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

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 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

SUBMITTER: Liu Y 

PROVIDER: S-EPMC12528264 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature