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  3. Potentiating immunotherapy in "immune-cold" solid tumors through orchestrating T cell immunity via tumor-specific genetic engineering

Potentiating immunotherapy in "immune-cold" solid tumors through orchestrating T cell immunity via tumor-specific genetic engineering

  • Cell Rep Med. 2025 Dec 16;6(12):102510. doi: 10.1016/j.xcrm.2025.102510.
Jiaqi He 1,  Chunguang Zhang 2,  Chao Liang 1,  Wenchi Xue 3,  Yongheng Li 4,  Lili Dai 5,  Chunyuan Liu 6,  Wan-Ru Zhuang 7,  Xianbin Ma 3,  Ran Cheng 1,  Yao Lei 7,  Weidong Nie 8,  Hai-Yan Xie 9
Affiliations

Affiliations

  • 1 School of Life Science, Beijing Institute of Technology, Beijing 100081, China.
  • 2 State Key Laboratory of Crop Gene Resources and Breeding, Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, Beijing 100081, China.
  • 3 School of Medical Technology, Beijing Institute of Technology, Beijing 100081, China.
  • 4 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, China.
  • 5 Department of Respiratory and Digestive, Qian'an Yanshan Hospital, Tangshan 064400, China.
  • 6 Department of Otorhinolaryngology, Qian'an Yanshan Hospital, Tangshan 064400, China.
  • 7 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Chemical Biology Center, Peking University, Beijing 100191, China.
  • 8 School of Life Science, Beijing Institute of Technology, Beijing 100081, China. Electronic address: [email protected].
  • 9 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Chemical Biology Center, Peking University, Beijing 100191, China; Peking University Ningbo Institute of Marine Medicine, Ningbo 315832, China. Electronic address: [email protected].
PMID: 41406950 DOI: 10.1016/j.xcrm.2025.102510
Abstract

We engineer a tumor-targeted genetic plasmid vector (PαCD3&LIGHT) to systematically modulate T cell immunity. The tumor-specific telomerase Reverse Transcriptase (TERT) promoter drives simultaneous expression of tumor necrosis factor superfamily member 14 (LIGHT) and membrane-anchored anti-CD3 single-chain variable fragment (αCD3), which are important immunomodulators with closely clinical relevance. Secreted LIGHT induces high endothelial venule formation and chemokine secretion to recruit circulating lymphocytes, while remodeling extracellular matrix to facilitate immune cell penetration into tumor parenchyma. αCD3 establishes artificial immunological synapses between tumor cells and T lymphocytes. This dual mechanism synergistically establishes tertiary lymphoid structures de novo even within deep tumor regions, harboring stem cell-like CD8+ T cells and driving sustained immunity. Concurrently, αCD3-mediated T cell redirection not only amplifies TCR signaling but also reverses exhausted T cells. The orchestrated T cell immunity significantly potentiates checkpoint inhibitor and chimeric antigen receptor (CAR)-T cell therapies in "immune-cold" tumors without obvious side effects and also remarkably enhances the outcome of human CAR-T cells, demonstrating translational potential in solid tumor immunotherapy.

Keywords

LIGHT; T cell immunotherapy; anti-CD3 scFv; chimeric antigen receptor T cell; immune checkpoint inhibitor; tumor-specific genetic engineering; “immune-cold” solid tumor.

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