Parkin是一种E3泛素连接酶，在帕金森病的发展中起着关键作用。Parkin缺陷也在许多癌症中发生，并且越来越多的证据表明Parkin功能为抑制肿瘤的肿瘤抑制基因，在抑制肿瘤发生过程中干扰了一系列细胞过程。在这项研究中，我们生成了与Parkin缺陷在晚期肿瘤中相似的小鼠和人类模型，以深入研究Parkin的肿瘤抑制功能。Parkin表达的丧失导致了侵袭性肿瘤的生长，与肿瘤抗原呈现能力差以及抗肿瘤CD8+ T细胞浸润和活化能力受限相关。在CD8+ T细胞耗尽后，Parkin缺陷对肿瘤生长的影响消失。与之前的发现一致，Parkin缺陷与线粒体相关的代谢应激、PTEN降解和AKT信号增强相关。 增强的AKT信号传导导致抗原呈递的失调，而AKT抑制剂MK2206-HCl的治疗可以恢复Parkin缺陷肿瘤中的抗原呈递。 对透明细胞肾癌患者的数据分析表明，Parkin在肿瘤中表达下调，并且低表达与整体生存率降低相关。此外，低Parkin表达与患者对免疫治疗的反应减弱相关。 总体而言，这些结果确定了Parkin缺陷在促进肿瘤免疫逃避中的作用，这可能解释了Parkin丧失在多种癌症中与不良预后相关的原因。

Parkin is an E3 ubiquitin ligase that plays a key role in the development of Parkinson's disease. Parkin defects also occur in numerous cancers, and a growing body of evidence indicates that Parkin functions as a tumor suppressor that impedes a number of cellular processes involved in tumorigenesis. Here, we generated murine and human models that closely mimic the advanced-stage tumors where Parkin deficiencies are found to provide deeper insights into the tumor suppressive functions of Parkin. Loss of Parkin expression led to aggressive tumor growth that was associated with poor tumor antigen presentation and limited antitumor CD8+ T cell infiltration and activation. The effect of Parkin deficiency on tumor growth was lost following depletion of CD8+ T cells. In line with previous findings, Parkin deficiency was linked with mitochondria-associated metabolic stress, PTEN degradation, and enhanced AKT activation. Increased AKT signaling led to dysregulation of antigen presentation, and treatment with the AKT inhibitor MK2206-HCl restored antigen presentation in Parkin-deficient tumors. Analysis of data from clear cell renal cell carcinoma patients indicated that Parkin expression was downregulated in tumors and that low expression correlated with reduced overall survival. Furthermore, low Parkin expression correlated with reduced patient response to immunotherapy. Overall, these results identify a role for Parkin deficiency in promoting tumor immune evasion that may explain the poor prognosis associated with loss of Parkin across multiple types of cancer.