Genetically engineered cellular membrane-camouflaged nanoparticles amplify immune response against recurrent metastatic triple-negative breast cancer.

Abstract

Cancer progression is driven by the dynamic interplay between metabolic reprogramming and immune evasion. A central mechanism is aerobic glycolysis, which fuels tumor growth while simultaneously impairing antitumor immunity. To address recurrent metastatic triple-negative breast cancer (TNBC), we developed a biomimetic nanoplatform (3BP@CP NPs) composed of high-affinity programmed death-1 (PD-1)-modified cell-membrane nanovesicles encapsulating 3-bromopyruvate (3BP)-loaded nanoparticles. The optimized nanoparticles exhibit enhanced pharmacokinetics with prolonged circulation, enabling dual programmed death-ligand 1 (PD-L1)-targeted tumor homing and checkpoint inhibition. The glycolytic inhibitor 3BP specifically inhibits hexokinase II (HK₂) activity, triggering metabolic collapse and immunogenic cell death while reversing immunosuppression in the tumor microenvironment (TME). This synergistic metabolic-immunological intervention elicits robust systemic antitumor responses, curtailing tumor recurrence and metastasis while extending survival in aggressive TNBC models. Collectively, this study establishes a therapeutic paradigm combining immune checkpoint receptor-modified cell-membrane nanovesicles (ICB CVs) with metabolic modulators to enhance immunotherapy efficacy in recurrent metastatic TNBC, providing a clinically translatable approach for PD-L1-expressing malignancies.