Tumor-antigen peptide–MHC class I complex (pMHC-I complex)

Patient-specific neoantigen and tumor-associated antigen (TAA) peptide–MHC class I complexes are the fundamental molecular signatures used by the immune system to identify malignant cells. These complexes consist of a short peptide fragment, derived from either a tumor-specific mutation (neoantigen) or an overexpressed self-protein (TAA), presented within the binding groove of a Major Histocompatibility Complex (MHC) class I molecule on the cell surface [1, 6]. Their primary biological role is to act as ligands for CD8+ T-cell receptors (TCRs), signaling the presence of intracellular abnormalities and triggering a targeted cytotoxic response [6, 13]. In modern oncology, these complexes are exploited as highly specific therapeutic targets for personalized medicine, including TCR-engineered T-cell (TCR-T) therapies, bispecific TCR-engagers (ImmTACs), and mRNA-based neoantigen vaccines [2, 3, 4]. By targeting these unique peptide-HLA fingerprints, therapies aim to achieve potent anti-tumor efficacy with high selectivity [1, 8]. However, therapeutic success is often challenged by the heterogeneity of antigen expression and the potential for tumor resistance through the loss of MHC presentation machinery [8, 9].

Other names

Neoantigen-MHC complexTumor-associated antigen-MHC complexpHLA complexPeptide-HLA class I complexTumor-specific antigen-MHC complex

Drugs targeting these complexes function by providing an engineered T-cell receptor (TCR) or TCR-mimetic that binds the specific peptide-MHC complex on the tumor cell surface, leading to T-cell recruitment and cytotoxic lysis [1, 2]. Alternatively, personalized vaccines induce the presentation of these complexes by host antigen-presenting cells to prime and expand endogenous neoantigen-specific CD8+ T cells [3, 4].