A novel switch receptor enhances CAR-T cell fitness in TGF-β-enriched solid tumors 3396

Description Immunosuppression in the tumor microenvironment is a major barrier to the efficacy of CAR-T cells in solid cancers, especially driven by TGF-β. We engineered a novel chimeric receptor to overcome TGF-β-induced immunosuppression in CAR-T cells. The switch receptor comprised a truncated type II TGF-β receptor linked to a 4-1BB intracellular domain. The receptor’s structure, signaling network and in vitro function were tested upon TGF-β stimulation. In vivo efficacy and mechanism studies were performed in TGF-βhi prostate and breast tumor models. Switch receptors formed TGF-β-dependent homodimers without disrupting the endogenous TGF-β receptor complex and preserved TGF-β-SMAD homeostatic signaling in CAR-T cells. Switch CAR-T cells promoted MAPK-mediated immune activation, a unique transcriptional profile, enhanced effector function, and increased mitochondria biogenesis and proliferative capacity after chronic antigen exposure in response to TGF-β. Switch CAR-T cells showed superior efficacy in both xenograft models and prolonged survival in mice. Tumor-infiltrating switch CAR-T cells had enhanced activation, sustained cytokine production and reduced exhaustion-related molecules. Switch CAR-T cells were only activated in the tumor, in the periphery they preserved a naïve/memory-like phenotype. Switch receptors rewire TGF-β-induced suppression into tumor-specific immune activation while preserving TGF-β homeostasis signaling, thereby improving CAR-T cell fitness in solid tumors.