PKCλ/ι inhibition activates an ULK2-mediated interferon response to repress tumorigenesis

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. [Display omitted] •Low PKCλ/ι levels correlate with enhanced IFN signaling and good prognosis in CRC•PKCλ/ι loss inhibits intestinal tumorigenesis through IFN and CD8+ T cell recruitment•PKCλ/ι inactivation selectively stimulates ULK2 to promote TBK1-STING-IRF3 signaling•Macroautophagy activation by PKCλ/ι loss prevents CMA-dependent degradation of STING Linares et al. describe how PKCλ/ι loss activates intestinal epithelial ULK2 and leads to its accumulation by inhibiting its degradation by microautophagy. Activated ULK2 phosphorylates TBK1 to promote the STING-mediated IFN signaling that triggers a CD8+ anti-tumor response. Activation of macroautophagy by PKCλ/ι deficiency prevents STING degradation by chaperone-mediated autophagy.