The m1A-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 immune evasion.

METHODS

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.

RESULTS

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.

CONCLUSION

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.

CLINICAL TRIAL NUMBER: Not applicable.