Tumor-specific neoantigen peptide–major histocompatibility complex (Neoantigen-MHC complex)

Tumor-specific neoantigen peptide–major histocompatibility complex (MHC) molecules are unique cell-surface structures that serve as the primary targets for personalized cancer immunotherapy. These complexes are formed when somatic mutations—such as single nucleotide variants, insertions, or deletions—result in novel amino acid sequences (neoantigens) that are processed by the proteasome and loaded onto MHC Class I or II molecules for presentation to T cells [1][2]. Because these neoantigens are derived from non-germline mutations, they are absent from healthy tissues, providing a high degree of tumor specificity and reducing the likelihood of central tolerance [3]. Recognition of these complexes by the T-cell receptor (TCR) is essential for the induction of a robust anti-tumor immune response. Current therapeutic strategies include personalized mRNA or DNA vaccines designed to prime the immune system against these specific epitopes, as well as adoptive cell therapies using TCR-engineered T cells (TCR-T) that directly recognize the neoantigen-MHC complex [2][4]. While highly promising for precision medicine, the clinical utility of targeting these complexes is often limited by the heterogeneity of neoantigen expression within a tumor and the sophisticated mechanisms tumors use to escape immune detection, such as the loss of MHC expression [1][3]. Sources: [1] Schumacher & Schreiber, Science (2015); [2] Blass & Ott, Nature Reviews Clinical Oncology (2021); [3] Xie et al., Signal Transduction and Targeted Therapy (2023); [4] National Cancer Institute (NCI).

Other names

Neoantigen-HLA complexNeoepitope-MHC complexTumor-specific antigen-MHC complexpHLA complexMutation-derived neoantigen-MHC

Therapeutic agents target these complexes by either delivering the neoantigen (vaccines) to be processed and presented, or by providing engineered T-cell receptors (TCR-T) and antibodies that specifically bind the peptide-MHC complex to trigger cytotoxic T-lymphocyte mediated lysis of tumor cells [1][3].