Tumor peptide-major histocompatibility complex (pMHC)

The tumor peptide-major histocompatibility complex (pMHC) is a molecular assembly on the surface of malignant cells consisting of a short peptide fragment derived from intracellular proteins bound to an MHC molecule (typically HLA in humans). This complex serves as the primary signal for immune surveillance, allowing T-cell receptors (TCRs) to recognize and eliminate cells expressing mutated or overexpressed internal antigens that are otherwise inaccessible to traditional antibody therapies [4, 8]. In the context of oncology, pMHC complexes present a diverse array of targets, including neoantigens and cancer-testis antigens, which are highly specific to tumor cells [15]. Therapeutic interventions such as TCR-engineered T cells (TCR-T) and bispecific T-cell engagers (e.g., ImmTACs) are designed to bind these complexes with high affinity to trigger a potent cytotoxic immune response [7, 14]. However, the efficacy of these treatments is often limited by the heterogeneity of MHC expression and the risk of off-target toxicity if the targeted peptide sequence is shared by proteins in vital organs [7, 16].

Other names

Peptide-MHC complexpMHC complexHLA-peptide complexTumor-specific MHC-peptide complextsMHCAntigen-MHC complex

Drugs targeting the tumor peptide/MHC complex typically function through T-cell redirection (bispecific molecules), adoptive cell transfer (TCR-engineered T cells), or direct antibody-mediated cytotoxicity (TCR-mimetic antibodies) to induce the lysis of malignant cells presenting specific intracellular antigens [3, 7, 10].