Rewiring dendritic cell function with CLEC9A and DEC205-based chimeric antigen receptors

Abstract Dendritic cells (DCs) are central orchestrators of anti-tumor immunity, yet their therapeutic utility has been limited by dysfunction and insufficient activation within solid tumors. Here, we report chimeric antigen receptor-engineered DCs (CAR-DCs) that potently prime T cells and reprogram the tumor microenvironment. We identify the intracellular domains of CLEC9A or DEC205 as essential for functional CAR-DC activity, enabling enhanced antigen uptake, cross-presentation, and robust cytokine production that drive strong T cell expansion and effector differentiation. Mechanistically, CARs incorporating CLEC9A or DEC205 intracellular domains triggered SYK phosphorylation and downstream signaling pathways. In both murine and humanized models, CAR-DC therapy suppressed tumor growth and promoted expansion of tumor-reactive T cells. These findings establish CAR-DCs as a scalable and clinically translatable platform for next-generation solid tumor immunotherapy.