Tumor-intrinsic PTPN12 suppresses anti-tumor immunity in colorectal cancer by restraining a dual epigenetic and cytoskeletal dsRNA sensing program

Innate sensing of endogenous double-stranded RNA and the ensuing interferon response are crucial for the efficacy of immune checkpoint inhibition. Microsatellite stable colorectal cancer characteristically lacks this response, remaining immune-refractory with undefined intrinsic regulators. Here, through an in vivo clustered regularly interspaced short palindromic repeats screen, we identify PTPN12 as a physiological barrier that suppresses double-stranded RNA sensing and interferon response. TRIM28 was identified as a direct PTPN12 substrate here; PTPN12 removes phosphorylation at Y370 to stabilize repressive complexes and silence transposable elements, while concurrently rewiring the adhesive cytoskeleton to disrupt the spatially organization of cytosolic double-stranded RNA required for efficient innate sensing. Pharmacological inducible PTPN12 knockdown inhibits pre-established tumor growth and overcomes immunotherapy resistance in vivo, recapitulating PTPN12 ablation-induced massive double-stranded RNA accumulation. Our findings reveal a role for PTPN12 in coupling epigenetic silencing with cytoskeletal surveillance, suggesting potential strategies to augment anti-tumor immunity and overcome immunotherapy resistance in microsatellite stable colorectal cancer. Abnormal endogenous dsRNA generation and/or sensing and the resulting interferon responses contribute to immunotherapy resistance in microsatellitestable colorectal cancer (MSS-CRC). Here, the authors identify the cytosolic tyrosine phosphatase PTPN12 as a central regulator that suppresses innate immune activation in MSS-CRC.