Targeting Intracellular Innate RNA-Sensing Systems Overcomes Resistance to CAR T-cell Therapy in Solid Tumors

Despite the remarkable success of chimeric antigen receptor to CAR T cells. Targeting tumor-intrinsic RIG-I is a potential (CAR) T cells in certain hematologic malignancies, only modest strategy to sensitize solid tumors to CAR T-cell treatment. responses have been achieved in solid tumors. Defective cell death pathways have recently been suggested as a tumor-intrinsic Significance: Insufficient activity of the RIG-I/MAVS pathway form of resistance to CAR T-cell treatment. In this study, we is a tumor intrinsic resistance mechanism to CAR T cells, pro-showed that insufficient activity of the innate RNA-sensing viding the rationale for targeting RIG-I to optimize CAR T effireceptor system retinoic acid–inducible gene I (RIG-I)/mito- cacy in patients with solid cancers. chondrial antiviral signaling protein (MAVS) leads to tumor cell–inherent resistance to CAR T-cell attack. Active RIG-I/MAVS CAR T cell Tumor cells signaling in tumor cells primed intrinsic mitochondrial apoptosis Therapeutic pathways and expression of cell death receptors, which funneled RNA Endogenous CAR RNA ? into CAR T-cell–triggered cell death. CAR T-cell reliance on tumor-intrinsic RIG-I signaling was observed in various murine IFN-I RIG-I Cytolytic and human cancer types, independent of the CAR construct used, FasL MAVS activity and the dependence was most pronounced under conditions with Proapoptotic low target antigen expression or low effector/target ratios. RIG-I–priming Death IFNaR1 Granzymes, induced proapoptotic priming of CAR T-cell susceptibility in-receptors IFNγ BH3-only volved auto-/paracrine type-I IFN signaling loops and could Cancer CAR T-cell spread to bystander tumor cells. Strong tumor-intrinsic RIG-I/ Proapoptotic resistance priming MAVS signaling imprinted an activated cytolytic phenotype on tumor-interacting CAR T cells. Agonist-mediated targeting of the Caspase-3 RIG-I pathway in the tumor microenvironment rendered murine Apoptosis melanoma susceptible to CAR T-cell therapy in vivo with enhanced infiltration of active CAR T cells. Together, these data Cancer identify insufficient RIG-I/MAVS activity and associated impaired susceptibility cell death signaling in malignant cells as a resistance mechanism Created in BioRender. Heidegger, S. (2025) https://BioRender.com/v1z2d0c