Tumor-associated or tumor-specific peptide–MHC complex (pMHC)

The tumor-associated or tumor-specific peptide–MHC (pMHC) complex is a critical molecular structure formed by the binding of intracellularly processed protein fragments to Major Histocompatibility Complex molecules, which are then displayed on the surface of tumor cells. These complexes serve as the primary signal for the adaptive immune system, allowing T-cell receptors (TCRs) to distinguish malignant cells from healthy ones by recognizing mutated neoantigens or overexpressed self-antigens. In the context of oncology, pMHC complexes are highly specific therapeutic targets for advanced immunotherapies, including TCR-engineered T-cell (TCR-T) therapies and TCR-bispecific engagers. Unlike traditional antibody targets that are limited to cell-surface proteins, pMHC targeting allows the immune system to access the internal proteome of the cancer cell, significantly expanding the range of targetable oncogenic drivers. However, the efficacy of targeting these complexes is often limited by HLA downregulation in tumors and the requirement for specific patient HLA haplotypes, such as HLA-A*02:01.

Other names

Peptide-MHC complexpMHC complexHLA-peptide complexTumor-specific antigen-MHC complexNeoantigen-MHC complexTumor-associated antigen-MHC complex

Drugs targeting pMHC complexes typically function as T-cell receptor (TCR) therapies or TCR-mimetic antibodies that specifically bind the peptide-HLA complex on the tumor cell surface. This binding facilitates the direct killing of the tumor cell by cytotoxic T lymphocytes or through the recruitment of effector immune cells via bispecific engagers.