<p>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 H₂O₂ 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. </p> Graphic abstract <p></p>