Engineered macrophage membrane-mimicking nanodrugs activate cGAS/STING pathway to reverse tumor immune suppression after incomplete radiofrequency ablation

Incomplete radiofrequency ablation (iRFA) often results in tumor recurrence and therapeutic resistance, presenting significant clinical challenges. Tumors subjected to sublethal thermal injury activate the HSP70/ NQO1 antioxidant pathway and secrete elevated levels of CCL2, which recruits macrophages and fosters an immunosuppressive tumor microenvironment. To address these issues, this study engineered copper-doped ZIF-8 nanoparticles that co-deliver the hypoxia-activated prodrug TH-302 and the NQO1-targeting quinone β-lapachone, encapsulated within genetically engineered M1 macrophage membranes overexpressing CCR2 (CCR2-M). This innovative CCR2-M biomimetic coating enhances tumor targeting by sequestering excess CCL2, effectively reducing pro-tumoral macrophage infiltration. β-lapachone selectively targets NQO1-overexpressing tumor cells, elevating intracellular H 2 O 2 levels, while copper-doped ZIF-8 catalyzes Fenton-like reactions to generate cytotoxic hydroxyl radicals. Simultaneously, TH-302, responsive to hypoxia, complements β-lapachone by inducing cell death in hypoxic regions, thereby mitigating β-lapachone’s oxygen dependence. This synergistic ROS burst effectively suppressing tumor growth, activating the cGAS-STING pathway and enhancing tumor antigen presentation. This synergistic ROS burst effectively suppresses tumor growth, activates the cGAS-STING pathway and enhances tumor antigen presentation. This cascade recruits dendritic cells and cytotoxic CD8 + T cells, ultimately reversing the immunosuppressive microenvironment induced by iRFA. No drug-related toxicity was observed. Thus, this rationally designed nanotherapeutic strategy significantly curtails residual tumor growth and offers a promising immunomodulatory approach to overcoming therapeutic resistance in cancer treatment after iRFA.