Restoring tumor antigenicity activates the “bystander” T cell immune cycle

Tumor-specific T cells play a crucial role in tumor immunity. However, these cells are often scarce and functionally exhausted within the tumor microenvironment (TME), leading to the limited efficacy of immunotherapy in many cancer patients. In contrast, increasing evidence suggests that the TME is rich in "bystander" T cells (TBYS), most of which are virus-specific and unrelated to the tumor. These TBYS cells retain functional memory characteristics and the potential to kill tumor cells. To utilize TBYS cells in the TME for tumor elimination, we designed an intracellular delivery system, ASCP, encoding a TBYS epitope to redirect tumor cell antigen specificity toward pre-existing TBYS cells, resulting in effective tumor inhibition in multiple preclinical models. The ASCP-antigen peptide strategy restores the antigenicity of tumor cells and induces epitope spreading of tumor antigens, thereby eliciting more diverse tumor-specific T cell responses. Remarkably, this strategy incorporates MHC-II epitopes containing unnatural amino acids (p-nitrophenylalanine, termed NiraTh), which stimulate CD4+ T cell-mediated immunity and assist CD8+ T cells in clearing tumors. Overall, the ASCP-mediated tumor antigen reprogramming strategy provides important insights for cancer immunotherapy in populations with a history of common viral infections.