T cell receptor recognizing tumor neoantigen peptide–MHC complex (Neo-TCR)

The T cell receptor (TCR) recognizing tumor neoantigen peptide–MHC complexes is a specialized immune receptor that targets unique, patient-specific mutations (neoantigens) presented by Major Histocompatibility Complex (MHC) molecules on the surface of cancer cells. Unlike receptors targeting tumor-associated antigens (TAAs) that may also be expressed at low levels in healthy tissues, neoantigen-specific TCRs recognize 'non-self' epitopes resulting from somatic mutations, which significantly reduces the risk of central tolerance and off-target toxicity. These receptors are typically alpha-beta (αβ) heterodimers that engage the peptide-MHC (pMHC) complex through their complementarity-determining regions (CDRs). In therapeutic contexts, such as TCR-engineered T cell (TCR-T) therapy, autologous T cells are modified to express these high-affinity receptors to orchestrate a potent and precise anti-tumor response. This approach is particularly effective for solid tumors with high mutational burdens, where the TCR-T cells can infiltrate the tumor microenvironment and induce targeted cell death. However, the high degree of patient-specific customization required and the potential for tumor escape through HLA loss remain significant therapeutic challenges.

Other names

Neoantigen-specific T cell receptorTumor-specific T cell receptorMutation-specific T cell receptorNeo-TCRNeoantigen-reactive TCR

Engineered T cells expressing these receptors bind to specific neoantigen-MHC complexes on the surface of tumor cells, initiating a signaling cascade through the CD3 complex and ITAM phosphorylation that leads to T cell activation, cytokine release, and direct lysis of the target tumor cell.