基因工程细胞膜伪装纳米颗粒增强复发性转移性三阴性乳腺癌免疫应答的研究

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 (HK 2 ) 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.