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

Authors: Lin Gao et al.

Journal:ACS Nano (2025).

Research Areas:Nanomedicine, Cancer Immunotherapy, Breast Cancer Research, Tumor Immunology, Nanobiotechnology, Drug Delivery Systems.

Cell Lines:The 4T1 murine mammary carcinoma cell lines, CTLL-2 murine cytotoxic T lymphocyte cell lines, PC12 rat pheochromocytoma cell lines and DC2.4 dendritic cell lines.

Summary: Breast cancer immunotherapy is limited by multiple challenges, including weak T-cell priming, impaired trafficking, and T-cell exhaustion driven by the sympathetic nervous system (SNS).To develop a novel nanoplatform that simultaneously addresses multiple T-cell-related barriers and enhances the efficacy of breast cancer immunotherapy.A multifunctional MCLD nanoplatform was constructed, consisting of lipid nanoparticles loaded with carvedilol and S1PR1 mRNA, encapsulated by dendritic cell (DC) membranes pulsed with irradiated tumor lysates. During the experiments, Hiscore products were utilized to ensure the accuracy of cell-based assays: the Halo counter HD-4 Cell Counter(Hiscore Inc.) enabled precise counting of 4T1, PC12, and other cell lines, guaranteeing uniform seeding densities in experiments such as Transwell co-culture and minimizing errors; the EOS1 Cell Imaging System (Hiscore Inc.) allowed real-time observation of co-cultured cell status, intuitively capturing cell morphology and interactions to provide reliable basis for subsequent analyses. Therapeutic evaluation was conducted in murine models by combining this platform with PD-L1 blockade.The MCLD nanoplatform could target tumor-draining lymph nodes, enhance T-cell priming and trafficking, and inhibit T-cell exhaustion. When combined with PD-L1 blockade, it reduced tumor volume by 76%, achieved complete tumor regression in 60% of mice, significantly prolonged median survival, and induced long-term antitumor immune memory.

This study provides an integrated strategy for solid tumor immunotherapy, breaking through the bottlenecks of traditional treatments. Meanwhile, the application of Hiscore products offers critical support for the accuracy of cell experiments, providing a reference for methodological optimization in related research.

Keywords: Sympathetic nervous system, T cell exhaustion, S1PR1 mRNA, dendritic cell (DC) membranes, breast cancer.