Metabolic Nanoregulators\nInduce Ferroptosis and Change\nMetabolite Flow to Reverse Immunosuppressive Tumor Microenvironment

Aberrant energy and substance metabolic pathways of tumor\ncells\ncritically support tumor cell proliferation by hijacking the resources\nfrom nonmalignant cells, thereby establishing a metabolite flow favorable\nto tumor progression. This metabolic adaptation of tumor cells further\nmodulates the immune landscape, ultimately creating a tumor microenvironment\ncharacterized by drug resistance and immunosuppression. The synergistic\nregulation of energy and substance metabolic pathways might be a good\nantitumor therapeutic paradigm. However, due to the metabolic convergence,\nit is crucial to selectively modulate the aberrant metabolism of tumor\ncells without compromising the functionality of other cells. Small-molecule\ndrugs have the ability to target a wide range of biomolecules for\nantitumor therapy, but their application is limited by undesirable\ntoxicities. Constructing nanodrug delivery systems can improve their\nproperties and allow for the inclusion of multiple drugs, thereby\nexerting synergistic antitumor effects. In this study, we developed\na two-drug codelivery system using drugs-conjugated multibranched\npolymers to modulate tumor cell metabolism by exploiting synthetic\nlethal pathways for safe and effective antitumor therapy. By delivery\nof adapalene and erastin simultaneously through nanoparticles, the\nmaterial and energy metabolism of tumor cells can be regulated. This\nnanoparticle construction achieves tumor tissue targeting and responsive\ndrug release, alters metabolite flow within tumor cells, and effectively\nkills tumor cells. Additionally, the nanoparticles can reverse the\ntumor immunosuppressive microenvironment, starting from single-cell\nregulation to whole-lesion control.