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Conventional treatments, including chemotherapy and immunotherapy, often face challenges such as limited efficacy, adverse side effects, and high recurrence rates. To address these limitations, a family of tri\u2010block chimeric proteins, cysteine\u2010tagged silk\u2010elastin\u2010like proteins (cSELPs), is designed to form responsive in situ hydrogels for treating late\u2010stage and metastatic TNBC. These cSELPs are de novo designed to integrate multiple functional protein motifs, including a photothermal agent binding motif, silk\u2010inspired crosslinking motifs, and elastin\u2010like thermo\u2010responsive motifs. This unique sequence design enables the cSELP hydrogels to exhibit in situ gelation, photothermal responsive release of chemotherapeutic agent doxorubicin and immune checkpoint inhibitor anti\u2010PD\u2010L1, and antibacterial properties, leading to effective tumor microenvironment remodeling. By promoting immunogenic cell death and stimulating immune activation, this approach converts immunosuppressive \u201ccold\u201d tumors into immunologically active \u201chot\u201d tumors. The cSELP hydrogel system demonstrates potent therapeutic efficacy against both primary and metastatic TNBC while maintaining excellent biocompatibility and long\u2010term safety. This protein material platform offers an innovative strategy to reshape the tumor microenvironment and combine multimodal treatments into a single biocompatible system, highlighting its potential for clinical translation.<\/jats:p>","DOI":"10.1002\/advs.202512355","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T18:33:34Z","timestamp":1761762814000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Genetically Engineered Light\u2010Responsive In Situ Hydrogels for Immunomodulation and Multimodal Therapy in Metastatic Triple\u2010Negative Breast Cancer"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7053-1240","authenticated-orcid":false,"given":"Xinchen","family":"Shen","sequence":"first","affiliation":[{"name":"The Zhejiang University\u2010University of Edinburgh Institute Zhejiang University School of Medicine Zhejiang University  Hangzhou 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