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However, the molecular mechanism underlying its regulation of macrophage polarization remains incompletely defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, we analyzed the expression of FSTL1 and its correlations with clinical prognosis and M2 macrophage infiltration using data from The Cancer Genome Atlas (TCGA) database and clinical GC tissue microarrays. In vitro experiments were conducted to validate the effect of FSTL1 on M2 polarization, and a mouse subcutaneous syngraft tumor model was established to substantiate its in vivo role. Combined analyses involving transcriptome sequencing, single-cell sequencing, and coimmunoprecipitation were performed to identify the key receptors and signaling pathways involved in FSTL1-mediated regulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The expression of FSTL1 was significantly upregulated in GC tissues, and its high expression was positively correlated with advanced clinical stage, unfavorable clinical outcomes, and increased M2 macrophage infiltration. In vitro, GC cell-derived FSTL1 markedly increased M2 polarization in both THP-1-derived M0 macrophages and monocyte-derived macrophages. This effect was significantly attenuated by\n                      <jats:italic>FSTL1<\/jats:italic>\n                      knockdown in GC cells and was restored in a dose-dependent manner by supplementation with exogenous recombinant FSTL1. In vivo,\n                      <jats:italic>Fstl1<\/jats:italic>\n                      knockdown suppressed syngeneic tumor growth, reduced the proportions of M2 macrophages and regulatory T cells, and increased the proportion of Cd8a\u207a T cells in tumor tissues. Mechanistically, FSTL1 was found to bind to its functional receptor DIP2A to induce Smad2\/3 phosphorylation, thereby promoting macrophage M2 polarization, and blockade of either DIP2A or the TGF-\u03b2 signaling pathway attenuated this effect. Notably, we identified a reciprocal positive feedback loop between GC cells and macrophages: tumor-derived FSTL1 activated the TGF-\u03b2\/Smad2\/3 pathway in macrophages to promote M2 polarization, and polarized M2 macrophages in turn secreted large amounts of TGF-\u03b2 to further upregulate FSTL1 expression in GC cells. This positive feedback loop sustained M2 macrophage enrichment in the GC microenvironment, which reinforced the immunosuppressive landscape and contributed to the progression of tumors to malignancy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings indicate that FSTL1 represents a promising immunomodulatory target and highlight its potential as a therapeutic target to reprogram the immunosuppressive microenvironment and improve the efficacy of GC immunotherapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-026-08836-1","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T14:08:11Z","timestamp":1787321291000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["FSTL1 promotes M2 polarization of macrophages via the DIP2A\u2013Smad2\/3 Axis in gastric cancer"],"prefix":"10.1186","volume":"24","author":[{"given":"Ming","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongfei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonghui","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"issue":"3","key":"8836_CR1","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","volume":"74","author":"F Bray","year":"2024","unstructured":"Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. 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The IRB waived the requirement of written informed consent from the participants because of the retrospective nature of the study, anonymization of clinical samples, and lack of additional risk to participants. The animal study was approved by the Animal Ethical and Welfare Committee of The Fifth Affiliated Hospital of Sun Yat-sen University (no. 00655) and was conducted in accordance with local legislation and institutional requirements.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"1303"}}