Hybrid lipid nanoparticles with tumor antigen-primed dendritic cell membranes for post-surgical tumor immunotherapy.

Post-surgical tumor recurrence poses a major challenge in cancer treatment due to residual tumor cells and surgery-induced immunosuppression. Here, we developed hybrid nanoparticles, termed T-DCNPs, designed to promote antigen-specific activation of cytotoxic CD8+ T cells while concurrently inhibiting immunosuppressive pathways within the tumor microenvironment. T-DCNPs were formulated by co-extruding lipid nanoparticles containing a transforming growth factor β inhibitor with dendritic cells that were pre-treated with autologous neoantigens derived from surgically excised tumors. By using whole tumor antigens rather than specific peptides, T-DCNPs effectively overcame tumor heterogeneity and elicited a robust, targeted immune response. In vitro studies showed that T-DCNPs enhanced CD8+ T cell proliferation and reduced programmed death-1 (PD-1) expression, leading to increased antitumor cytotoxicity. In vivo experiments, involving intratumoral injections of T-DCNPs in distant tumor and post-surgical melanoma models, demonstrated a significant reduction in distant tumor growth, decreased recurrence rates, and extended survival compared to control groups. Flow cytometry and immunohistochemistry analyses further confirmed the enhanced infiltration of activated CD8+ T cells and a marked reduction in immunosuppressive markers, including PD-1 and Foxp3, within the treated tumors. These results suggest that T-DCNPs, through the dual mechanisms of tumor antigen-specific T cell activation and immune modulation, offer a promising strategy to prevent tumor recurrence following surgery and could potentially improve the efficacy of postoperative cancer immunotherapy.