Major histocompatibility complex–neoantigen–T-cell receptor complex (pMHC-TCR)

The Major Histocompatibility Complex (MHC)–neoantigen–T-cell receptor (TCR) complex is a tripartite molecular assembly that serves as the primary interface for the adaptive immune system to recognize cancer-specific mutations [1, 4]. It consists of an MHC molecule (HLA in humans) that presents a neoantigen—a peptide fragment derived from a tumor-specific somatic mutation—on the cell surface, where it is specifically engaged by a cognate TCR on a T cell [11, 20]. This interaction is highly specific and triggers a signaling cascade that leads to T-cell activation, proliferation, and the subsequent cytotoxic destruction of the tumor cell [9, 17]. Because neoantigens are absent from normal tissues, this complex represents an ideal target for precision oncology, minimizing the risk of damage to healthy cells [1, 12]. Therapeutic approaches targeting this complex include TCR-engineered T-cell (TCR-T) therapies, personalized neoantigen vaccines, and TCR-mimic antibodies or bispecific T-cell engagers [2, 7, 13]. However, the effectiveness of these therapies is often limited by the high degree of HLA polymorphism, low levels of neoantigen presentation, and the potential for immune escape through MHC downregulation [1, 18].

Other names

Peptide-MHC-TCR complexpMHC-TCR complexTCR-pMHC ternary complexNeoantigen-MHC-TCR complexMHC-restricted neoantigen complex

The primary mechanism of action involves the specific recognition of the peptide-MHC complex by a T-cell receptor, which can be achieved through adoptive transfer of TCR-engineered T cells (TCR-T), induction of endogenous T cells via neoantigen vaccines, or the use of bispecific molecules (e.g., TCR-mimic antibodies or ImmTACs) that redirect T cells to the tumor surface [2, 4, 7, 13].