铁死亡与肿瘤微环境在透明细胞肾细胞癌中的动态互作：从机制到治疗

Dynamic Interactions between Ferroptosis and the Tumor Microenvironment in Clear Cell Renal Cell Carcinoma: From Mechanisms to Therapies

摘要: 透明细胞肾细胞癌(ccRCC)是肾癌最常见亚型，具有分子异质性强、侵袭转移突出及治疗耐药等特征，其脂质–活性氧积累特性与肿瘤微环境(TME)调控密切相关，现有治疗因缺乏细胞亚群代谢动态的精准解析而受限。铁死亡作为铁依赖性、脂质过氧化驱动的程序性细胞死亡形式，在ccRCC中兼具抑癌作用与逃逸机制，且与TME存在动态互作，为疾病诊疗提供新方向。在分子机制上，ccRCC中铁死亡受STEAP3、NCOA4及长链非编码RNA等多重调控，TME的细胞异质性及微环境压力可调节铁死亡敏感性，CHOP介导的信号轴是铁死亡与免疫调控的核心枢纽。诊断预后方面，铁死亡相关基因模型及免疫–铁死亡联合标志物可有效预测患者生存与风险分层。治疗领域，索拉非尼、舒尼替尼、帕唑帕尼等一线激酶抑制剂可诱导铁死亡，人参皂苷Rh4等天然化合物为铁死亡增敏潜在候选药物，但目前尚无ccRCC直接研究证据，铁死亡诱导与免疫检查点抑制联合是核心研究方向。当前研究仍面临代谢调控争议、异质性解析及临床转化等挑战，未来需借助空间多组学等技术深化研究，推动ccRCC精准诊疗发展。

Abstract: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma, characterized by strong molecular heterogeneity, prominent invasiveness and metastasis, as well as therapeutic resistance. Its characteristic of lipid-reactive oxygen species accumulation is closely related to the regulation of the tumor microenvironment (TME), and current treatments are limited due to the lack of precise analysis of the metabolic dynamics of cell subpopulations. As an iron-dependent, lipid peroxidation-driven form of programmed cell death, ferroptosis exerts both tumor-suppressive effects and escape mechanisms in ccRCC, and exhibits dynamic interactions with the TME, providing a new direction for disease diagnosis and treatment. At the molecular mechanism level, ferroptosis in ccRCC is regulated by multiple factors including STEAP3, NCOA4, and long non-coding RNAs. The cellular heterogeneity of the TME and microenvironmental pressures can regulate ferroptosis sensitivity, and the CHOP-mediated signaling axis serves as the core hub connecting ferroptosis and immune regulation. In terms of diagnosis and prognosis, ferroptosis-related gene models and immune-ferroptosis combined biomarkers can effectively predict patients’ survival outcomes and risk stratification. In the therapeutic field, sorafenib, sunitinib, pazopanib and other first-line kinase inhibitors have been confirmed to induce ferroptosis, and natural compounds such as ginsenoside Rh4 are potential candidate drugs for ferroptosis sensitization, but there is no direct research evidence in ccRCC at present, and the combination of ferroptosis induction and immune checkpoint inhibition is a core research direction. Current studies still face challenges such as controversies in metabolic regulation, difficulties in heterogeneity analysis, and clinical transformation. In the future, it is necessary to deepen research with the help of spatial multi-omics and other technologies to promote the development of precise diagnosis and treatment of ccRCC.