2. Academic Validation
  3. Retinoic acid enhances γδ T cell cytotoxicity in nasopharyngeal carcinoma by reversing immune exhaustion

Retinoic acid enhances γδ T cell cytotoxicity in nasopharyngeal carcinoma by reversing immune exhaustion

  • Cell Commun Signal. 2025 Mar 29;23(1):156. doi: 10.1186/s12964-025-02161-8.
Guichao Liu # 1 2 3,  Qiang Quan # 1 3,  Lanhong Pan # 1 3 4,  Haibo Duan # 1 3,  Guojun Zhang 1 3,  Ke Li 5,  Xinhai Zhu 6 7,  Dongdong Zhang 8,  Peng Li 9 10,  Jianfu Zhao 11 12
Affiliations

Affiliations

  • 1 The First Affiliated Hospital, Jinan University, Guangzhou, China.
  • 2 Department of Radiation Oncology, The First People'S Hospital of Foshan City, Foshan, China.
  • 3 Department of Oncology, Research Center of Cancer Diagnosis and Therapy, The First Affiliated Hospital, Jinan University, Guangzhou, China.
  • 4 Department of Ultrasound Medicine, The First Affiliated Hospital, Jinan University, Guangzhou, China.
  • 5 Department of Geriatrics, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China.
  • 6 The First Affiliated Hospital, Jinan University, Guangzhou, China. robin82613@163.com.
  • 7 Department of Oncology, Research Center of Cancer Diagnosis and Therapy, The First Affiliated Hospital, Jinan University, Guangzhou, China. robin82613@163.com.
  • 8 Department of Thoracic Surgery, The First Affiliated Hospital, Jinan University, Guangzhou, China. zhangdd@jnu.edu.cn.
  • 9 Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People'S Hospital Affiliated with Jinan University, Jinan University, Zhuhai, China. pengli1991@jnu.edu.cn.
  • 10 Faculty of Medical Science, The Biomedical Translational Research Institute, Jinan University, Guangzhou, China. pengli1991@jnu.edu.cn.
  • 11 The First Affiliated Hospital, Jinan University, Guangzhou, China. zhaojianfu@jnu.edu.cn.
  • 12 Department of Oncology, Research Center of Cancer Diagnosis and Therapy, The First Affiliated Hospital, Jinan University, Guangzhou, China. zhaojianfu@jnu.edu.cn.
  • # Contributed equally.
PMID: 40158172 DOI: 10.1186/s12964-025-02161-8
Abstract

Recent studies have shown that the antitumor immunity of adaptive immune cells is regulated by Vitamin A (retinoic acid, RA). However, it remains unclear whether RA and retinoic acid receptor (RAR) signaling can modulate antitumor immunity by reversing immune exhaustion of innate-like γδ T cells in human nasopharyngeal carcinoma (NPC). Periphery blood samples from patients with NPC were prospectively collected, and phenotypic and functional analyses of γδ T cells were performed using flow cytometry. Tumor-bearing models and RAR inhibitor approaches were utilized to investigate RA/RAR-mediated regulation of T cell immunoglobulin domain and Mucin domain 3 (TIM-3) and the antitumor activity of γδ T cells. Here, our findings indicate that immune exhaustion markers are highly expressed on peripheral αβ and γδ T cells in NPC patients. Serum RA levels are negatively correlated with the abundance of TIM-3 on circulating Vδ2 T cells. Mechanistic studies have demonstrated that RA/RAR signaling directly targets Vδ2 T cells, repressing TIM-3 expression, promoting NF-κB activation, and enhancing the production of antitumor-related cytokines. Notably, RA supplementation improved the efficacy of Vδ2 T cell-mediated immunotherapy in human NPC by suppressing TIM-3 expression. Collectively, these findings suggest that RA/RAR signaling plays a crucial role in reversing immune exhaustion and represents a promising target for γδ T cell antitumor immunotherapy.

Keywords

Retinoic acid; Retinoic acid receptor; Tim-3; Tumor immunity; γδ T cells.

Figures
Products
Inhibitors & Agonists
Other Products