Noncanonical MAVS signaling restrains dendritic cell–driven antitumor immunity by inhibiting IL-12.

Mitochondrial antiviral signaling protein (MAVS)–mediated cytosolic RNA sensing plays a central role in tumor immunogenicity. However, the effects of host MAVS signaling on antitumor immunity remain unclear. Here, we demonstrate that the host MAVS pathway supports tumor growth and impairs antitumor immunity, whereas MAVS deficiency in dendritic cells (DCs) promotes tumor-reactive CD8⁺ T cell responses. Specifically, CD8⁺ T cell priming capacity was enhanced by MAVS ablation in a type I interferon–independent, but IL-12–dependent, manner. Mechanistically, loss of the RIG-I/MAVS cascade activated the noncanonical NF-κB pathway and in turn induced IL-12 production by DCs. MAVS-restrained IL-12 promoted cross-talk between CD8⁺ T cells and DCs, which was licensed by IFN-γ. Moreover, ablation of host MAVS sensitized tumors to immunotherapy and attenuated radiation resistance, thereby facilitating the maintenance of effector CD8⁺ T cells. These findings demonstrate that the host MAVS pathway acts as an immune regulator of DC-driven antitumor immunity and support the development of immunotherapies that antagonize MAVS signaling in DCs. Editor's summary: Intratumoral activation of innate immune sensing pathways generates a viral mimicry response that enhances tumor immunogenicity and can be leveraged for cancer immunotherapy. Cytosolic sensing of viral RNA by RIG-I–like receptors leads to activation of their adaptor protein mitochondrial antiviral signaling protein (MAVS) and production of type I interferon (IFN-I). Using genetically engineered mice, Wu et al. found that ablation of DC-intrinsic MAVS in tumor-bearing hosts enhanced antitumor immunity and slowed tumor growth. These effects were independent of IFN-I signaling and instead involved induction of IL-12 by MAVS-deficient DCs. Tumors in MAVS-deficient mice were more responsive to PD-L1 blockade and radiation therapy. These findings demonstrate that MAVS signaling in DCs restrains antitumor immunity, contrasting its tumor cell–intrinsic functions in promoting tumor immunogenicity. —Claire Olingy [ABSTRACT FROM AUTHOR]