Targeting Hypoxic Tumor Plasticity for Recapturing Photodynamic‐Immunotherapy Sensitivity via Fluorinated Polysensitizers

Abstract Metabolic reprogramming is a key characteristics of tumor cells, mainly manifested by abnormal metabolism and tumor hypoxia. Here, the design of Poly^FBODIPY characterized by the presence of BODIPY photosensitizers, fluorinated aliphatic chains as Oxygen affinity materials, and reactive oxygen species‐sensitive thioketal linkers is reported. Poly^FBODIPY subsequently self‐assembles into NP@Poly^FBODIPY which is capable of delivering oxygen and photosensitizers simultaneously and generating ROS under light irradiation, resulting in rapid polymer degradation and nanoparticle dissociation via breaking ROS‐sensitive thiol ketal linkers. NP@Poly^FBODIPY can target hypoxic tumor plasticity to reprogram metabolism for recapturing photodynamic‐immunotherapy sensitivity for completely inhibiting tumor growth on multi‐drug‐resistant patient‐derived lung cancer xenografts (PDX^MDR). Moreover, NP@Poly^FBODIPY‐mediated photodynamic‐immunotherapy activates antitumor immune responses and effectively inhibits tumor growth and lung metastasis on an orthotropic metastatic triple‐negative breast cancer model. Mechanistically, metabolomics and lipidomics analysis reveals that NP@Poly^FBODIPY‐mediated photodynamic‐immunotherapy not only destroys the redox state of cancer cells, but also affects the metabolism of lipid, amino acid, and d‐glutamine, thereby finally promoting autophagy and apoptosis and inhibiting the proliferation of cancer cells. These results highlight the potential of clinical translation of NP@Poly^FBODIPY in targeting hypoxic tumor plasticity via oxygen supply, which reprograms the cellular metabolism for recapturing photodynamic‐immunotherapy sensitivity.