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MFSD2A suppresses CD8+ T cell exhaustion in colorectal cancer by inhibiting ERK/p38 MAPK-PD-L1 signaling
Shu-Jiong Feng, Yi-Feng Zhou, Jian-Feng Yang, Yi-Shen Mao, Wen-Li Ruan, Xiao-Feng Zhang
Shu-Jiong Feng, Yi-Feng Zhou, Jian-Feng Yang, Yi-Shen Mao, Wen-Li Ruan, Xiao-Feng Zhang, Department of Gastroenterology, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou 310000, Zhejiang Province, China
Shu-Jiong Feng, Yi-Feng Zhou, Jian-Feng Yang, Yi-Shen Mao, Wen-Li Ruan, Xiao-Feng Zhang, Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
Shu-Jiong Feng, Yi-Feng Zhou, Jian-Feng Yang, Yi-Shen Mao, Wen-Li Ruan, Xiao-Feng Zhang, Hangzhou Institute of Digestive Diseases, Hangzhou 310000, Zhejiang Province, China
Shu-Jiong Feng, Yi-Feng Zhou, Jian-Feng Yang, Yi-Shen Mao, Wen-Li Ruan, Xiao-Feng Zhang, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
Co-corresponding authors: Yi-Feng Zhou and Xiao-Feng Zhang.
Author contributions: Feng SJ contributed to conceptualization and designed the study; Zhou YF conducted the experiments and provided software support; Yang JF and Mao YS performed data analysis; Ruan WL conducted investigations; Zhang XF provided methodological support and conducted data organization; Zhou YF and Zhang XF contributed equally as co-corresponding authors. All authors contributed to the writing-draft, writing-revision, and approved to submit the final version.
Supported by Medical and Health Science and Technology Planning Project of Zhejiang Province, No. 2025KY1188; and The Key Research and Development Program of Zhejiang Province, No. 2023C03054.
Institutional animal care and use committee statement: All animal experiments were conducted according to a protocol approved by the Institutional Animal Care and Use Committee of the Zhejiang Center of Laboratory Animals, No. ZJCLA-IACUC-20020244.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
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.
Corresponding author: Xiao-Feng Zhang, Department of Gastroenterology, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, No. 261 Huansha Road, Hangzhou 310000, Zhejiang Province, China.
zhangxiaofengsy@sina.com
Received: October 17, 2025
Revised: January 10, 2026
Accepted: March 12, 2026
Published online: May 28, 2026
Processing time: 218 Days and 5.1 Hours
BACKGROUND
Although immune checkpoint inhibitors have shown remarkable efficacy in multiple malignancies, their clinical benefit remains limited in the majority of colorectal cancers (CRC). This resistance is attributed to CD8+ T cell exhaustion. The extracellular signal-regulated kinase (ERK)/p38 mitogen-activated protein kinase (p38 MAPK) pathway plays a pivotal role in both tumor progression and immune evasion, but its upstream regulators in CRC are unclear. Major facilitator superfamily domain containing 2A (MFSD2A), a recognized tumor suppressor and lipid transporter, has not been well characterized in terms of its immunological functions, suggesting its function as a regulator of this critical immunosuppressive axis in CRC.
AIM
To define the role of MFSD2A in CRC and elucidate its novel mechanism in alleviating CD8+ T cell exhaustion through the ERK/p38 MAPK-programmed death-ligand 1 axis.
METHODS
CRC cell lines with stable MFSD2A overexpression or knockdown were established via lentiviral transduction. In vitro assays were conducted to assess tumor cell proliferation, apoptosis, migration, and invasion. Co-culture systems incorporating CD8+ T cells were employed to evaluate cytotoxic activity, expression of exhaustion markers (programmed cell death protein 1 and cytotoxic T lymphocyte-associated antigen 4), and cytokine secretion. Epidermal growth factor was used in rescue experiments to reactivate ERK/p38 MAPK. The tumor-suppressive and immunomodulatory effects of MFSD2A were further validated in vivo using a subcutaneous tumor model.
RESULTS
MFSD2A expression was significantly downregulated in CRC cells compared with normal colonic epithelial cells. Overexpression of MFSD2A markedly inhibited proliferation, migration, and invasion while promoting apoptosis in MC38 cells, whereas MFSD2A knockdown exacerbated malignant phenotypes in Caco-2 cells. Mechanistically, MFSD2A suppressed ERK and p38 MAPK phosphorylation, reduced programmed death-ligand 1 expression in tumor cells, and decreased programmed cell death protein 1 and cytotoxic T lymphocyte-associated antigen 4 expression in co-cultured CD8+ T cells. These effects were reversed by epidermal growth factor-mediated reactivation of ERK/p38 MAPK signaling. In vivo, MFSD2A overexpression significantly inhibited tumor growth, reduced Ki67 expression, attenuated ERK/p38 MAPK activation and CD8+ T cell exhaustion, and concomitantly enhanced CD8+ T cell infiltration within the tumor microenvironment.
CONCLUSION
MFSD2A suppresses CRC progression by inhibiting ERK/p38 MAPK signaling, thereby reducing CD8+ T cell exhaustion and enhancing antitumor immunity. These findings identify MFSD2A as a promising immunotherapeutic target for CRC.
Core Tip: Major facilitator superfamily domain containing 2A, a known tumor suppressor and lipid transporter, is identified as a novel immune regulator in colorectal cancer. Major facilitator superfamily domain containing 2A exerts dual antitumor effects by suppressing the extracellular signal-regulated kinase/p38 mitogen-activated protein kinase-programmed death-ligand 1 signaling axis, thereby alleviating CD8+ T cell exhaustion and providing a potential strategy to overcome immunotherapy resistance in colorectal cancer.
