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.
Niu et al. (Fri,) studied this question.