The interferon (IFN) pathway is critical for cytotoxic T cell activation, which is central to tumor immunosurveillance and successful immunotherapy. We demonstrate here that PKCλ/ι inactivation results in the hyper-stimulation of the IFN cascade and the enhanced recruitment of CD8⁺ T cells that impaired the growth of intestinal tumors. PKCλ/ι directly phosphorylates and represses the activity of ULK2, promoting its degradation through an endosomal microautophagy-driven ubiquitin-dependent mechanism. Loss of PKCλ/ι results in increased levels of enzymatically active ULK2, which, by direct phosphorylation, activates TBK1 to foster the activation of the STING-mediated IFN response. PKCλ/ι inactivation also triggers autophagy, which prevents STING degradation by chaperone-mediated autophagy. Thus, PKCλ/ι is a hub regulating the IFN pathway and three autophagic mechanisms that serve to maintain its homeostatic control. Importantly, single-cell multiplex imaging and bioinformatics analysis demonstrated that low PKCλ/ι levels correlate with enhanced IFN signaling and good prognosis in colorectal cancer patients.

干扰素 (IFN) 通路对细胞毒性 T 细胞活化至关重要，这对肿瘤免疫监视和成功的免疫治疗至关重要。我们在此证明 PKCλ/ι 失活导致 IFN 级联的过度刺激和 CD8 ^{+的增强募集}阻碍肠道肿瘤生长的 T 细胞。PKCλ/ι 直接磷酸化和抑制 ULK2 的活性，通过内体微自噬驱动的泛素依赖性机制促进其降解。PKCλ/ι 的缺失导致酶活性 ULK2 水平升高，ULK2 通过直接磷酸化激活 TBK1 以促进 STING 介导的 IFN 反应的激活。PKCλ/ι 失活也会触发自噬，从而防止分子伴侣介导的自噬对 STING 的降解。因此，PKCλ/ι 是调节 IFN 通路和三种自噬机制的中枢，用于维持其稳态控制。重要的是，单细胞多重成像和生物信息学分析表明，低 PKCλ/ι 水平与增强的 IFN 信号传导和结直肠癌患者的良好预后相关。