Melanoma-associated antigen A4 peptide–MHC complex (MAGE-A4 pMHC)

Melanoma-associated antigen A4 (MAGE-A4) peptide–MHC complexes are specialized cell-surface targets formed when the intracellular cancer-testis antigen MAGE-A4 is degraded by the proteasome and its resulting peptides are presented by Major Histocompatibility Complex (MHC) class I molecules (Frontiers in Oncology, 2025). The most clinically relevant epitope is the MAGE-A4 230–239 peptide (GVYDGREHTV) presented by HLA-A*02:01 (NIH, 2024). These complexes are highly tumor-specific because MAGE-A4 is expressed in various solid tumors—such as synovial sarcoma, non-small cell lung cancer, and ovarian cancer—but is restricted to immune-privileged tissues like the testis and placenta in healthy adults (OncLive, 2024). Therapeutic strategies targeting these complexes include T-cell receptor (TCR) engineered T-cell therapies and bispecific T-cell engagers, which allow the immune system to recognize and eliminate cells based on their internal protein expression (NIH, 2025). The approval of afamitresgene autoleucel in 2024 marked a milestone as the first TCR-T therapy for solid tumors targeting this complex (FDA, 2024).

Other names

MAGE-A4/HLA-A*02:01 complexMAGE-A4 p230-239/HLA-A2 complexMAGE-A4 peptide-HLA complexMAGE-A4-MHC complexMelanoma-associated antigen 4 peptide-MHC complex

Engineered T-cell receptors (TCRs) or TCR-like antibodies bind specifically to the MAGE-A4 peptide presented within the MHC class I groove on the tumor cell surface, triggering T-cell activation, cytokine release, and direct cytolytic destruction of the target cell (NIH, 2025; OncLive, 2024).