Single-Cell RNA Editing Identifies T Cell ADAR1 as a Key Regulator of Immune Exhaustion and Anti-PD-1 Resistance in Colorectal Cancer.

ADAR1-mediated RNA editing has been implicated in tumor immune evasion, primarily through tumor-intrinsic interferon (IFN) signaling.

However, its cell-type-specific roles within immune compartments, particularly T cells, remain unclear in colorectal cancer (CRC). RNA editing landscapes were profiled using bulk RNA sequencing and full-length single-cell RNA sequencing. ADAR1 expression and RNA editing activity were analyzed across the tumor microenvironment (TME), followed by functional validation and multi-cohort clinical evaluation. Single-cell analyses revealed elevated ADAR1 activity in tumor-infiltrating T cells, defining an exhausted and proliferative T cell state associated with immune dysfunction.

Functional experiments demonstrated that ADAR1 promotes T-cell exhaustion and impairs cytotoxic activity. In vivo adoptive transfer models further confirmed that ADAR1 overexpression in T cells limits antitumor efficacy. Mechanistically, ADAR1 activated the TGF-β-SMAD signaling pathway. Clinically, elevated ADAR1 expression in T cells was associated with reduced response to anti-PD-1 therapy across immunotherapy cohorts.

These findings identify ADAR1 as a key regulator of dysfunctional T cell states in CRC and suggest that targeting ADAR1 activity in T cells may represent a promising strategy for improving immunotherapy efficacy and developing predictive biomarkers.