Background <p>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.</p> Methods <p>We analyzed m¹A 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.</p> Results <p>High-m¹A tumors exhibited an immunosuppressive microenvironment dominated by exhausted TIM-3⁺PD-1⁺ T cells and poor ICIs responses. Mechanistically, m¹A-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.</p> Conclusion <p>Our study unveils m¹A-dependent epitranscriptomic control of SFRP2 as a novel regulator of the NFAT/TOX-mediated immune evasion axis in GC. The m¹A scoring system may refine patient stratification, and targeting SFRP2 represents a promising strategy to overcome ICI resistance.</p> Clinical trial number <p>Not applicable.</p>