Active Iron‐Drug Nanocomplexes Improve Photodynamic and Photothermal Cancer Therapy by Mitigating Tumor Hypoxia and Counteracting Tumor Heat Resistance

Abstract Photodynamic therapy (PDT) and photothermal therapy (PTT) offer the advantages of precise temporal and spatial selectivity in cancer treatment, minimizing damage to normal cells while effectively eliminating tumor cells. However, the therapeutic efficacy of phototherapy is always hindered by challenges such as hypoxia and tumor heat resistance. Herein, a pH‐responsive metal‐drug nanocomplex (denoted as PAFH) comprising hypericin (HYP), apigenin (APG), polyvinylpyrrolidone (PVP), and Fe 3+ is developed to enhance the therapeutic efficacy of PDT and PTT. The PAFH nanocomplex exhibits photothermal properties under 808 nm laser irradiation, which can disassociate in response to the acidic tumor microenvironment and the temperature increase induced by PTT, thereby eventually triggering the on‐site release of APG and HYP. The released APG inhibits the synthesis of heat shock protein HSP‐90, facilitating the PAFH‐mediated PTT to kill tumor cells at mild temperature. Additionally, APG alleviates hypoxia and then regulates the expression of hypoxia‐inducible factor HIF‐1𝛼, increasing cellular oxygen levels to produce singlet oxygen for enhanced HYP‐mediated PDT and inhibiting tumor metastasis. Ultimately, this sophisticated nanosystem represents an advanced strategy to promote PDT and PTT by mitigating tumor hypoxia and counteracting tumor heat resistance, significantly improving therapeutic efficacy for precise cancer therapy.