Targeting nucleic acid sensors in tumor cells to reprogram biogenesis and RNA cargo of extracellular vesicles for T cell-mediated cancer immunotherapy

Tumor-derived extracellular vesicles (EVs) have been associated with immune evasion and tumor progression. We show that the RNA-sensing receptor RIG-I within tumor cells governs biogenesis and immunomodulatory function of EVs. Cancer-intrinsic RIG-I activation releases EVs, which mediate dendritic cell maturation and T cell antitumor immunity, synergizing with immune checkpoint blockade. Intact RIG-I, autocrine interferon signaling, and the GTPase Rab27a in tumor cells are required for biogenesis of immunostimulatory EVs. Active intrinsic RIG-I signaling governs composition of the tumor EV RNA cargo including small non-coding stimulatory RNAs. High transcriptional activity of EV pathway genes and RIG-I in melanoma samples associate with prolonged patient survival and beneficial response to immunotherapy. EVs generated from human melanoma after RIG-I stimulation induce potent antigen-specific T cell responses. We thus define a molecular pathway that can be targeted in tumors to favorably alter EV immunomodulatory function. We propose “reprogramming” of tumor EVs as a personalized strategy for T cell-mediated cancer immunotherapy. • RIG-I activity regulates biogenesis and function of tumor cell-derived EVs • Cancer-intrinsic RIG-I signaling governs the composition of the EV RNA cargo • Immunostimulatory EVs trigger T cell-based antitumor immunity in mice and humans • EV and RIG-I gene signatures in melanomas correlate with response to immunotherapy Extracellular vesicles harbor extraordinary potential for cancer therapy, but one limitation is an inadequate understanding of signaling pathways that regulate their biogenesis and function. Heidegger et al. define a tumor-intrinsic molecular pathway that can be targeted to modulate tumor EV cargo constituents and thus their immunomodulatory potential on T cell immunity.