Dual-Pronged Lipid Nanocarriers Promote Immunotherapy for TNBC by Inducing Immunogenic Cell Death and Activating Lymphoid Immune Cells.

Triple-negative breast cancer (TNBC) is recognized as the notoriously difficult molecular subtype of breast cancer to manage therapeutically, creating a pressing need for more effective treatment approaches. Immunochemotherapy is an emerging strategy with great clinical potential, but most focus on the tumor microenvironment itself and ignore the immune regulation of lymph nodes. Herewith, we report a dual-pronged approach of tumor-targeted paclitaxel-encapsulated nanoemulsion (PTX Emul, Phase II clinical trial) and lymph node-targeted chlorogenic acid-encapsulated self-emulsifying nanocarriers (CHA-SME) to elicit strong and selective immunogenic cell death (ICD) in the tumor and to activate immune cells in the lymph nodes, respectively, to achieve highly effective cancer immunotherapy. PTX Emul exhibited evident tumor targetability and superior tumor accumulation, induced potent ICD, and then efficiently stimulated the maturation of dendritic cells (DCs). CHA-SME demonstrates a substantial capacity to enhance drug accumulation within the mesenteric lymph nodes through the lymphatic transport pathway. Of note, PTX Emul combined with CHA-SME augmented the immunotherapeutic effects through highly efficient ICD induction within the tumor microenvironment of 4T1 orthotopic tumor, the potent DC maturation, and the effective activation of T cell-based antitumor immunity, resulting in a substantial enhancement in the inhibition of 4T1 orthotopic tumors and, notably, a reduction in lung metastasis. The dual-pronged approach of TNBC-targeted PTX Emul and lymph node-targeted CHA-SME by inducing ICD and activating lymphoid immune cells, which amplifies the systemic antitumor immune response, provides an interesting platform for potent immunochemotherapy of TNBC.