ICAM2 loss drives 5-fluorouracil resistance via TGF-β/Smad/SP1/PTN-dependent apoptosis evasion and macrophage remodeling in gastric cancer

Sep 23, 2026

Uploaded by James

Chemoresistance limits the efficacy of neoadjuvant chemotherapy (NACT) in advanced gastric cancer, creating an urgent need for predictive biomarkers and mechanistic insight. This study evaluates whether intercellular adhesion molecule 2 (ICAM2) predicts NACT response and how ICAM2 loss promotes resistance to 5-fluorouracil. Using molecular assays and xenograft models, results link low ICAM2 to poor NACT response, advanced disease, worse survival, and TGF-β/Smad-SP1/PTN-driven apoptosis evasion with macrophage remodeling.

LanguageEnglish

CategoryHealthcare

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Pages24

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| W | J | G | World Journal of
Gastroenterology | | --- | --- | --- | --- | Submit a Manuscript: [https://www.f6publishing.com](https://www.f6publishing.com) World J Gastroenterol 2026 February 7; 32(5): 115301 DOI: 10.3748/wjg.v32.i5.115301 ISSN 1007-9327 (print) ISSN 2219-2840 (online) ORIGINAL ARTICLE Basic Study ICAM2 loss drives 5-fluorouracil resistance via TGF-β /Smad/SP1/PTN-dependent apoptosis evasion and macrophage remodeling in gastric cancer Xiao-Cheng Tang, Zi-Jian Chen, Chun-Yu Chen, Jun Qiu, Jin-Tuan Huang, Rong-Chang Tan, Wei-Yao Li, Hao Chen, Zu-Li Yang Specialty type: Gastroenterology and hepatology Provenance and peer review: Unsolicited article; Externally peer reviewed. Peer-review model: Single blind Peer-review report’s classification Scientific Quality: Grade A, Grade A Novelty: Grade B, Grade B Creativity or Innovation: Grade B, Grade B Scientific Significance: Grade A, Grade A P-Reviewer: Arslan HE, MD, Türkiye; Chen X, Associate Professor, China Received: October 16, 2025 Revised: November 13, 2025 Accepted: December 8, 2025 Published online: February 7, 2026 Processing time: 106 Days and 6.5 Hours Xiao-Cheng Tang, Zi-Jian Chen, Chun-Yu Chen, Jun Qiu, Jin-Tuan Huang, Rong-Chang Tan, WeiYao Li, Hao Chen, Zu-Li Yang, Department of Gastric Surgery Section 2, Department of General Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, Guangdong Province, China Co-first authors: Xiao-Cheng Tang and Zi-Jian Chen. Co-corresponding authors: Hao Chen and Zu-Li Yang. Corresponding author: Zu-Li Yang, Professor, Chief Physician, Department of Gastric Surgery Section 2, Department of General Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, No. 26 Yuancun Erheng Road, Guangzhou 510655, Guangdong Province, China. [yangzuli@mail.sysu.edu.cn](yangzuli@mail.sysu.edu.cn) Abstract BACKGROUND 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. AIM To investigate the predictive significance and mechanistic role of ICAM2 in mediating 5-fluorouracil (5-FU) resistance in gastric cancer (GC) . METHODS 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- [https://dx.doi.org/10.3748/wjg.v32.i5.115301](https://dx.doi.org/10.3748/wjg.v32.i5.115301) 1 February 7, 2026 Volume 32 Issue 5 Tang XC et al. ICAM2 loss drives 5-FU resistance seq), nuclear-cytosolic fractionation, co-immunoprecipitation, luciferase reporter, and chromatin immunoprecipitation assays. RESULTS 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 microenvironmen

FAQs

What is the study’s main objective regarding ICAM2 in advanced gastric cancer?

To determine whether ICAM2 predicts neoadjuvant chemotherapy response and to define the mechanism by which ICAM2 mediates 5-fluorouracil resistance in gastric cancer.

How did the researchers assess ICAM2 and 5-FU resistance?

They used real-time PCR, Western blotting, ELISA, and immunohistochemistry to compare ICAM2 levels between 5-FU-sensitive and resistant cells and patient samples, alongside cytotoxicity, colony formation, flow cytometry, apoptosis-protein analyses, and xenograft experiments.

What mechanism links ICAM2 loss to chemoresistance?

ICAM2 knockdown induces 5-FU resistance by inhibiting caspase-dependent apoptosis and promoting immunosuppressive M2 macrophage polarization, mediated through TGF-β/Smad signaling that activates SP1 and upregulates pleiotrophin (PTN).

Did blocking TGF-β reverse ICAM2-associated resistance?

Yes. Targeted inhibition of TGF-β signaling reversed ICAM2-linked chemoresistance in both cell culture and xenograft models.

Sep 23, 2026

Uploaded by James