A Senescent Tumor Cell-Derived Nanovesicle Directly Primes Splenic T cells to Potentiate Radiotherapy

Senescent tumor cells (STCs) play a crucial role for radiotherapy-induced immunosuppressive tumor microenvironments (ITM). However, current senolytic strategies lack specificity for STCs and often cause off-target toxicity. Here, we first identified the antigen presenting potential of STCs in patient-derived tumor tissues and demonstrated their capacity for directly priming and inducing STC-specific CD8+ T cells. We thereafter engineered STC-derived nanovesicles for directly priming CD8+ T cells through their upregulated antigen-presenting machinery (termed as nano-APM). Upon systemic administration, nano-APMs specifically accumulated in the spleen and directly primed CD8? T cell, thereby establishing STC-specific T cell pool. Based on these finding, we sequentially combining nano-APM with RT to achieve spatiotemporally-confined activation of anti-senescence immunity via RT-controlled tumor senescence induction. In preclinical mouse models of pancreatic ductal adenocarcinoma and bladder cancer, the sequential combination of the nano-APM with RT effectively eliminated STCs, reprogramed RT-induced ITM (e.g., 21.5-folds higher CD8+ T cell to Tregs ratio than the control group), and induced durable antitumor response. Overall, this study pioneered a STC-derived nanovesicle platform to directly prime splenic T cells and achieve spatiotemporally-confined senolysis for potentiating RT. Overall design: Senescent or none-senescent tumor cells (MB49 cell, sMB49 cells, KPC cells, and sKPC cells) were treated with 8 Gy-RT and cultured for 48 h.Then the cells were collected for total RNA sequence.