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 PKC lambda/iota 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. PKC lambda/iota directly phosphorylates and represses the activity of ULK2, promoting its degradation through an endosomal microautophagy-driven ubiquitin-dependent mechanism. Loss of PKC lambda/iota results in increased levels of enzymatically active ULK2, which, by direct phosphorylation, activates TBK1 to foster the activation of the STING-mediated IFN response. PKC lambda/iota inactivation also triggers autophagy, which prevents STING degradation by chaperone-mediated autophagy. Thus, PKC lambda/iota 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 PKC lambda/iota levels correlate with enhanced IFN signaling and good prognosis in colorectal cancer patients.