Enhancing Breast Cancer Immunotherapy by Suppressing Sympathetic Nervous System-Driven T-Cell Exhaustion and Promoting T-Cell Priming and Trafficking.

Immunotherapy has transformed cancer treatment, yet its efficacy in solid tumors such as breast cancer remains limited by weak T cell priming, impaired trafficking, and functional exhaustion within the tumor microenvironment. Sympathetic nervous system (SNS) hyperactivation has recently emerged as a driver of T cell exhaustion, representing a therapeutically actionable target. Here, we develop a multifunctional nanoplatform in which irradiated tumor lysate-pulsed dendritic cell (DC) membranes wrap lipid nanoparticles, enabling the codelivery of the β-adrenergic receptor blocker carvedilol and S1PR1 mRNA. These nanovesicles preferentially accumulate in tumor-draining lymph nodes, where they enhance antigen presentation and T cell priming. S1PR1 expression promotes T cell egress and trafficking, while carvedilol attenuates SNS-mediated exhaustion. In combination with PD-L1 blockade, this approach reinforced effector function in tumors, reduced tumor volume by 76%, extended median survival from 30 to 54 days, and achieved complete regression in 60% of animals. By simultaneously targeting priming, trafficking, activation, and exhaustion, this strategy provides an integrated approach to overcoming resistance in breast cancer.