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Here, a cysteine-inspired conjugated polymer photosensitizer (CP-PCys) was developed to integrate enhanced tumor accumulation, hydrogen sulfide (H2S) generation, photodynamic therapy (PDT), and photothermal therapy (PTT). Dense cysteine functionalization promoted cellular uptake, resulting in approximately 2.4-fold higher accumulation in 4T1 cells than that of the polyethylene glycol-functionalized control after 24 h. Meanwhile, the conjugated backbone enabled NIR-II fluorescence imaging, a photothermal conversion efficiency of 52.3%, and efficient reactive oxygen species generation (58.6%). Intracellular H2S disrupted energy metabolism and suppressed HSP70 expression, while PDT-generated reactive oxygen species further reinforced this effect. Combined irradiation reduced HSP70 expression to approximately 57% of the PBS control level, thereby sensitizing tumor cells to PTT. Conversely, PTT-induced hyperthermia enhanced reactive oxygen species generation and potentiated PDT, aggravating mitochondrial dysfunction and DNA damage. In 4T1 tumor-bearing mice, CP-PCys rapidly accumulated in tumors and produced stable mild photothermal heating. Combined PDT\u2013PTT achieved an 89% tumor inhibition rate without detectable skin injury or systemic toxicity, demonstrating the potential of CP-PCys for effective and atraumatic cancer phototherapy.<\/jats:p>","DOI":"10.1021\/acsami.6c14572","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T20:02:25Z","timestamp":1789675345000},"page":"52154-52167","source":"Crossref","is-referenced-by-count":0,"title":["Cysteine-Inspired Photosensitizer with Efficient Tumor Accumulation Enables Thermoresistance Reversal for Reciprocal Enhancement of Photodynamic\u2013Photothermal Therapy"],"prefix":"10.1021","volume":"18","author":[{"given":"Yan","family":"Yuan","sequence":"first","affiliation":[{"name":"State Key Laboratory of Flexible Electronics (LoFE) & Institute of Advanced Materials (IAM), School of Flexible Electronics (Future Technologies), Nanjing Tech University (NanjingTech) , ,","place":["Nanjing, China, 211816"]},{"name":"Nanjing Tech University , , ,","place":["Nanjing, China, 211816"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijie","family":"Fang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Flexible Electronics (LoFE) & Institute of Advanced Materials (IAM), School of Flexible Electronics (Future Technologies), Nanjing Tech University (NanjingTech) , ,","place":["Nanjing, China, 211816"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiqing","family":"Yue","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Flexible Electronics (LoFE) & Institute of Advanced Materials (IAM), School of Flexible Electronics (Future Technologies), Nanjing Tech University (NanjingTech) , ,","place":["Nanjing, China, 211816"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liuqi","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Flexible Electronics (LoFE) & Institute of Advanced Materials (IAM), School of Flexible Electronics (Future Technologies), Nanjing Tech University (NanjingTech) , ,","place":["Nanjing, China, 211816"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Cao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Flexible Electronics (LoFE) & Institute of Advanced Materials (IAM), School of Flexible Electronics (Future Technologies), Nanjing Tech University (NanjingTech) , ,","place":["Nanjing, China, 211816"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zilong","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Flexible Electronics (LoFE) & Institute of Advanced Materials (IAM), School of Flexible Electronics (Future Technologies), Nanjing Tech University (NanjingTech) , ,","place":["Nanjing, China, 211816"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8017-6844","authenticated-orcid":true,"given":"Xiaojun","family":"Chen","sequence":"additional","affiliation":[{"name":"Nanjing Tech University , , ,","place":["Nanjing, China, 211816"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8841-2373","authenticated-orcid":true,"given":"Jie","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Flexible Electronics (LoFE) & Institute of Advanced Materials (IAM), School of Flexible Electronics (Future Technologies), Nanjing Tech University (NanjingTech) , ,","place":["Nanjing, China, 211816"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"2026093001081803700_cit1","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1038\/s41573-020-0090-8","article-title":"Engineering precision nanoparticles for drug delivery","volume":"20","author":"Mitchell","year":"2021","journal-title":"Nat. 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