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Besides, hypoxia seriously restricts O2-dependent reactive oxygen species (ROS) generation, thereby severely compromising the therapeutic efficacy of photodynamic therapy (PDT). To address these challenges, we developed a multifunctional manganese (Mn)-based nanozyme (MLDHI) loaded with indocyanine green (ICG) to reprogram the immunosuppressive TME for potentiated phototherapy combined with immunotherapy. Upon intratumoral injection, the Mn4+ doped within the nanozyme shell catalyzes the decomposition and conversion of overexpressed H2O2 in the tumor tissue into O2, markedly alleviating hypoxia and supplying O2 for ICG-mediated PDT to enhance cytotoxic ROS production. The resulting phototherapeutic efficacy promotes immunogenic cell death (ICD) of tumor cells and releases double-stranded deoxyribonucleic acid (dsDNA), which together with Mn2+ embedded in the lamellar structure synergistically activates the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway, triggering interferon (IFN)-\u03b2 release and dendritic cell (DC) maturation. In a breast tumor model, a single intratumoral injection of MLDHI plus laser irradiation achieved 75% tumor ablation and elicited robust immune memory to prevent recurrence and metastasis.<\/jats:p>","DOI":"10.1021\/acsnano.6c11600","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T09:01:47Z","timestamp":1788771707000},"page":"25720-25734","source":"Crossref","is-referenced-by-count":0,"title":["Nanozyme-Driven\nTumor Microenvironment Remodeling\nfor Potentiated Phototherapy\u2013Immunotherapy"],"prefix":"10.1021","volume":"20","author":[{"given":"Chenlu","family":"Huang","sequence":"first","affiliation":[{"name":"Chinese Academy of Medical Sciences & Peking Union Medical College , , ,","place":["Tianjin, China, 300192"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanyong","family":"Wang","sequence":"additional","affiliation":[{"name":"Chinese Academy of Medical Sciences & Peking Union Medical College , , ,","place":["Tianjin, China, 300192"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Yang","sequence":"additional","affiliation":[{"name":"Chinese Academy of Medical Sciences & Peking Union Medical College , , ,","place":["Tianjin, China, 300192"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxi","family":"Yu","sequence":"additional","affiliation":[{"name":"Chinese Academy of Medical Sciences & Peking Union Medical College , , ,","place":["Tianjin, China, 300192"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shamei","family":"Luo","sequence":"additional","affiliation":[{"name":"Chinese Academy of Medical Sciences & Peking Union Medical College , , ,","place":["Tianjin, China, 300192"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai","family":"Wang","sequence":"additional","affiliation":[{"name":"Chinese Academy of Medical Sciences & Peking Union Medical College , , ,","place":["Tianjin, China, 300192"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangzhou","family":"Li","sequence":"additional","affiliation":[{"name":"Chinese Academy of Medical Sciences & Peking Union Medical College , , ,","place":["Tianjin, China, 300192"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1857-8444","authenticated-orcid":true,"given":"Linhua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Chinese Academy of Medical Sciences & Peking Union Medical College , , ,","place":["Tianjin, China, 300192"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2401-3001","authenticated-orcid":true,"given":"Dunwan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Chinese Academy of Medical Sciences & Peking Union Medical College , , ,","place":["Tianjin, China, 300192"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"issue":"1","key":"2026092210073607200_cit1","doi-asserted-by":"publisher","first-page":"8416","DOI":"10.1038\/s41467-024-51995-2","article-title":"Hypoxia induces ROS-resistant memory upon reoxygenation\nin vivo promoting metastasis in part via MUC1-C","volume":"15","author":"Godet","year":"2024","journal-title":"Nat. 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