Mutant RAS peptide–Major Histocompatibility Complex (MHC) (Mutant RAS-MHC)

The Mutant RAS peptide–Major Histocompatibility Complex (MHC) is a tumor-specific neoantigen target formed by the presentation of mutated RAS protein fragments on the surface of cancer cells (Prior et al., 2020, Cancer Research). RAS genes (KRAS, NRAS, and HRAS) are among the most frequently mutated oncogenes in human cancers, particularly in pancreatic, colorectal, and lung adenocarcinomas (Wang et al., 2021, Science Immunology). These mutations result in unique peptide sequences that are processed by the cellular proteasome and loaded onto MHC Class I or Class II molecules for recognition by T cells. Because these mutant peptides are absent in healthy tissues, the mutant RAS-MHC complex serves as a highly specific target for immunotherapies, including TCR-engineered T cells (TCR-T), cancer vaccines, and bispecific T-cell engagers (Leidner et al., 2022, NEJM). These therapies aim to leverage the immune system to selectively eliminate cancer cells expressing the mutant RAS-MHC complex while sparing normal cells that express only wild-type RAS (Elicio Therapeutics, 2024; Affini-T Therapeutics, 2024). This approach is particularly valuable for targeting historically 'undruggable' RAS mutations by focusing on the extracellular presentation of intracellular protein fragments.

Other names

Mutant RAS-HLA complexRAS neoantigen-MHC complexKRAS-MHC complexNRAS-MHC complexHRAS-MHC complexpMHC complex

T-cell receptor (TCR) mediated recognition of the mutant RAS peptide presented by MHC molecules, leading to T-cell activation, secretion of cytotoxic granules (perforin/granzyme), and direct lysis of tumor cells (Leidner et al., 2022, NEJM; Wang et al., 2021, Science Immunology).