Parkin activates innate immunity and promotes antitumor immune responses.

The activation of innate immunity and associated interferon (IFN) signaling have been implicated in cancer, but the regulators are elusive and links to tumor suppression remain undetermined. Here, we found that Parkin, an E3 ubiquitin ligase altered in Parkinson's Disease, was epigenetically silenced in cancer and its reexpression by clinically approved demethylating therapy stimulated transcription of a potent IFN response in tumor cells. This pathway required Parkin E3 ubiquitin ligase activity, involved the subcellular trafficking and release of the alarmin High Mobility Group Box 1 (HMGB1) and was associated with inhibition of NF-κB gene expression. In turn, Parkin-expressing cells released an IFN secretome that upregulated effector and cytotoxic CD8+ T cell markers, lowered the expression of immune inhibitory receptors TIM3 and LAG3, and stimulated high content of the self renewal/stem cell factor, TCF1. PRKN-induced CD8+ T cells selectively accumulated in the microenvironment and inhibited transgenic and syngeneic tumor growth in vivo. Therefore, Parkin is an epigenetically regulated activator of innate immunity and dual mode tumor suppressor, inhibiting intrinsic tumor traits of metabolism and cell invasion, while simultaneously reinvigorating CD8 T cell functions in the microenvironment.