UCSF

T-cell-based immunotherapies hold promise in treating cancer by leveraging the immune system’s recognition of cancer-specific antigens. However, their efficacy is often limited in tumors with few somatic mutations and significant intratumoral heterogeneity. Here, we introduce a previously uncharacterized class of tumor-wide and public neoantigens originating from RNA-splicing aberrations in diverse cancer types. Notably, we identified T-cell receptor clones capable of recognizing and targeting neoantigens derived from aberrant splicing in GNAS and RPL22. In multi-site-directed biopsies, we detected the tumor-wide expression of the GNAS neojunction within glioma, mesothelioma, prostate cancer, and liver cancer. Importantly, these neoantigens are endogenously generated and presented by tumor cells under physiological conditions and are sufficient to trigger cancer cell eradication by neoantigen-specific CD8+ T-cells. Moreover, our study resolves the complex interplay of dysregulated splicing factor expression in specific cancer subtypes, leading to recurrent patterns of neojunction upregulation. These findings establish a molecular basis for T-cell-based immunotherapies addressing the challenges of intratumoral heterogeneity.