{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T18:13:17Z","timestamp":1793211197887,"version":"4.5.0"},"reference-count":40,"publisher":"Baishideng Publishing Group Inc.","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["World J Gastroenterol"],"abstract":"BACKGROUND<\/jats:p>\n Chemoresistance significantly limits the therapeutic efficacy of neoadjuvant chemotherapy (NACT) in advanced gastric cancer (AGC). There is an urgent need to identify robust biomarkers predictive of NACT response and to elucidate the molecular mechanisms that drive resistance. In this study, we systematically assess whether intercellular adhesion molecule 2 (ICAM2 ) predicts NACT response in patients with AGC and delineate its mechanistic role in chemoresistance.<\/jats:p>\n AIM<\/jats:p>\n To investigate the predictive significance and mechanistic role of ICAM2 in mediating 5-fluorouracil (5-FU) resistance in gastric cancer (GC).<\/jats:p>\n METHODS<\/jats:p>\n Real-time PCR, Western blotting, enzyme-linked immunosorbent assay, and immunohistochemistry were conducted to assess alterations in ICAM2 expression between 5-FU-sensitive and -resistant GC cells as well as in AGC patient samples. Cytotoxicity assays, colony formation, flow cytometry, analyses of apoptosis-related proteins, and xenograft experiments were employed to elucidate the role of ICAM2 in mediating chemoresistance. The mechanism underlying ICAM2 -mediated chemoresistance was further explored through RNA sequencing (RNA-seq), nuclear-cytosolic fractionation, co-immunoprecipitation, luciferase reporter, and chromatin immunoprecipitation assays.<\/jats:p>\n RESULTS<\/jats:p>\n Low ICAM2 expression correlated significantly with poor NACT response, advanced tumor stage, worse differentiation, and reduced overall survival and disease-free survival in AGC patients. Pre-NACT serum ICAM2 demonstrated high predictive accuracy (area under the curve = 0.876) in discriminating chemotherapy responders from non-responders. Mechanistically, ICAM2 knockdown conferred 5-FU resistance through two intertwined processes: Inhibition of caspase-dependent apoptosis and promotion of immunosuppressive M2 macrophage polarization within the tumor microenvironment. At the molecular level, loss of ICAM2 activated the TGF-\u03b2\/Smad pathway, leading to transcription factor SP1-mediated pleiotrophin (PTN) upregulation. Elevated PTN further enhanced GC cell survival and may contribute to M2 macrophage polarization, thereby amplifying chemoresistance. Importantly, targeted inhibition of TGF-\u03b2 signaling reversed ICAM2-associated chemoresistance in both cell culture and xenograft models.<\/jats:p>\n CONCLUSION<\/jats:p>\n Our study highlights the clinical impact of ICAM2 downregulation predicting poor outcome and NACT response in AGC patients, and reveals a novel ICAM2\/TGF-\u03b2\/Smad\/SP1\/PTN signaling mediating 5-FU resistance in GC.<\/jats:p>","DOI":"10.3748\/wjg.v32.i5.115301","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T07:00:36Z","timestamp":1769497236000},"source":"Crossref","is-referenced-by-count":2,"title":["ICAM2<\/i>\n loss drives 5-fluorouracil resistance\n via<\/i>\n TGF-\u03b2\/Smad\/SP1\/PTN-dependent apoptosis evasion and macrophage remodeling in gastric 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