F-box only protein 38 (FBXO38) is a member of the F-box family that mediates the ubiquitination and proteasome degradation of programmed death 1 (PD-1), and thus has important effects on T cell-related immunity. While its powerful role in adaptive immunity has attracted much attention, its regulatory roles in innate immune pathways remain unknown. The cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway is an important innate immune pathway that regulates type I interferons. STING protein is the core component of this pathway. In this study, we identified that FBXO38 deficiency enhanced tumor proliferation and reduced tumor CD8⁺ T cells infiltration. Loss of FBXO38 resulted in reduced STING protein levels in vitro and in vivo, further leading to preventing cGAS–STING pathway activation, and decreased downstream product IFNA1 and CCL5. The mechanism of reduced STING protein was associated with lysosome-mediated degradation rather than proteasomal function. Our results demonstrate a critical role for FBXO38 in the cGAS–STING pathway.

F-box 唯一蛋白 38 (FBXO38) 是 F-box 家族的成员，介导程序性死亡 1 (PD-1) 的泛素化和蛋白酶体降解，因此对 T 细胞相关免疫具有重要影响。虽然其在适应性免疫中的强大作用引起了广泛关注，但其在先天免疫途径中的调节作用仍然未知。环 GMP-AMP 合酶-干扰素基因刺激剂 (cGAS-STING) 途径是调节 I 型干扰素的重要先天免疫途径。STING 蛋白是该通路的核心成分。在这项研究中，我们发现 FBXO38 缺陷会增强肿瘤增殖并减少肿瘤 CD8 ⁺ T 细胞浸润。FBXO38 的缺失导致体外和体内STING 蛋白水平降低，进一步导致阻止 cGAS-STING 通路激活，并减少下游产物 IFNA1 和 CCL5。STING 蛋白减少的机制与溶酶体介导的降解有关，而不是与蛋白酶体功能有关。我们的结果证明了 FBXO38 在 cGAS-STING 通路中的关键作用。