Simultaneous Cholesterol Reduction and cGAS-STING Pathway Amplification: A Novel Enzyme Cascade Strategy against Tumor Resistance

Drug resistance remains a significant challenge in cancer therapy, and current strategies typically involve the use of P-glycoprotein (P-gp) inhibitors. Unfortunately, the rigid surface of drug-resistant cancer cell membranes and the immunosuppressive tumor microenvironment severely limit the therapeutic efficacy. Here, we report a novel nanoparticle platform named DOX@CM@M, which can efficiently reverse tumor resistance through cholesterol depletion, while robustly enhancing antitumor effects by activating innate immunity. The platform utilizes Fe/Mn hybrid metal–organic frameworks (MOF) to encapsulate doxorubicin (DOX) and cholesterol oxidase (COD), and further modifies with the cancer cell membrane (CCM) to enhance tumor targeting. The acidic and GSH-rich environment within tumor cells provides the possibility of responsive degradation. Based on the release of the natural enzyme COD and the peroxidase-like properties of Fe³⁺/Mn²⁺, cholesterol is effectively depleted in a “turning foe into friend” manner, promoting the effective accumulation of the chemotherapy model drug DOX and reversing tumor resistance. Notably, the activation of the cGAS-STING pathway by DOX can be further amplified by Mn²⁺, synergistically enhancing the innate immune response. In vivo results demonstrate that DOX@CM@M nanoparticles (NPs) significantly inhibit tumor growth, reduce cholesterol content, and promote DC maturation, providing a new approach to reversing tumor resistance.