Work

The m1A-SFRP2-NFAT/TOX axis governs T cell exhaustion in gastric cancer

Year: 2025

Type: article

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

Source: Cellular Oncology

DOI: 10.1007/s13402-025-01096-z