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©The Author(s) 2026. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 7, 2026; 32(5): 115301
Published online Feb 7, 2026. doi: 10.3748/wjg.v32.i5.115301
Published online Feb 7, 2026. doi: 10.3748/wjg.v32.i5.115301
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, 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.
Author contributions: Tang XC and Chen ZJ contributed equally to this work as co-first authors; Yang ZL and Chen H generated the hypothesis and designed the experiments; Tang XC and Chen ZJ performed the experiments; Tang XC, Chen ZJ, Chen CY, Qiu J, Huang JT, Tan RC, and Li WY interpreted the data; Tang XC, Chen ZJ, Chen H, and Yang ZL wrote the manuscript; both Yang ZL and Chen H have played important and indispensable roles in the experimental design, data interpretation and manuscript preparation as the co-corresponding authors; all authors have read and approved the final version to be published.
Supported by National Natural Science Foundation of China, No. 81772594, No. 81802322 and No. 81902949; Natural Science Foundation of Guangdong Province, No. 2020A1515011362 and No. 2022A1515010262; and Science and Technology Program of Guangdong Province, No. 2022A0505030004.
Institutional review board statement: This study was conducted in accordance with the Declaration of Helsinki and approved by the Research Ethics Committee of the Sixth Affiliated Hospital of Sun Yat-sen University (Approval No. 2023ZSLYEC-343).
Institutional animal care and use committee statement: Animal care was provided in compliance with the Guidelines for the Care and Use of Laboratory Animals published by the National Institutes of Health. Animal experiments were approved by the Laboratory Animal Ethics Committee of the Sixth Affiliated Hospital of Sun Yat-sen University (Approval No. IACUC-2022052401).
Conflict-of-interest statement: The authors declare that they have no conflicts of interest.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: Data are available upon reasonable requests from the corresponding author.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
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 Uni
Received: October 16, 2025
Revised: November 13, 2025
Accepted: December 8, 2025
Published online: February 7, 2026
Processing time: 106 Days and 8.5 Hours
Revised: November 13, 2025
Accepted: December 8, 2025
Published online: February 7, 2026
Processing time: 106 Days and 8.5 Hours
Core Tip
Core Tip: Intercellular adhesion molecule 2 (ICAM2) is both a predictive biomarker and a mechanistic mediator of chemoresistance in advanced gastric cancer. Low serum and tissue ICAM2 identify neoadjuvant nonresponders and predict shorter survival. Functionally, ICAM2 loss increases 5-fluorouracil (5-FU) resistance by impairing caspase-dependent apoptosis and remodeling an immunosuppressive, M2-biased macrophage milieu. Mechanistically, ICAM2 loss activates TGF-β/Smad signaling, which upregulates the transcription factor SP1; SP1 then directly transactivates pleiotrophin (PTN). Targeting TGF-β suppresses PTN and restores 5-FU sensitivity in preclinical models, positioning the ICAM2/TGF-β/Smad/SP1/PTN axis as a clinically actionable pathway.