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

ABSTRACT 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.