2. Academic Validation
  3. FcεRIγ Reinforces Double-Negative T cell-mediated Antibody-dependent Cellular Cytotoxicity Against Tumor Cells

FcεRIγ Reinforces Double-Negative T cell-mediated Antibody-dependent Cellular Cytotoxicity Against Tumor Cells

  • J Mol Cell Biol. 2026 Jan 2:mjaf059. doi: 10.1093/jmcb/mjaf059.
Shuai Shao 1 2 3 4,  Xiaotong Han 5 6,  Tianzhen Zhang 1 2 3 4,  Lu Yang 1 2 3 4,  Mingyang Li 1 2 3,  Zihan Zhang 5 6,  Xiaonan Du 5 6,  Hua Jin 5 6,  Songlin Wang 7,  Yingchi Yang 1 2 3 4,  Zhongtao Zhang 1 2 3 4,  Guangyong Sun 5 6,  Dong Zhang 5 6 7,  Dan Tian 1 2 3 4
Affiliations

Affiliations

  • 1 General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
  • 2 Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing Clinical Research Institute and Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
  • 3 National Clinical Research Center for Digestive Disease, Beijing 100050, China.
  • 4 State Key Lab of Digestive Health, Beijing 100050, China.
  • 5 Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
  • 6 Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
  • 7 Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing 100069, China.
PMID: 41481135 DOI: 10.1093/jmcb/mjaf059
Abstract

Double-negative T (DNT) cells (TCRαβ+CD4-CD8-NK1.1-/CD56-) exhibit strong tumor-killing capabilities. Our single-cell transcriptome analysis has revealed high Fcer1g expression in DNT cells, but its role in tumor immunity remains unclear. In this study, we demonstrated that IgG1 stimulation significantly upregulated IgG Fc Receptors and cytotoxic molecules in DNT cells, enhancing their cytotoxicity against MC38 tumor cells in vitro. Fcer1g-deficient DNT cells failed to respond effectively to IgG1 stimulation. Inhibiting the downstream spleen tyrosine kinase (Syk) of FcεRIγ reduced cytotoxicity of DNT cells and phosphorylation levels of molecules such as Akt and NF-κB. In a subcutaneous tumor model, combined treatment with DNT cells and tumor-specific antibodies more effectively inhibited tumor growth compared to DNT cells alone, while Fcer1g-deficient DNT cells combined with antibodies showed no significant difference in efficacy compared to DNT cells alone, suggesting that DNT cells enhance tumor cell killing via FcεRIγ-mediated antibody-dependent cellular cytotoxicity (ADCC). These results indicate that DNT cells mediate antitumor ADCC effects through high FcεRIγ expression. Binding of IgG1 to FcεRIγ activates the FcεRIγ/Syk/Akt/NF-κB pathway, consequently enhancing tumor cell killing. Thus, DNT cells may play a significant role in Cancer immunity, providing a basis for novel immune cell and antibody combination therapies.

Keywords

Fc receptor γ chain; T cell therapy; antibody-dependent cellular cytotoxicity; double-negative T cells; tumor immunology.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15968
    99.49%, Syk Inhibitor
    Syk