Tumor-associated and neoantigenic peptide–Major Histocompatibility Complex (pMHC)

Tumor-associated and neoantigenic peptide–Major Histocompatibility Complex (pMHC) complexes represent a sophisticated class of therapeutic targets that allow the immune system to recognize intracellular oncogenic proteins [1]. These complexes are formed when intracellular proteins are degraded by the proteasome into short peptides, which are then loaded onto MHC molecules and transported to the cell surface [3]. Tumor-associated antigens (TAAs) are derived from overexpressed or lineage-specific proteins, while neoantigens arise from somatic mutations unique to the tumor, making them highly specific targets [3]. Therapeutic interventions such as TCR-engineered T cells (TCR-T) and soluble TCR-bispecifics (e.g., Tebentafusp) are designed to bind these pMHC complexes with high affinity, bypassing the limitations of traditional antibodies that only target surface-bound proteins [2, 4]. By engaging the pMHC, these therapies trigger a potent cytotoxic T-cell response against the cancer cell [1]. However, the effectiveness of these therapies is often limited by the heterogeneity of MHC expression and the risk of lethal cross-reactivity if the target peptide sequence is shared by proteins in vital organs [5].

Other names

Tumor-associated antigen-MHC complexNeoantigen-MHC complexHLA-peptide complexTAA-MHCTSA-MHCTumor-specific antigen-MHC complex

Targeting of tumor cells through T-cell receptor (TCR) recognition of specific peptide fragments presented by MHC molecules, inducing T-cell mediated cytotoxicity.