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However, the therapeutic efficacy of phototherapy is always hindered by challenges such as hypoxia and tumor heat resistance. Herein, a pH\u2010responsive metal\u2010drug nanocomplex (denoted as PAFH) comprising hypericin (HYP), apigenin (APG), polyvinylpyrrolidone (PVP), and Fe<jats:sup>3+<\/jats:sup> is developed to enhance the therapeutic efficacy of PDT and PTT. The PAFH nanocomplex exhibits photothermal properties under 808\u00a0nm laser irradiation, which can disassociate in response to the acidic tumor microenvironment and the temperature increase induced by PTT, thereby eventually triggering the on\u2010site release of APG and HYP. The released APG inhibits the synthesis of heat shock protein HSP\u201090, facilitating the PAFH\u2010mediated PTT to kill tumor cells at mild temperature. Additionally, APG alleviates hypoxia and then regulates the expression of hypoxia\u2010inducible factor HIF\u20101\ud835\udefc, increasing cellular oxygen levels to produce singlet oxygen for enhanced HYP\u2010mediated 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.<\/jats:p>","DOI":"10.1002\/adhm.202404485","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T18:43:26Z","timestamp":1741718606000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Active Iron\u2010Drug Nanocomplexes Improve Photodynamic and Photothermal Cancer Therapy by Mitigating Tumor Hypoxia and Counteracting Tumor Heat Resistance"],"prefix":"10.1002","volume":"14","author":[{"given":"Yuying","family":"Yin","sequence":"first","affiliation":[{"name":"State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macau  Macau SAR 999078 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