Tumor-derived peptide–Major Histocompatibility Complex (pMHC)

Tumor-derived peptide–Major Histocompatibility Complex (pMHC) molecules are cell-surface structures formed by the association of intracellularly processed tumor antigens with MHC (or HLA in humans) proteins (Source: Nature Reviews Drug Discovery, 2021). These complexes serve as the primary signal for T-cell recognition, allowing the immune system to distinguish malignant cells from healthy ones by displaying fragments of mutated or overexpressed proteins (Source: NIH/NCI). In oncology, pMHCs are highly specific therapeutic targets for TCR-engineered T-cell therapies (TCR-T), TCR-bispecific engagers, and cancer vaccines (Source: PubMed, PMID: 33854242). Unlike traditional antibody targets that are limited to surface proteins, pMHCs allow the targeting of the entire intracellular proteome, significantly expanding the range of druggable tumor antigens (Source: Science, 2021). However, therapeutic success depends on precise HLA matching and the avoidance of cross-reactivity with similar peptides found in vital organs (Source: Journal of Clinical Oncology). Additionally, tumors may escape detection by downregulating MHC expression or through mutations in the antigen processing machinery (Source: Nature).

Other names

Tumor-associated antigen-MHC complexTumor-specific antigen-MHC complexpHLANeoantigen-MHC complexHLA-peptide complexAntigen-MHC complex

Drugs targeting these complexes typically utilize T-cell receptor (TCR) or TCR-like binding domains to recognize specific peptide-HLA combinations on the tumor cell surface, leading to T-cell mediated cytotoxicity and immune-driven tumor lysis (Source: Nature Reviews Immunology).