A senescent tumor cell-derived nanovesicle directly primes splenic T cells to potentiate cancer radiotherapy.

Abstract

Radiotherapy (RT)-induced senescent tumor cells (STCs) reinforce an immunosuppressive tumor microenvironment (ITM) and compromise therapeutic outcomes. However, current senolytic strategies lack specificity for STCs and often cause off-target toxicity. Here, we observe that STCs possess enhanced antigen-presenting capacity in patient-derived tumor tissues and murine tumor models. Leveraging this phenomenon, we engineer STC-derived nanovesicles (termed nano-APM) for preserving endogenous antigens and antigen-presenting cues. We demonstrate that systemically administered nano-APMs accumulate in the spleen and establish a pool of STC-specific CD8⁺ T cells. Sequential integration of RT induces local tumor senescence, and nano-APMs then effectively mobilize the STC-specific T cells to stimulate a confined recall response. In murine tumor models, the combination of nano-APM plus RT selectively eliminates STCs, reprograms RT-induced ITM, and elicits durable antitumor immunity. Collectively, this study establishes STC-derived nanovesicles as a practical means to enhance RT efficacy by enabling splenic T cell priming and spatiotemporally confined senolysis.