线粒体自噬在各种与癌症相关的生物过程中的作用被广泛认可，然而对于透明细胞肾细胞癌（ccRCC）中线粒体自噬的全面意义仍需要进一步探索。基于包含25个线粒体自噬相关基因（MRGs）的转录组数据，我们确定了763个ccRCC样本中独特的线粒体自噬模式。随后，采用机器学习算法构建了一个与线粒体自噬相关的预测标志，命名为风险评分（RiskScore），以量化ccRCC患者的个体线粒体自噬状态。通过多光谱免疫荧光（mIF）和免疫组织化学染色（IHC），我们检测了PTEN诱导的潜在激酶1（PINK1）对ccRCC的预后和免疫微环境的影响。我们的分析首先对ccRCC中的25个MRGs的表达谱、基因组变异和相互作用进行了全面评估。随后，应用共识聚类算法将ccRCC患者分为三个具有不同预后结果、肿瘤微环境（TME）特征和潜在生物通路的类群。我们筛选出了八个关键基因（CLIC4、PTPRB、SLC16A12、ENPP5、FLRT3、HRH2、PDK4和SCD5）构建了一个与线粒体自噬相关的预测标志，该标志在ccRCC患者中具有良好的预后价值。此外，通过风险评分将患者亚群分为不同的免疫检查点（ICPs）表达水平、免疫细胞数量和免疫治疗反应。此外，我们建立了一个结合风险评分和临床特征的有力预测模型。值得注意的是，我们观察到PINK1的表达与良好的治疗反应和高级三次淋巴结构成熟阶段显著相关，这有望为增强ccRCC的抗肿瘤免疫提供新的思路。综上所述，本研究首次开发了一个与线粒体自噬相关的标志，该标志在预测ccRCC患者的临床预后、TME特征和靶向治疗以及免疫治疗反应方面具有出色的能力。值得特别注意的是，PINK1在调节ccRCC患者的治疗反应和免疫微环境方面发挥了关键作用。© 2023年作者（们），在Springer-Nature出版集团的Springer-Verlag GmbH Germany的专属许可下。

The role of mitophagy in various cancer-associated biological processes is well recognized. Nonetheless, the comprehensive implications of mitophagy in clear cell renal cell carcinoma (ccRCC) necessitate further exploration.Based on the transcriptomic data encompassing 25 mitophagy-related genes (MRGs), we identified the distinct mitophage patterns in 763 ccRCC samples. Subsequently, a mitophage-related predictive signature with machine learning algorithms was constructed, designated as RiskScore, to quantify the individual mitophagy status in ccRCC patients. Employing multispectral immunofluorescence (mIF) and immunohistochemistry (IHC) staining, we detected the effect of PTEN-induced putative kinase 1 (PINK1) in the prognosis and immune microenvironment of ccRCC.Our analysis initially encompassed a comprehensive assessment of the expression profiling, genomic variations, and interactions among the 25 MRGs in ccRCC. Subsequently, the consensus clustering algorithm was applied to stratify ccRCC patients into three clusters with distinct prognostic outcomes, tumor microenvironment (TME) characteristics, and underlying biological pathways. We screened eight pivotal genes (CLIC4, PTPRB, SLC16A12, ENPP5, FLRT3, HRH2, PDK4, and SCD5) to construct a mitophagy-related predictive signature, which showed excellent prognostic value for ccRCC patients. Moreover, patient subgroups divided by the RiskScore showed contrasting expression levels of immune checkpoints (ICPs), abundance of immune cells, and immunotherapy response. Additionally, a nomogram was established with robust predictive power integrating the RiskScore and clinical features. Notably, we observed that PINK1 expression markedly correlated with favorable treatment response and advanced maturation stages of tertiary lymphoid structures, which potentially shed light on enhancing anti-tumor immunity of ccRCC.Collectively, this study initially developed a signature associated with mitophagy, which demonstrated an excellent ability to predict the clinical prognosis, TME characterization, and responsiveness to targeted therapy and immunotherapy for ccRCC patients. Of particular note is the pivotal role of PINK1 in mediating the treatment response and immune microenvironment for ccRCC patients.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.