Tumor peptide–Major Histocompatibility Complex (pMHC)

Tumor peptide–Major Histocompatibility Complex (pMHC) complexes are essential molecular targets in immuno-oncology, consisting of a short peptide fragment derived from intracellular tumor antigens bound to an MHC molecule on the cell surface. These complexes allow the immune system to 'see' the internal proteome of a cell, enabling T-cells to distinguish malignant cells from healthy ones through T-cell receptor (TCR) recognition. Unlike traditional antibody targets that must be surface-expressed proteins, pMHC targets open the door to the vast majority of the proteome, including intracellular oncogenic drivers and cancer-testis antigens. Therapeutic modalities 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 and specificity. However, clinical application is restricted by the requirement for specific patient HLA genotypes and the risk of off-target cross-reactivity with similar peptides in normal tissues. Additionally, tumors may evade these therapies by downregulating MHC expression or altering antigen processing pathways.

Other names

Peptide-HLA complexpMHC complexTumor-associated antigen-MHC complexNeoantigen-MHC complexpMHC-IpMHC-IIPeptide-MHC class I complex

Drugs targeting tumor pMHC complexes utilize engineered T-cell receptors (TCRs) or TCR-like antibodies to recognize specific peptide fragments presented by HLA molecules. This binding redirects and activates T-cells (often via a CD3-engaging domain or direct cellular engineering) to release cytotoxic granules like perforin and granzymes, leading to tumor cell lysis.