conducted research on the formation mechanism of edge states and their controllability. It was found that the edges with exciton dissociation ability are triggered by the loss of BA ligands. Thereby, the edge states can be eliminated by adding additional BA cations and regenerated by BA‐to‐MA cation exchange 3) nanoplatelets (NPs) with gradient bandgap have been fabricated using chemical vapor deposition followed with bromide–iodide substitution by exposure FAPbI3 to FABr vapor. In such gradient bandgap structures, photogenerated carriers can effectively transfer and emit in the low bandgap region by energy funnelling. Moreover, spatially resolved modulation of the fluorescence of this special NPs can be realized by femtosecond direct laser writing (fs‐DLW). Since the NPs possess a gradual bromide–iodide composition along the depth, the replacement of iodide ions by bromide ions can be activated under a controlled laser pulse and fluorescence is thus modulated from red to green.Energy funneling refers to a cascaded energy transfer/carrier diffusion in a funnel‐like gradient bandgap profile.92 Com They observed four distinctive peaks in the transient absorption (TA) spectrum and steady‐state absorption spectrum in 2D PEA lead iodide RPPs of 〈n〉 = 3. The four peak positions are in good agreement with bandgaps of 2D RPPs with different n values. Therefore, the results suggest that the solution‐processed 2D RPP films are not single‐phase, but rather consist of a collection of grains exhibiting a variety of n values. In other words, a typical film with an expected n value of 〈n〉 = 3 also contain n = 2, 4, and 5 phases in significant proportions. As well established, the bandgaps of these grains decrease as the n values increase. As illustrated in Figure Regarding multilayered 2D LHPs, the energy funnelling was pioneeringly proposed by Yuan et al.29 Then〉 = 3 and 〈n〉 = 5 show substantially intensive PL with respective PL QY values of 10.1% and 10.6% under the a low excitation of 6 mW cm−2. 2D RPP LEDs with a high EQE of 8.8% and a bright radiance of 80 W sr−1 m−2 were built based on this unique energy funneling process.Importantly, the unique energy funneling leads to the concentration of carriers. In this scenario, only the subset of trap states appearing in the lowest‐energy inclusions need to be filled and there is an increased local excitation intensity within small bandgap grains, enabling radiative recombination successfully outcompetes defect trapping and nonradiative recombination, which is absent in 3D perovskites. Hence it is beneficial for high‐efficiency LEDs. Consequently, 2D RPP films with 〈 mW cm−2.29 2D 10H7CH2NH2) lead iodide ((NMA)2PbI4) RPPs. Photo‐induced changes in TA spectra (ΔA) of the 〈n〉 = 2 RPPs show photobleaching bands at 2.18, 1.95, and 1.64 eV, corresponding to excitonic absorption of domains with n = 2, 3, and 4 respectively. The evolution of TA bands shows that the excitons funnel to the large‐n domains with bandgap of around 1.64 eV after a short time delay. Normalized bleaching kinetics at 2.18, 1.95, and 1.64 eV following excitation at 400 nm suggest a fast exciton localization time and a relatively slow exciton localization time, indicating that a substantial portion of the photogenerated excitons from the dominant domains of n = 2 will be localized to large‐n domains within 0.5 ps. Subsequently, a slower decay also matches well with the relative slower formation of the large‐n QWs photobleaching. This relatively slower exciton localization time is fitted to be about 50 ps. Similar carrier concentration with enhanced PL intensity has been observed in different 2D RPP polycrystalline films with organic spacers of alkyl ammonium, phenylethylammonium, 1‐naphthylmethylammonium, and phenylbutylammonium. Moreover, the directional exciton transfer along the bandgap cascade from small n to large n phases, converging excitations at the lowest energy phases, resulting in the population inversion for stimulated emission. Thus, optically pumped laser with low thresholds (27–31 µJ cm−2) has been fabricated based on (BA)2(FA)n−1PbnBr3n+1 with average 〈n〉 = 3.Almost at the same period, energy funneling was also reported in multilayered 1‐naphthylmethylamine (NMA = CI4) RPPs.35 Pho3.2.2 which relies on the distance, spectral overlap, and dipole orientation between donor and acceptor. Whereas, the CT mechanism suggests the photogenerated charge carriers cascade along with the “ladder‐like” energy levels then ultimately accumulate on the domains with the narrowest bandgap  and Förster resonance energy transfer (FRET) are the two most possible pathways for the energy funneling. For an energy transfer, the energy cascades from wide‐bandgap domains to the narrow‐bandgap domains via virtual photon at ultrafast timescale (within a timeframe of ps),99 whip Figure . octahedra, the dimensionality of electronic structures reduces, leading to the localization of carriers. The effective masses of carriers are larger than those of the 3D counterparts. The unique excitonic properties, with large exciton binding energies and high oscillator strengths, enable strong electron–phonon coupling, and polarons of 2D perovskites. In recent years, 2D RPPs with different structures are synthesized and diverse novel photophysics have been successively excavated in 2D perovskites, which are highlighted in this review to inspire future developments of solar cells, LEDs, photodetectors, lasers, spintronics, quantum information, integrated photonic chips, and beyond.2D RPPs with unique photophysics have recently gained growing interest as candidates for the next generation optoelectronic devices for their improved stabilities under ambient conditions. However, current studies and review on 2D RPPs are mainly focused on their linear photophysics properties, with relatively rare reports on their quasiparticle dynamics, anisotropy, transient photophysics, nonlinear, and spin‐related properties. Due to the absence of connectivity between the [BXn values to pursuit a higher emission efficiency. For another example, as reviewed in Section 2PbI4 perovskites are even converse. Therefore, the existence of Rashba effect in specific 2D RPPs is still a controversy. Moreover, the impact of Rashba effect on the carrier dynamics and the detailed origins of the observed Rashba effect are still unclear. There is still a lack of effective approaches to modulate the amplitude of Rashba splitting. Therefore, more investigations on the photophysics are still highly desirable to clarify these controversies.The research on photophysics of 2D RP perovskites is still in their infancy although significant efforts and progresses have been made. There are still many debates that required further clarifications. For example, the energy funneling effect plays a critical role on the high‐efficient light emission. However, as discussed in Section Unlike the conventional inorganic QWs, the organic cationic ligands in the 2D RPPs can be flexibly modified. The excitons are confined within the inorganic layers, due to the energetic barriers of low dielectric screening from the surrounding organic spacers. Such quantum confinement effect including band structure, exciton binding energy, and exciton recombination rate can be regulated by changing the organic cationic ligands with different lengths, dielectric constants, and stacking order. Moreover, structural symmetry of the 2D RPPs can be controlled by introducing chiral organic cationic spacers or aligning the dipolar organic cationic spacers, so that Rashba effect, nonlinear optical properties, spin‐selective optical Stark effect can be introduced. The design of organic sites has afforded a versatile platform for the modulation and functionalization of the 2D RPPs. Therefore, more future research efforts could be devoted to engineering the organic cationic ligands.n, or with other 2D atomic layers, which will boost the optoelectronic performances. Moreover, the chiral 2D RPPs have shown prospect as spintronic semiconductors. The function of chirality by organic cationic spacers, combining with the excellent optoelectronic properties, will increasingly attract interest in the field of spintronics. Spin‐polarized excitons generated in chiral 2D RPPs might be utilized to construct the optically controlled “spin‐torque” switches, which will revolutionize future quantum information technologies, such as quantum computing, nonvolatile memory devices, and photonic chips etc. The spin‐related optical behaviors of chiral 2D perovskites deserve more attention in the future. It is of great significance to promote their untapped potential beyond LEDs and photovoltaics.In terms of functional devices, controllable carrier/exciton/energy transport may be designed by heterojunctions of 2D RPPs with different The authors declare no conflict of interest.


The high energy density of room temperature (RT) sodium–sulfur batteries (Na‐S) usually rely on the efficient conversion of polysulfide to sodium sulfide during discharging and sulfur recovery during charging, which is the rate‐determining step in the electrochemical reaction process of Na‐S batteries. In this work, a 3D network (Ni‐NCFs) host composed by nitrogen‐doped carbon fibers (NCFs) and Ni hollow spheres is synthesized by electrospinning. In this novel design, each Ni hollow unit not only can buffer the volume fluctuation of S during cycling, but also can improve the conductivity of the cathode along the carbon fibers. Meanwhile, the result reveals that a small amount of Ni is polarized during the sulfur‐loading process forming a polar Ni—S bond. Furthermore, combining with the nitrogen‐doped carbon fibers, the Ni‐NCFs composite can effectively adsorb soluble polysulfide intermediate, which further facilitates the catalysis of the Ni unit for the redox of sodium polysulfide. In addition, the in situ Raman is employed to supervise the variation of polysulfide during the charging and discharging process. As expected, the freestanding S@Ni‐NCFs cathode exhibits outstanding rate capability and excellent cycle performance. 2Sx. Benefiting from the structural and compositional advantages, as‐assembled batteries show outstanding rate capability and improved cycling ability.A network‐like Ni‐NCFs composite (nitrogen‐doped carbon fibers implanted with Ni) with excellent conductivity and catalysis is synthesized as host for Na‐S batteries. Among it, the Ni hollow units both can buffer the volume fluctuation of S and accelerate the redox kinetics of Na Since the first commercialization of the LiCoO2Sx, 4 ≤ x ≤ 8) intermediate is another question, which will eventually undergoes redox reactions to form lower‐order polysulfides (Na2S2 and Na2S) on the anode surface, finally leading to a significant reduction in capacity. In addition, Na has a lower reactivity with S than that of Li due to its larger ion radius.The development of the conventional Na‐S battery can be traced to the 1960s. Generally, its actual operating temperature at around 270 to 350 °C with molten Na/S as electrodes and a solid beta‐alumina as electrolyte is now commercially available.2, MnO2, Fe3O4),2, Co9S8).2S.Against this background, for an anticipant cathode of Na‐S batteries, the sulfur host needs to meet the following requirements generally to alleviate the performance deterioration: first, the host should possess desirable electronic conductivity to counteract that of S; besides, abundant pore structure or hollow structure is needed to buffer the volume expansion of S and physically restrict the shuttle of polysulfide; finally, as proved by reported literatures that the polar material with intrinsic sulfiphilic property is necessary because of the excellent chemical adsorption for soluble polysulfide. Therefore, several homologous hosts have been explored to improve the electrochemical performances of RT Na‐S and Li‐S batteries, such as heteroatom‐doped porous carbon,Figure2 atmosphere, during which the NiO is reduced to Ni while the PAN is carbonized to carbon fiber. Finally, after a vacuum heating process, the obtained Ni‐NCFs are employed as substrate for loading S to get S@Ni‐NFCs composite.In this work, we designed and synthesized a 3D host consisting of carbon fiber concatenated nickel hollow sphere for accelerating the electrochemical kinetics of RT Na‐S batteries. The typical preparation process is schematically depicted in In our proposed unique structure Figure b, each n23BTC) and Ni2+ is first characterized by field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM) as shown in Figure S1a–c in the Supporting Information. They are presented as intact and solid spheres with a smooth surface and the diameter of 1.3–1.5 µm. The X‐ray diffraction (XRD) pattern as exhibited in Figure S1d in the Supporting Information agrees well with the reported literatures.2 g−1 and 0.15 cm3 g−1, respectively. Along with the pore diameter distribution curve in the inset of Figure S3b in the Supporting Information, it can be seen that the macropores and mesopores mainly exist in NiO hollow spheres.The morphology of the Ni‐MOF precursor from the coordination of 1,3,5‐benzenetricarboxylic acid , (2 0 0) and (2 2 0) lattice planes of metallic Ni (JCPDS No. 04‐0850), respectively, while a broad diffraction peak located at 2θ = 26° is assigned to (0 0 2), the plane of partially graphitized carbon.−1 are related to the defective and graphitic carbon, respectively, while the 2 D band at around 2780 cm−1 is associated with highly crystalline carbon material.ID/IG value and wide 2 D band suggest a low graphitization degree of the carbon in Ni‐NCFs composite, which is beneficial for the insertion of sodium ions during cycling. The carbon content in the Ni‐NCFs composite is calculated to be about 29% based on the thermogravimetric analysis  present a lower BET specific surface area and pore volume (22.7 m2 g−1 and 0.13 cm3 g−1). It is observed that the specific surface area of Ni‐NCFs is larger and the pore structure is more abundant, which may result from the plentiful gaps and spaces offered by joints of hollow spheres and carbon fibers.Subsequently, the NiO hollow spheres are mixed with PAN in dimethylformamide solution to fabricate the NiO‐PAN interconnected frameworks by electrospinning. As shown in Figure S4a,b in the Supporting Information, each NiO sphere is connected in series and well wrapped by PAN fibers forming a 3D network. According to the XRD pattern in Figure8 and NiS2 can also be observed. The TEM image in Figure 2 g−1 and 0.03 cm3 g−1) decrease obviously when compared with the pristine Ni‐NCFs (35.6 m2 g−1 and 0.09 cm3 g−1). Above results suggest that the S is successful diffused into the Ni‐NCFs. Meanwhile, the existence of some mesopores after the loading of S may serve as an accommodation for the volume expansion of S during cycles.The S@Ni‐NCFs cathode is prepared by melting diffusion of S into the Ni hollow spheres and N‐doped carbon fibers of Ni‐NCFs at 155 °C. 3/2) and 855.3 eV (Ni 2p1/2) are assigned to metallic Ni, while the peaks at binding energies of ≈873.2 eV (Ni 2p3/2) and 869.5 eV (Ni 2p1/2) correspond to the Ni2+ due to the partial oxidation of Ni on the surface of the product. In addition, a peak at the binding energy of 860.7 eV is derived from the satellite peak of Ni.3/2 and S 2p1/2, respectively. Compared with pure S (at ≈163.9 and ≈165.1 eV), the binding energies for both S 2p3/2 and S 2p1/2 decrease, which is well matched with typical S 2p spectrum of Ni—S reported by Niu et al. and our previous report.To further compare the superficial bonding information of Ni‐NCFs and S@Ni‐NCFs, the X‐ray photoelectron spectroscopy (XPS) measurement is performed. As shown in Figure Figure8 to soluble long‐chain polysulfide , while the peak at around 1.18 V results from the subsequent solidification of Na2Sn to short‐chain polysulfide  and the formation of solid electrolyte interphase film. The broad peak at around 0.62 V may stem from the sodiation of the small quantity of NiS2.8 emerge at 259 and 456 cm−1.8 becomes weak gradually and other two new peaks originated from Na2S6 and Na2S4 appear at about 374 and 473 cm−1, respectively. When the discharge process continues to 1.2 V, the peak of Na2S at about 428 cm−1 is observed and its strength increases continuously until fully discharged to 0.5 V.8 always exist throughout the whole discharge process, which suggests that the S8 is not completely reduced due to its poor electronic conductivity and limited reactivity. Afterward, the subsequent charge as an opposite process shows three anodic peaks at near 1.65, 1.95, and 2.35 V in the CV curves of Figure 2, while the other two peaks are ascribed to the oxidation of Na2S to short‐chain Na2Sx (1.95 V) and the successive conversion of Na2Sx to long‐chain sodium polysulfide and finally to S (2.35 V).−1 emerged in the Raman spectrum indicates the formation of Na2S6.2S can be detected, revealing that the reaction is partially reversible. However, during the subsequent scan, the cathodic and anodic peaks shift toward higher and lower potential, respectively.The as‐obtained S@Ni‐NCFs freestanding electrode is used as cathode against sodium to evaluate its electrochemical properties and energy storage mechanism in Na‐S batteries. The cyclic voltammetry (CV) and in situ Raman are measured to trace the changes of sulfur species during the discharge/charge process. As shown in −1), the specific capacity of the S@NCFs composite decreases rapidly from 593 to 31 mAh g−1. By contrast, the S@Ni‐NCFs cathode can deliver much higher average reversible specific capacities of about 738.7, 565.6, 481.1, 401.9, 311.1, 249.8, and 181.7 mAh g−1 at 0.2 C, 0.3 C, 0.5 C, 1.0 C, 2.0 C, 3.0 C, and 5.0 C, respectively. After that, when the current density is switched back to 0.2 C, the capacity can recover to 578.5 mAh g−1 with the capacity retention of ≈78.3%, exhibiting an improved rate performance. The typical galvanostatic discharge/charge profiles of S@Ni‐NCFs at different current densities are displayed in Figure 2, simultaneously. To investigate the possible sodium storage performance of NiS2 in the S@Ni‐NCFs composite, the S is removed intentionally by CS2 to obtain Ni‐NCFs/S composite. As shown by the HRTEM image of Ni‐NCFs/S , the lattice fringes with interplanar spacing of 0.20 and 0.23 nm exist simultaneously, which are consisted with (111) and (211) planes of Ni and NiS2, respectively. Besides, the fast Fourier transform image in the illustration of Figure S9 in the Supporting Information belongs to the (211) plane of NiS2 as well, further confirming the presence of NiS2 in Ni‐NCFs/S composite. Figure S10 in the Supporting Information displays the electrochemical performance of Ni‐NCFs/S and Ni‐NCFs electrode. After 200 cycles at 0.5 C, the capacity of Ni‐NCFs/S electrode rapidly decays from 103.0 to 31.8 mAh g−1, while the capacity of Ni‐NCFs electrode remains at about 16 mAh g−1. Above results demonstrate that the capacity contribution from NiS2 is negligible even though NiS2 does exist in S@Ni‐NCFs composite, but it is not contributed much capacity during charge and discharge processes due to the low content. In addition, the S@Ni‐NCFs electrode presents superior cycling stability than that of S@NCFs as shown in Figure −1, which is much higher than that of S@NCFs (only ≈306 mAh g−1). After 270 cycles, the capacity of S@Ni‐NCFs can retain ≈233 mAh g−1 along with an attenuation rate of 0.17% per cycle and the Coulombic efficiency keeps over 90%. In contrast, the capacity of S@NCFs drops quickly to 71 mAh g−1 after 100 cycles under the same condition with attenuation rate as high as 0.77% per cycle. The remarkable difference in performance is mainly caused by the distinction of their interfacial electrochemical kinetics, which is closely related with chemisorption ability and electronic conductivity of hosts as reported by Zhang et al.Figure 2S. Obviously, the deposition amount on the surface of S@Ni‐NCFs is much less than that of S@NCFs due to the catalytic action of Ni. In addition, only a small quantity of nickel hollow spheres in the S@Ni‐NCFs electrode still remains intact. Thus, it can be concluded that the attenuation of the capacity mainly originates from the collapse of electrode microstructure and the loss of active substances caused by the deposition of Na2S. Moreover, the electrochemical performance of the S@Ni‐NCFs electrode with a relatively high sulfur loading of 45% is satisfactory as well . The discharge capacity at 0.2 C is as high as 703 mAh g−1 , even though the rapid capacity decays at high current rate and long‐term cycling because of the worse conductivity.To explore the reasons of capacity decay, the FESEM images of S@NCFs and S@Ni‐NCFs after cycling are shown in Figure S13 in the Supporting Information. There is a deposited layer appears on the surface of both cathodes, which should be nonconductive Na2S6 electrolyte. As shown in Figure2S6, it can be clearly observed that the Ni‐NCFs electrode presents a larger current response than that of the pristine NCFs electrode, demonstrating the helpful effect of metallic Ni to accelerate the electrochemical reactions of sodium polysulfides. Besides, as shown in Figure 2S, thus slowing down reaction kinetics. The accelerated dynamics of the Ni‐NCFs electrode can also be directly reflected by the CV and charge/discharge curves of as‐assembled Na‐S batteries as displayed in Figure 2S, whereas pure NCFs cannot. Therefore, taking consideration of the experimental data and the theoretical analysis, the adsorption and conversion process of sodium polysulfide on the surface of the Ni‐NCFs can be briefly depicted by Figure To verify the above claim, the catalytic effect of Ni‐NCFs substrate on polysulfide transformation is indirectly probed by the CV of symmetric cell with Na3−1 at 0.2 C and remain 249.8 mAh g−1 at 2.0 C. After 270 cycles at 1.0 C, the capacity decay rate of S@Ni‐NCFs cathode is only about 0.17% per cycle, which is much lower than that of S@NCFs (≈0.77%). The excellent performance suggests that improving the electronic conductivity and making the best of catalysis are two important principles for the design of cathode materials of Na‐S batteries, which indicates the direction of our future efforts.In summary, a flexible and freestanding S@Ni‐NCFs cathode is successfully prepared by electrostatic spinning, subsequent carbonization, and sulfur‐loading process. Among it, the Ni hollow spheres are connected in series along with carbon fibers, which can not only contribute to the transportation of electrons, but also effectively accommodate the volume expansion of active species. Meanwhile, the catalytic effect of Ni units on the conversion of polysulfide is well demonstrated by comparing the current response and potential polarization of S@Ni‐NCFs and S@NCFs cathodes. Therefore, along with the Ni—S polar bonds and nitrogen heteroatoms, the S@Ni‐NCFs composite can inhibit the shuttle of polysulfide. As a consequence, the RT Na‐S batteries assembled with S@Ni‐NCFs deliver a high capacity of 738.7 mAh gThe authors declare no conflict of interest.Supporting InformationClick here for additional data file.


Fibrosis is characterized by fibroblast activation, extracellular matrix (ECM) accumulation and infiltration of inflammatory cells that sometimes leads to irreversible organ dysfunction. Considerable evidence now indicates that inflammation plays a critical role in the initiation and progression of organ fibrosis. S100A4 protein, a ubiquitous member of the S100 family, has recently been discovered as a potential factor implicated in fibrotic diseases. S100A4 protein is released at inflammatory site and has a certain biological function to promote cell motility, invasion, ECM remodelling, autophagy and angiogenesis. In addition, extracellular S100A4 is also a potential causation of inflammatory processes and induces the release of cytokines and growth factors under different pathological conditions. Elevated S100A4 level in patients’ serum closely correlates with disease activity in several fibrotic diseases and serves as a useful biomarker for diagnosis and monitoring disease progression. Analyses of knockout mouse models have identified a functional role of extracellular S100A4 protein in fibrotic diseases, suggesting that suppressing its expression, release or function might be a promising therapeutic strategy. This review will focus on the role of extracellular S100A4 as a key regulator of pro‐inflammatory signalling pathways and its relative biological processes involved in the pathogenesis of fibrosis. Wound maladaptation caused by chronic inflammation can result in fibrosis.S100A4 ) is a member of the S100 calcium‐binding protein family. The most well‐known function of S100A4 is to induce and promote tumour metastasis.Here, we summarize the role of extracellular S100A4 protein enhancing inflammation in the pathophysiology of fibrotic diseases  increased. Our research suggests that extracellular S100A4 or S100A4‐positive macrophages within the lung as promising targets for early clinical diagnosis or therapy of IPF. Coincidentally, another research from Zhang et al also supports our view that S100A4 is produced and secreted by M2 polarized alveolar macrophages and enhances the proliferation and activation of lung fibroblasts.+CD11b+F4/80+ macrophages and M2 macrophages belong to the same group of cells remains to be confirmed by further research.In pulmonary fibrosis, fibroblasts are largely responsible for the production and deposition of interstitial collagen and other ECM molecules.Rheumatoid arthritis (RA) is characterized by inflammatory infiltration, activated fibroblasts and tissue remodelling.The variety of diseases and S100A4‐producing cell types leave many open questions, but clearly place extracellular S100A4 as a major contributor to the progression of fibrosis in chronic inflammatory diseases and make it be a candidate therapeutic target for antifibrotic treatment.33.1Like other members of the S100 family, the S100A4 protein exists in both intracellular and extracellular. The intracellular S100A4 protein is mainly localized in the cytoplasm and nucleus. Changes in intracellular S100A4 function depend on the morphology of the protein and are pre‐conditioned through the interaction and regulation of multiple intracellular protein targets located in different cell compartments. As the role of intracellular S100A4 has been widely described, we solely focus on extracellular S100A4 and related mechanism .ECM is a highly dynamic structure that is present in all tissues and undergoes controlled remodelling continuously. In fact, dysregulated ECM remodelling is linked to pathological conditions and may aggravate disease progression. For instance, abnormal ECM deposition and stiffness are noticed in fibrosis and cancer,In addition to the above functions, extracellular S100A4 also shows the ability to inhibit autophagy in lung cancer cells through activating β‐catenin signalling pathway in a RAGE‐dependent manner.Besides, a recent study found that binding of extracellular S100A4 to embigin (a transmembrane glycoprotein belonging to the immunoglobulin superfamily) mediated prostate cancer progression by inhibition of adenosine monophosphate‐activated protein kinase (AMPK) activity, activation of nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB), MMP‐9 and mammalian target of rapamycin complex 1 (mTORC1) signalling, and inhibition of autophagy, which increased prostate cancer cell motility.3.3With the exception of embryos cell death caused by tissue damage always leads to inflammation. Inflammation is involved both in tissue regeneration and development of fibrosis.The S100A4 protein has been confirmed to be expressed in multiple cell types of lymphoid and myeloid lineages, including macrophages, neutrophils, mast cells and memory T cells, indicating a role of S100A4 in the regulation of immune cells.According to the existing research on the biological characteristics of extracellular S100A4, it can be categorized as an effective DAMP protein, but its specific functions and cellular effects need to be further explored in the future. Extracellular S100A4 plays a substantial role in modulation of the immune system in many different ways also indicating that this protein could be a key player in a multitude of fibrotic diseases where the inflammatory pathway(s) play a large contributing role.3.4S100 proteins form heterodimers. These complexes display different affinities to target protein, depending on their oligomerization state.D≈0.5 μM).D = 138 nMThe interaction of S100B with RAGE has been demonstrated in many cell‐types. In RAGE overexpressing myocytes, S100B (100 nM) resulted in increases in VEGF mRNA, VEGF protein, VEGF secretion and activation of the transcription factor NF‐κB.4To date, several studies have proposed speculation as to whether extracellular S100A4 could be a prognostic biomarker for fibrotic diseases. Firstly, Yan et al clarified diagnostic accuracy of serum S100A4 level in patients with chronic hepatitis B (CHB).5Considerable progress has been made in the specific blockade of cytokines or their downstream signalling pathways for the treatment of fibrotic diseases; however, these therapies often have adverse effects; a substantial number of patients do not respond satisfactorily and long‐lasting remission is generally not achieved after medication is withdrawn. An urgent need still exists for innovative therapeutic approaches. Elevated extracellular S100A4 level contributes to the development and progression of many fibrotic diseases, implying that extracellular S100A4 could be a potential therapeutic target for treating fibrosis pathologies. In addition, extracellular S100A4 can function as a DAMP protein, thereby triggering pro‐inflammatory responses via binding to PRRs. Therefore, a wide range of treatment strategies need to be proposed, including inhibition of S100A4 protein expression and secretion, blocking S100A4 protein‐receptor interactions and reducing inflammatory response induced by S100A4 protein Figure .+F4/80+ macrophages.Several studies are currently available that confirm the effective blocking of extracellular S100A4 protein expression in vivo. The utilization of specific hairpin RNA to decrease the expression of S100A4 in CD11b‐positive macrophages from mice with liver fibrosis led to a reduction in the expression of α‐SMA and collagen deposition.Experimental data indicate that targeting PRRs might be a therapeutic option in fibrotic diseases. The TLR4 antagonist CRX‐526, a synthetic lipid A mimetic molecule, also known as an aminoalkyl‐glucosaminide‐phosphate (AGP), has therapeutic potential to attenuate renal injuries and slow the progression of advanced diabetic nephropathy in wild‐type and endothelial nitric oxide synthase (eNOS) knockout mice.Furthermore, small‐molecule inhibitors have also been developed that specifically block the interaction of S100A4 with target proteins. Simvastatin was reported to up‐regulate the expression of Annexin A10 protein but down‐regulate S100A4 expression.6The multifaceted roles of S100A4 in the development of cancer have been identified in plenty of studies.Of course, we have to admit that there are still many issues to be resolved regarding extracellular S100A4. S100A4 can act degenerative or regenerative; it can be a cause or result of fibrotic disease progression. These questions are so far not answered comprehensively. The multifunctional character of S100A4, functioning intra‐ and extracellularly, may impede its suitability as a therapeutic target. S100A4 in‐ and outside of cells display mediate cell movement via various mechanisms, however, cardio‐ and neuroprotective effects may depend solely on extracellular S100A4. That being a guess, an up‐regulation in intracellular S100A4 protein may lead to more S100A4 release into extracellular, but only after injury or disease. In order to have a better understanding of these mechanisms, it is necessary for us to further understand how S100A4 is released and how S100A4 interacts with specific or promiscuous receptors. Since extracellular S100A4 acts as a DAMP protein, it is a worthwhile problem for us to discuss whether its release is associated with necrosis, pyroptosis or activation of inflammasome during fibrosis in the future work.We think that future research could focus on the following major topics: (i) Verification of extracellular S100A4 as a marker in early fibrosis development and predicting treatment responses; (ii) Definition of the specific mechanisms underlying extracellular S100A4 up‐regulation in fibrosis; (iii) Definition of the functional overlaps and differences for extracellular S100A4 in tumorgenesis, neoangiogenesis and fibrotic diseases; (iv) Evaluation and validation of targeting extracellular S100A4 through S100A4 specific compounds for the therapy in pre‐clinical and clinical settings.The authors confirm that there are no conflicts of interest.Q.Z conceived and designed the study. LZ LY and LS collected and analysed experiment data. LZ wrote and prepared the original draft.