Tumor-specific neoantigen (TSA)

Tumor-specific neoantigens (TSAs) are novel proteins arising from somatic mutations—such as single-nucleotide variants, insertions, or deletions—within a cancer cell's genome [1, 4]. Unlike tumor-associated antigens, these proteins are uniquely expressed in malignant tissues and absent in normal cells, making them highly specific therapeutic targets with a reduced risk of autoimmune toxicity [1, 4, 10]. Many of these mutant proteins function as oncogenic drivers, such as the KRAS G12C or BRAF V600E mutants, which constitutively activate signaling pathways that promote cell survival and proliferation [9, 13, 18]. Therapeutic strategies targeting these proteins include direct pharmacological inhibition using small molecules like sotorasib, which lock the protein in an inactive state, as well as personalized cancer vaccines (e.g., mRNA-4157) designed to stimulate a patient's T cells to recognize these "non-self" epitopes [9, 11, 13]. Despite their therapeutic potential, targeting these proteins faces significant challenges, including the rapid development of secondary resistance mutations and the inherent heterogeneity of the tumor mutational landscape [9, 17, 18].

Other names

Tumor-specific mutant proteinNeoantigenSomatic mutation-derived antigenMutant oncoproteinTumor-specific antigen (TSA)

Direct inhibition of mutant protein activity (e.g., covalent binding to mutant cysteine residues), immune-mediated destruction via T-cell recognition of MHC-presented mutant peptides, and targeted degradation via proximity-inducing agents or PROTACs [9, 13, 16, 18].