RAS INHIBITION AND ANTI-TUMOR IMMUNITY IN PANCREATIC CANCER

Mutations in KRAS drive oncogenesis in over 90% of pancreatic ductal adenocarcinoma (PDAC) cases, making it one of the most RAS-addicted cancers. The emergence of allele-specific KRAS inhibitors and broad-spectrum RAS inhibitors has important implications for PDAC, which currently lacks effective treatment options. Beyond promoting tumor cell growth, mutant KRAS shapes an immunosuppressive tumor microenvironment (TME) characterized by abundant myeloid cells and limited T cell infiltration. This immunologically “cold” TME contributes to poor clinical responses to immunotherapy. Thus, there is rationale for using mutant KRAS inhibition as a strategy to increase the susceptibility of PDAC tumors to immune-based therapy. Broad-spectrum RAS inhibitors, such as the RAS(ON) multi-selective inhibitor RMC-7977, are active against a range of RAS driver mutations and resistance mechanisms, including secondary RAS mutations and wild-type RAS. Given the role of RAS in immune cell signaling pathways, particularly in T cells, it remains unknown whether RAS inhibition is compatible with immune modulation. Using immunocompetent mouse models of PDAC, we investigated the role of the adaptive immune system in mediating the anti-tumor effects of RAS inhibition. We found that RAS inhibition reshapes the PDAC TME, promoting T cell infiltration and creating permissive conditions for immunotherapy. T cells remain functional under broad-spectrum RAS inhibition, and can be leveraged with combination immunotherapy, leading to deeper and more durable responses. Our preclinical data suggest that T cell infiltration and other immune features of tumors may help guide the design of future clinical trials. These findings also support the clinical evaluation RAS inhibition with immunotherapy like anti-PD-1, anti-CTLA-4, and CD40 agonists. In summary, concurrent inhibition of mutant and wild-type RAS enhances the efficacy of T cell-based immunotherapies, positioning RAS inhibitors as a promising immune-sensitizing strategy in PDAC.