先天免疫的激活和相关的干扰素 (IFN) 信号传导与癌症有关，但调节因子难以捉摸，并且与肿瘤抑制的联系尚未确定。在这里，我们发现 Parkin（一种在帕金森病中发生改变的 E3 泛素连接酶）在癌症中表观遗传沉默，并且通过临床批准的去甲基化疗法重新表达，可刺激肿瘤细胞中有效 IFN 应答的转录。该通路需要 Parkin E3 泛素连接酶活性，涉及警报蛋白高迁移率组盒 1 (HMGB1) 的亚细胞运输和释放，并与 NFκB 基因表达的抑制相关。反过来，表达 Parkin 的细胞释放出 IFN 分泌组，上调效应子和细胞毒性 CD8 T 细胞标记物，降低免疫抑制受体 TIM3 和 LAG3 的表达，并刺激自我更新/干细胞因子 TCF1 的高含量。 Parkin 诱导的 CD8 T 细胞在微环境中选择性积累，并在体内抑制转基因和同基因肿瘤的生长。因此，Parkin是一种表观遗传调节的先天免疫激活剂和双重模式肿瘤抑制因子，抑制肿瘤代谢和细胞侵袭的内在特征，同时重振微环境中的CD8 T细胞功能。

The activation of innate immunity and associated interferon (IFN) signaling have been implicated in cancer, but the regulators are elusive and a link to tumor suppression undetermined. Here, we found that Parkin, an E3 ubiquitin ligase altered in Parkinson's Disease was epigenetically silenced in cancer and its re-expression 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 NFκB 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. Parkin-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.