Tumor cell peptide–Major Histocompatibility Complex (pMHC)

Tumor cell peptide–Major Histocompatibility Complex (pMHC) complexes are molecular structures formed when intracellular proteins, including mutated neoantigens or overexpressed tumor-associated antigens, are processed into short peptides and presented on the cell surface by MHC molecules (HLA in humans) (Nature Reviews Drug Discovery, 2024). These complexes serve as the primary ligands for T-cell receptors (TCRs), enabling the adaptive immune system to monitor the internal state of a cell and identify malignant transformations (PMC, 2025). Unlike traditional monoclonal antibodies that target surface-bound proteins, therapies targeting pMHC complexes can access the vast landscape of intracellular antigens, which comprise approximately 90% of the proteome (NIH/PMC, 2025). Therapeutic modalities hitting these targets include TCR-engineered T cells (TCR-T), bispecific T-cell engagers like ImmTACs, and TCR-like antibodies (bioRxiv, 2025). Drugs such as tebentafusp and afamitresgene autoleucel utilize high-affinity TCR domains to recognize specific pMHC combinations, triggering T-cell activation and the subsequent destruction of tumor cells (FDA, 2024; Patsnap Synapse, 2024). However, the clinical utility of these targets is often restricted by the requirement for specific HLA alleles and the potential for tumor immune escape through MHC downregulation (Frontiers in Immunology, 2025).

Other names

pMHC complexHLA-peptide complexTumor-associated antigen-MHC complexNeoantigen-MHC complexAntigen-MHC complexTCR-like antibody target

T-cell receptor (TCR) binding and T-cell redirection to induce cytotoxic lysis of tumor cells