The tumor targetome in CAR-T and TCR-T cell therapy

Genetically engineered T cells are reshaping cancer treatment. Chimeric antigen receptor (CAR)-T cells have produced durable and, in selected settings, potentially curative responses in hematologic malignancies, whereas the first T cell receptor-engineered T-cell (TCR-T) therapy received FDA approval in 2024 for a solid tumor. CARs recognize extracellularly accessible targets independently of the major histocompatibility complex, whereas TCRs read MHC-presented peptides, giving the platforms access to complementary target spaces. Target choice governs both efficacy and toxicity. Target prioritization therefore balances four translational dimensions: tumor specificity, population shareability, sufficient abundance and intratumoral uniformity, and fitness dependence, whereby target loss imposes a biological cost on the tumor. This review reframes both modalities around the tumor targetome: the subset of tumor antigens that engineered receptors can safely, effectively, and tractably engage. This space extends beyond the protein surfaceome to glycoepitopes and glycolipids, and through peptide-MHC presentation to the far larger intracellular proteome. We map major antigen classes and their discovery through immunopeptidomics, proteogenomics, structural biology, and machine learning, together with CAR, TCR, hybrid, and soluble formats that engage them. We then review target failure through antigen escape, loss of presentation, and normal-tissue or off-target recognition, and analyze receptor engineering, multi-antigen targeting, genome editing, manufacturing, and in vivo strategies designed to mitigate these vulnerabilities. A target-centered framework unifies CAR-T and TCR-T therapy and supports rational development of safer and more durable engineered T-cell treatments.