TBC1 domain family member 23 is essential for STING-mediated anti-melanoma effect

  • Mol Biomed. 2026 Feb 27;7(1):16. doi: 10.1186/s43556-026-00418-3.
Shenghui Niu  #  1 ,  Guangmei Li  #  2 ,  Pengcheng Wei  1 ,  Xiang Hu  2 ,  Junhong Qin  1 ,  Yin Yuan  1 ,  Jinrui Wang  1 ,  Yingfeng Tu  1 ,  Lin Zhao  1 ,  Luoting Yu  3  4 ,  Da Jia  5  6
Affiliations
  • 1. Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, 610041, China.
  • 2. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, 610041, China.
  • 3. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, 610041, China. [email protected].
  • 4. Children's Medicine Key Laboratory of Sichuan Province, Sichuan University, Chengdu, 610041, China. [email protected].
  • 5. Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, 610041, China. [email protected].
  • 6. Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu, 610041, China. [email protected].
  • # Contributed equally.
PMID: 41748771 DOI: 10.1186/s43556-026-00418-3
Abstract

The innate immune cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway plays a central role in antitumor immune responses. Cytosolic DNA recognition by cGAS leads to cGAMP production, activating STING and downstream effectors TANK-binding kinase 1 (TBK1) and Interferon regulatory factor 3 (IRF3). This signaling induces the production of type I interferons (IFN-I) and chemokines, facilitating CD8⁺ T cell activation and recruitment to enhance antitumor immunity. The cGAS-STING pathway is critically regulated by vesicular trafficking, which governs its spatially resolved activation across multiple subcellular compartments, thereby facilitating precise control of innate immune signaling. TBC1 domain family member 23 (TBC1D23), a member of the Tre2-Bub2-Cdc16 (TBC) family, is a key regulator of intracellular vesicle transport and is required for trafficking TBK1 from endosomes to the trans-Golgi network. Although Tbc1d23 deletion impairs STING-induced IFN-I production, its physiological role in antitumor immunity remains unclear. Here, we report that high TBC1D23 expression correlates with enhanced immune infiltration and favorable prognosis in melanoma. Conversely, TBC1D23 deficiency severely impairs the STING-dependent expression of key IFN-inducible chemokines, suppresses immunostimulatory macrophage maturation, and diminishes the infiltration, activation, and cytotoxic function of tumor-antigen-specific CD8⁺ T cells. Consequently, loss of TBC1D23 accelerates melanoma progression. Our findings establish TBC1D23 as an essential regulator of STING signaling and a critical mediator of antitumor immunity.

Keywords
Antitumor immunity; CD8+ T cell infiltration; Melanoma; Stimulator of interferon genes (STING) signaling; TBC1 domain family member 23 (TBC1D23).
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