The mA-SFRP2-NFAT/TOX axis governs T cell exhaustion in gastric cancer.
[BACKGROUND] While immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, their efficacy in gastric cancer (GC) remains limited, underscoring the need for mechanistic biomarkers of im
APA
Liu Y, Liu G, et al. (2025). The mA-SFRP2-NFAT/TOX axis governs T cell exhaustion in gastric cancer.. Cellular oncology (Dordrecht, Netherlands), 48(5), 1553-1569. https://doi.org/10.1007/s13402-025-01096-z
MLA
Liu Y, et al.. "The mA-SFRP2-NFAT/TOX axis governs T cell exhaustion in gastric cancer.." Cellular oncology (Dordrecht, Netherlands), vol. 48, no. 5, 2025, pp. 1553-1569.
PMID
40788471
Abstract
[BACKGROUND] While immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, their efficacy in gastric cancer (GC) remains limited, underscoring the need for mechanistic biomarkers of immune evasion.
[METHODS] We analyzed mA RNA modification patterns in the TCGA-STAD cohort, stratifying patients into three subtypes. Functional assays (including CRISPR-based SFRP2 modulation, NFAT/TOX reporter systems, and ex vivo T-cell exhaustion models) were employed to dissect the m1A-SFRP2-NFAT/TOX axis.
[RESULTS] High-mA tumors exhibited an immunosuppressive microenvironment dominated by exhausted TIM-3PD-1 T cells and poor ICIs responses. Mechanistically, mA-modified transcripts stabilized SFRP2, which activated NFAT1/2-TOX signaling to drive T-cell dysfunction-independent of PD-L1 or TMB. SFRP2 overexpression induced irreversible T-cell exhaustion, while its blockade restored antitumor immunity in preclinical models.
[CONCLUSION] Our study unveils mA-dependent epitranscriptomic control of SFRP2 as a novel regulator of the NFAT/TOX-mediated immune evasion axis in GC. The mA scoring system may refine patient stratification, and targeting SFRP2 represents a promising strategy to overcome ICI resistance.
[CLINICAL TRIAL NUMBER] Not applicable.
[METHODS] We analyzed mA RNA modification patterns in the TCGA-STAD cohort, stratifying patients into three subtypes. Functional assays (including CRISPR-based SFRP2 modulation, NFAT/TOX reporter systems, and ex vivo T-cell exhaustion models) were employed to dissect the m1A-SFRP2-NFAT/TOX axis.
[RESULTS] High-mA tumors exhibited an immunosuppressive microenvironment dominated by exhausted TIM-3PD-1 T cells and poor ICIs responses. Mechanistically, mA-modified transcripts stabilized SFRP2, which activated NFAT1/2-TOX signaling to drive T-cell dysfunction-independent of PD-L1 or TMB. SFRP2 overexpression induced irreversible T-cell exhaustion, while its blockade restored antitumor immunity in preclinical models.
[CONCLUSION] Our study unveils mA-dependent epitranscriptomic control of SFRP2 as a novel regulator of the NFAT/TOX-mediated immune evasion axis in GC. The mA scoring system may refine patient stratification, and targeting SFRP2 represents a promising strategy to overcome ICI resistance.
[CLINICAL TRIAL NUMBER] Not applicable.
MeSH Terms
Humans; Stomach Neoplasms; NFATC Transcription Factors; T-Lymphocytes; Animals; Cell Line, Tumor; Tumor Microenvironment; Hepatitis A Virus Cellular Receptor 2; Signal Transduction; Mice; Immune Checkpoint Inhibitors; T-Cell Exhaustion
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