Exploiting the therapeutic implications of KRAS inhibition on tumor immunity

Over the past decade, RAS oncogenic proteins have transitioned from being deemed undruggable to having two clinically approved drugs, with several more in advanced stages of development. Despite the initial benefit of KRAS-G12C inhibitors for patients with tumors harboring this mutation, the rapid emergence of drug resistance underscores the urgent need to synergize these inhibitors with other therapeutic approaches to improve outcomes. RAS mutant tumor cells can create an immunosuppressive tumor microenvironment (TME), suggesting an increased susceptibility to immunotherapies following RAS inhibition. This provides a rationale for combining RAS inhibitory drugs with immune checkpoint blockade (ICB). However, achieving this synergy in the clinical setting has proven challenging. Here, we explore how understanding the impact of RAS mutant tumor cells on the TME can guide innovative approaches to combining RAS inhibition with immunotherapies, review progress in both pre-clinical and clinical stages, and discuss challenges and future directions. New drugs targeting the KRAS oncoprotein provide only short-term clinical benefit. Molina-Arcas and Downward review how oncogenic KRAS creates an immune-suppressive tumor microenvironment, providing a rationale for the combination of KRAS inhibitors with immunotherapies. They review the progress of these combinations, discuss the challenges, and propose future research directions.