An in situ forming immunomodulatory hydrogel reinvigorates exhausted CD8 ⁺ T cells via preserving their mitochondrial fitness
7 affiliations
- 1Shanghai Key Laboratory for Molecular Engineering for Chiral Drugs, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P.R. China.
- 2Department of Pharmacy, Putuo People’s Hospital, School of Medicine, Tongji University, Shanghai 200060, P.R. China.
- 3Instrumental Analysis Centre, Shanghai Jiao Tong University, Shanghai 200240, P.R. China.
- 4Rehabilitation Department, Yancheng No.1 People’s Hospital, Affiliated Hospital of Medical School, Nanjing University, Yancheng 224000, P.R. China.
- 5Biomedical 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. China.
- 6Shanghai Frontiers Science Center of Drug Target Identification and Delivery, Shanghai Jiao Tong University, Shanghai, P.R. China.
- 7School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, P.R. China.
Abstract
CD8⁺ T cell exhaustion driven by mitochondrial dysfunction remains a major barrier to effective cancer immunotherapy. Here, we report an in situ forming d-α-tocopheryl polyethylene glycol succinate (TPGS)-based hydrogel [multifunctional thermosensitive composite gel (MTC Gel)] that reinvigorates exhausted CD8⁺ 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-mediated mitochondrial hijacking. Meanwhile, NLG919-loaded hybrid nanoparticles released from MTC Gel synergistically restore mitochondrial biogenesis in CD8⁺ T cells suppressed by indoleamine 2,3-dioxygenase 1. Across multiple murine tumor models, MTC Gel reprograms T cell immunity by reducing CD8⁺ 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.
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BibTeX
@article{qi2026situ,
title = {{An in situ forming immunomodulatory hydrogel reinvigorates exhausted CD8 ⁺ T cells via preserving their mitochondrial fitness}},
author = {Yiming Qi and Jing Li and Ziyan Chen and Chenming Zou and Haichao Zhu and Alice Shen Yi Shan and Yuli Fu and Jingwen Hou and Chaozhu Zheng and Qiongzhe Ren and Yu Qiao and Zhu Jin and Feihu Wang and Shengrong Guo},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.adz0039},
url = {https://www.science.org/doi/10.1126/sciadv.adz0039},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - An in situ forming immunomodulatory hydrogel reinvigorates exhausted CD8 ⁺ T cells via preserving their mitochondrial fitness
AU - Yiming Qi
AU - Jing Li
AU - Ziyan Chen
AU - Chenming Zou
AU - Haichao Zhu
AU - Alice Shen Yi Shan
AU - Yuli Fu
AU - Jingwen Hou
AU - Chaozhu Zheng
AU - Qiongzhe Ren
AU - Yu Qiao
AU - Zhu Jin
AU - Feihu Wang
AU - Shengrong Guo
PY - 2026
DA - 2026/10/23
JO - Science Advances
DO - 10.1126/sciadv.adz0039
UR - https://www.science.org/doi/10.1126/sciadv.adz0039
AB - CD8⁺ T cell exhaustion driven by mitochondrial dysfunction remains a major barrier to effective cancer immunotherapy. Here, we report an in situ forming d-α-tocopheryl polyethylene glycol succinate (TPGS)-based hydrogel [multifunctional thermosensitive composite gel (MTC Gel)] that reinvigorates exhausted CD8⁺ 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-mediated mitochondrial hijacking. Meanwhile, NLG919-loaded hybrid nanoparticles released from MTC Gel synergistically restore mitochondrial biogenesis in CD8⁺ T cells suppressed by indoleamine 2,3-dioxygenase 1. Across multiple murine tumor models, MTC Gel reprograms T cell immunity by reducing CD8⁺ 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.
SN - 2375-2548
ER -