Targeting KRAS in colorectal cancer immunotherapy: rationale, challenges and future directions

Kirsten rat sarcoma (KRAS) is frequently mutated in colorectal cancer (CRC). In recent years, mutant KRAS has shed its “undruggable” label, with two clinically approved inhibitors now available. Besides aberrantly activating intrinsic tumor cell growth signaling, oncogenic KRAS contributes to the development of an immunosuppressive tumor microenvironment (TME), especially in CRC. This suggests KRAS inhibition may enhance responsiveness to immunotherapy, supporting the rationale for combining mutant KRAS inhibitors with immune checkpoint blockade (ICB). Mutant KRAS is considered as an ideal immunological target. Emerging therapeutics, including vaccines, TCR-T cell therapies and antibodies, are being developed to treat KRAS-mutant CRC patients that leverage peptides or peptide/major histocompatibility complex class I (MHC-I) complexes generated by mutant KRAS. Here, we provide an overview of targeting mutant KRAS in CRC immunotherapy, discussing challenges and future directions.