Cellular oncology (Dordrecht, Netherlands) · 2025
The m1A-SFRP2-NFAT/TOX axis governs T cell exhaustion in gastric cancer.
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Liu Yifan, Liu Gege, Wang Xuanlin, Zhang Xueru, Wu Junlu, Li Yaran, Lu Yao, Shi Ce, Ye Feng, Sun Ruixin
Аннотация
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.
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.