A smart polymer-based nanoplatform potentiates cancer ferroptosis-immunotherapy via perturbing metabolic compensation.

Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a promising strategy for antitumor immunotherapy. However, its therapeutic efficacy is hindered by the persistently high intracellular glutathione (GSH) level driven by metabolic compensation. Herein, we report a ferroptosis-inducible polymeric nanovesicle encapsulated with BAY-876 and ferrous ion (Fe2+) (FIPNV/B@Fe2+) to potentiate ferroptosis-immunotherapy via perturbing metabolic compensation. Mechanically, double bonds in the polymeric side chain deplete the intracellular GSH and coordinated Fe2+ facilitates lipid peroxidation, a process concomitant with GSH consumption. BAY-876 abrogates glucose utilization and suppresses the production of adenosine triphosphate (ATP), prostaglandin D2 (PGD2) and lactate. Consequently, GSH biosynthesis is inhibited through energy depletion and NADPH competition, thereby amplifying ferroptosis. Additionally, reduced extracellular lactate coupled with elevated glucose in the tumor microenvironment (TME) remodels the immunosuppressive TME by modulating tumor-associated macrophage polarization and T lymphocyte proliferation. In vivo studies validate that FIPNV/B@Fe2+ effectively suppresses 4 T1 tumor growth, recurrence, and rechallenge progression. Upon combination with the immune checkpoint inhibitor, this strategy further inhibits lung metastasis in both 4 T1 and B16F10 models. Overall, this study highlights the regulatory role of ATP and PGD2 in boosting ferroptosis and establishes a smart nanoplatform for synergistic regulation of ferroptosis-immunotherapy through metabolic compensation perturbation.