Targeting SIRT2 Induces MLH1-deficiency and Boosts Anti-Tumor Immunity in Colorectal Cancer

Low tumor mutation burden and immunosuppressive tumor microenvironment (TME) contribute to resistance to immune-checkpoint inhibitors. Unraveling the mechanisms of cancer immune evasion may help to develop novel therapeutic strategies. Here, leveraging Mass Spectrometry-based proteomic profiling data and clinical validation, we identified that low Sirtuin 2 (SIRT2) expression is significantly associated with improved prognosis and an immune-active TME in colorectal cancer (CRC). Specifically, genetic knockdown or pharmacological inhibition of SIRT2 results in enhanced infiltration and cytotoxicity of CD8+ T cells, leading to tumor regression across multiple CRC mouse models and patient-derived organoids. Further analysis demonstrated that SIRT2 interacts with and deacetylates MutL protein homolog 1 (MLH1) at Lys 402/443/461, thereby preventing MLH1 ubiquitination and degradation. SIRT2 knockdown or inhibition downregulates MLH1, increasing DNA damage and activating the cGAS-STING pathway. Additionally, SIRT2 inhibition stimulates the production of tumor neoantigens and enhances Major histocompatibility complex class I (MHC-I) expression, reprogramming the TME towards an immune-active status and inducing long-lasting immune memory. Finally, a combination strategy using SIRT2 inhibitor AGK2 and anti-PD-1 therapy significantly enhances immune response, making tumors susceptible to immunotherapy and driving substantial tumor regression in vivo. Our study uncovers a role of SIRT2 in reprogramming TME and underscores the potential of targeting SIRT2 to sensitize CRC to immunotherapy by shifting the immune-cold phenotype towards an immune-activation one.