HLA class I-restricted mutant KRAS peptide-T-cell receptor complex (mKRAS pMHC-TCR complex)

The HLA class I-restricted mutant KRAS peptide-T-cell receptor (TCR) complex is a tripartite molecular assembly central to the immune recognition of one of the most common oncogenic drivers in human cancer [3, 9]. It consists of a mutant KRAS-derived neoantigen (such as G12D, G12V, or G12C) presented by a specific Human Leukocyte Antigen (HLA) class I molecule on the surface of tumor cells, which is then recognized by a cognate T-cell receptor [4, 10]. Because KRAS mutations are highly tumor-specific and essential for cancer cell survival, this complex serves as an ideal target for precision immunotherapies, including TCR-engineered T-cell (TCR-T) therapies and bispecific T-cell engagers [5, 16]. These therapies are designed to bypass the immune evasion mechanisms of solid tumors like pancreatic, colorectal, and lung cancers by providing high-affinity TCRs that specifically bind the mutant peptide-MHC complex [1, 8]. Successful binding triggers a potent cytotoxic T-cell response, characterized by the release of perforins, granzymes, and pro-inflammatory cytokines like interferon-gamma, leading to selective tumor cell lysis [2, 13]. However, the therapeutic application of this target requires precise matching of the patient's HLA genotype and the specific KRAS mutation, and carries risks such as cytokine release syndrome or potential cross-reactivity with wild-type KRAS [6, 17].

Other names

KRAS neoantigen-HLA-TCR complexMutant KRAS peptide-MHC-TCR complexKRAS G12D/HLA-A*11:01 TCR complexKRAS G12V/HLA-A*02:01 TCR complexmKRAS pMHC-TCR complex

The complex facilitates the specific recognition of tumor cells by T-cells. Engineered TCRs or T-cell engagers bind to the mutant KRAS peptide presented by HLA class I molecules, triggering T-cell receptor signaling, secretion of cytotoxic granules (perforin/granzyme), and pro-inflammatory cytokines, ultimately leading to the selective destruction of KRAS-mutant tumor cells [3, 5, 13, 16].