Engineered IL-15/IL-15Rα-expressing cellular vesicles promote T cell anti-tumor immunity

Interleukin 15 (IL-15) is a pivotal immune cytokine that responses to cancer stress signals and maintains tissue-resident memory T (TRM) cells. It is therefore considered as a potent therapeutic immunomodulator agonist cancer. However, in addition to the aberrant expression of programmed cell death 1 ligand 1 (PD-L1), certain types of tumors lack surface expression of IL-15 and thereby leads to the deficiency of T cell-mediated anti-tumor response. Herein, we engineered cellular nanovesicles presenting IL-15/IL-15Rα (IL-15/IL-15Rα-NVs) complex. IL-15/IL-15Rα-NVs trans-present IL-15 to T cells and then boost the activation, proliferation and survival of tumor-infiltrated T cells to antagonize cancer cells. Small-molecule programmed cell death protein 1 (PD-1)/PD-L1 inhibitor 1 was loaded into the NVs and simultaneously prevented CD8+ T cell exhaustion mediated via PD-L1. Moreover, IL-15/IL-15Rα-NVs intensively evoked the activity and proliferation of CD8+ TRM cells, and could exert permanent anti-tumor response.