Mutated KRAS peptide-MHC class I complex

A mutated KRAS peptide-MHC complex is a cell-surface molecular structure formed when intracellular mutant KRAS proteins (such as G12C, G12V, G12D) are processed into short peptide fragments that are then loaded onto MHC class I molecules (such as HLA-A*03:01 or HLA-A*11:01) for presentation to T cells. In some therapies, these peptides are further modified by covalent binding with small-molecule inhibitors (e.g., sotorasib or ARS1620), allowing generation of tumor-specific neoantigens that can be recognized with high specificity by engineered antibodies, T cell receptors, bispecific T cell engagers, or CAR-T constructs. Such complexes are considered highly valuable targets for immuno-oncology, as they offer selectivity for mutated cancer cells and enable the immune system or artificial antibodies to selectively kill tumors, overcoming resistance to standard KRAS inhibitors. Notably, only tumors with the relevant KRAS mutation and presenting peptides on compatible HLA alleles will be susceptible to these therapies; this represents both a precision advantage and a clinical limitation. While off-target risks and tumor immune escape remain challenges, the approach is at the forefront of cancer immunotherapy research.

Other names

Mutant KRAS neoantigen-MHC complexSotorasib-modified KRAS peptide-MHC complexARS1620-modified KRAS peptide-MHC complexKRAS mutant peptide-HLA complex

Drug inhibition: Covalent inhibitors (sotorasib, ARS1620) modify mutant KRAS, leading to formation and presentation of drug-modified peptides on MHC class I, creating tumor-specific neoantigens. Immune cell activation: Antibodies and CARs recognize these neoantigen-MHC complexes and redirect cytotoxic T cell activity to tumor cells. TCR targeting: Select T cell receptors bind mutant KRAS peptides presented by specific HLA alleles (e.g., HLA-A*11:01).