透明细胞肾细胞癌（ccRCC）是一种常见的恶性肿瘤，上皮细胞内具有复杂的异质性，在肿瘤进展和免疫调节中发挥着至关重要的作用。然而，恶性上皮细胞相关基因 (MECRG) 在 ccRCC 中的临床重要性仍不清楚。本研究旨在对ccRCC中恶性上皮细胞相关基因的功能和临床相关性进行全面研究，为分子机制提供有价值的理解，并为治疗策略提供潜在靶点。利用单细胞测序数据，我们成功识别了 219 个 MECRG，并通过使用 10 种不同算法协同分析 101 个机器学习模型，建立了预后模型 MECRGS（MECRG 的签名）。值得注意的是，与传统的临床特征和 6 个队列中先前发布的 92 个特征相比，MECRGS 表现出了卓越的预测性能，展示了其独立性和准确性。使用指定的截止阈值将患者分为高 MECRGS 亚组和低 MECRGS 亚组后，我们注意到 MECRGS 评分升高的患者表现出免疫抑制性肿瘤微环境 (TME) 的特征，并且在免疫治疗后表现出更差的结果。此外，我们发现了一种独特的 ccRCC 肿瘤细胞亚型，其特征是 PLOD2（原胶原赖氨酸，2-氧化戊二酸 5-双加氧酶 2）和 SAA1（血清淀粉样蛋白 A1）的高表达，我们在 Renji 组织微阵列（TMA）中进一步验证了这一点队列。最后，“Cellchat”揭示了这些细胞与其他细胞类型之间的潜在串扰模式，表明它们在招募 CD163 巨噬细胞和调节性 T 细胞 (Treg) 方面的潜在作用，从而建立免疫抑制性 TME。 PLOD2  SAA1  具有复杂串扰模式的癌细胞确实显示出潜在治疗干预的希望。© 2024。作者。

Clear cell renal cell carcinoma (ccRCC) is a prevalent malignancy with complex heterogeneity within epithelial cells, which plays a crucial role in tumor progression and immune regulation. Yet, the clinical importance of the malignant epithelial cell-related genes (MECRGs) in ccRCC remains insufficiently understood. This research aims to undertake a comprehensive investigation into the functions and clinical relevance of malignant epithelial cell-related genes in ccRCC, providing valuable understanding of the molecular mechanisms and offering potential targets for treatment strategies. Using data from single-cell sequencing, we successfully identified 219 MECRGs and established a prognostic model MECRGS (MECRGs' signature) by synergistically analyzing 101 machine-learning models using 10 different algorithms. Remarkably, the MECRGS demonstrated superior predictive performance compared to traditional clinical features and 92 previously published signatures across six cohorts, showcasing its independence and accuracy. Upon stratifying patients into high- and low-MECRGS subgroups using the specified cut-off threshold, we noted that patients with elevated MECRGS scores displayed characteristics of an immune suppressive tumor microenvironment (TME) and showed worse outcomes after immunotherapy. Additionally, we discovered a distinct ccRCC tumor cell subtype characterized by the high expressions of PLOD2 (procollagen-lysine,2-oxoglutarate 5-dioxygenase 2) and SAA1 (Serum Amyloid A1), which we further validated in the Renji tissue microarray (TMA) cohort. Lastly, 'Cellchat' revealed potential crosstalk patterns between these cells and other cell types, indicating their potential role in recruiting CD163 + macrophages and regulatory T cells (Tregs), thereby establishing an immunosuppressive TME. PLOD2 + SAA1 + cancer cells with intricate crosstalk patterns indeed show promise for potential therapeutic interventions.© 2024. The Author(s).