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Adv."],"published-print":{"date-parts":[[2026,10,23]]},"abstract":"<jats:p>\n                    CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell exhaustion driven by mitochondrial dysfunction remains a major barrier to effective cancer immunotherapy. Here, we report an in situ forming\n                    <jats:sc>d<\/jats:sc>\n                    -\u03b1-tocopheryl polyethylene glycol succinate (TPGS)\u2013based hydrogel [multifunctional thermosensitive composite gel (MTC Gel)] that reinvigorates exhausted CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells by preserving mitochondrial fitness through a two-pronged strategy. After intratumoral injection, MTC Gel rapidly undergoes gelation at physiological temperature and dissociates to generate a high local concentration of TPGS, which targets cancer cell mitochondria to trigger prodeath mitophagy. This process induces robust immunogenic cell death (ICD) and blocks tunneling nanotube\u2013mediated mitochondrial hijacking. Meanwhile, NLG919-loaded hybrid nanoparticles released from MTC Gel synergistically restore mitochondrial biogenesis in CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells suppressed by indoleamine 2,3-dioxygenase 1. Across multiple murine tumor models, MTC Gel reprograms T cell immunity by reducing CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells exhaustion while enhancing effector and cytotoxic functions, thereby eliciting potent tumoricidal activity. These findings highlight this rationally designed hydrogel system as a clinically translatable platform for next-generation ICD-based cancer immunotherapies.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.adz0039","type":"journal-article","created":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T17:58:42Z","timestamp":1792778322000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["An in situ forming immunomodulatory hydrogel reinvigorates exhausted CD8\n                    <sup>+<\/sup>\n                    T cells via preserving their mitochondrial fitness"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0530-6661","authenticated-orcid":true,"given":"Yiming","family":"Qi","sequence":"first","affiliation":[{"name":"Shanghai Key Laboratory for Molecular Engineering for Chiral Drugs, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P.R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0571-6022","authenticated-orcid":true,"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Putuo People\u2019s Hospital, School of Medicine, Tongji University, Shanghai 200060, P.R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8297-1258","authenticated-orcid":true,"given":"Ziyan","family":"Chen","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory for Molecular Engineering for Chiral Drugs, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P.R. 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China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7977-4453","authenticated-orcid":true,"given":"Alice","family":"Shen Yi Shan","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory for Molecular Engineering for Chiral Drugs, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P.R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuli","family":"Fu","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory for Molecular Engineering for Chiral Drugs, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P.R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwen","family":"Hou","sequence":"additional","affiliation":[{"name":"Instrumental Analysis Centre, Shanghai Jiao Tong University, Shanghai 200240, P.R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaozhu","family":"Zheng","sequence":"additional","affiliation":[{"name":"Rehabilitation Department, Yancheng No.1 People\u2019s Hospital, Affiliated Hospital of Medical School, Nanjing University, Yancheng 224000, P.R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0904-3627","authenticated-orcid":true,"given":"Qiongzhe","family":"Ren","sequence":"additional","affiliation":[{"name":"Biomedical Polymers Laboratory, College of Chemistry Chemical Engineering and Materials Science and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, P.R. 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