肾透明细胞癌联合免疫治疗新策略——有氧糖酵解的研究进展及展望

肾恶性肿瘤的发病率逐年上升,其中肾透明细胞癌约占所有肾恶性肿瘤的80%,肾透明细胞癌独特的遗传背景和突变特征往往涉及以乏氧信号、糖酵解代谢、氨基酸代谢、线粒体氧化磷酸化等通路为代表的肿瘤微环境（tumor microenvironment,TME）内稳态失调。免疫检查点抑制剂（immune checkpoint inhibitor,ICI）联合酪氨酸激酶抑制剂（tyrosine kinase inhibitor,TKI）已经成为晚期肾透明细胞癌患者的一线治疗方案,但是,联合治疗方案的疗效仍有待提高,且缺乏明确诊断、指导用药、评估预后的生物标志物。近年来,多组学研究从不同层次探索肾透明细胞癌分子通路的异常改变。肾透明细胞癌发生代谢重编程,在氧气充足的情况下也以低效能的糖酵解为能量供应来源,促进自身无限生长,并且有氧糖酵解通路展现的显著异常与不良预后相关。肾透明细胞癌异常的糖酵解信号能促进肿瘤生长,并与TME中的免疫细胞相互作用,使促肿瘤免疫和抗肿瘤免疫平衡失调,造成抑制性免疫微环境,介导肿瘤免疫逃逸,从而对免疫治疗产生不利影响。因此,通过阻断异常糖代谢来抑制肿瘤生长,以有氧糖酵解通路和免疫微环境为切入点,可为肾透明细胞癌以及泛肿瘤治疗提供新的研究方向。然而,如何在复杂的肿瘤免疫微环境中最大程度地将肿瘤细胞代谢重编程转化为用药靶点并运用于临床实践仍待探讨。在肾透明细胞癌中,糖酵解抑制剂联合ICI或TKI作为新方案或能协同发挥抗肿瘤效应,逆转治疗抵抗。本文通过对糖酵解代谢途径中的关键限速酶、转运体及其抑制剂与肿瘤免疫微环境之间的关系进行综述,探讨糖酵解抑制剂在肾透明细胞癌中的作用机制和肿瘤免疫微环境的变化,及其与靶向治疗或免疫治疗联合应用的巨大临床转化价值,未来将为肾透明细胞癌的临床诊疗提供新思路,为患者带来临床获益。

New strategies for combined with immunotherapy of clear cell renal cell carcinoma: advances in aerobic glycolysis

The incidence of renal malignancies is increasing each year. Clear cell renal cell carcinoma (ccRCC) accounts for approximately 80% of all renal malignancies. Its unique genetic background and mutation features involve dysregulation of homeostasis within the tumor microenvironment (TME) represented by pathways such as hypoxic signaling, glycolytic metabolism, amino acid metabolism, and mitochondrial oxidative phosphorylation. Immune checkpoint inhibitor (ICI) in combination with tyrosine kinase inhibitor (TKI) has become the first line of treatment for patients with advanced ccRCC. However, the efficacy of combination therapy has yet to be improved, and there is an urgent need for biomarkers that can assist the diagnosis, treatment, and prognosis. Multi-omics studies have investigated aberrant abnormalities in molecular pathways of ccRCC in recent years. The ccRCC undergoes metabolic reprogramming and prefers inefficient glycolysis as a significant energy source even under normoxia to support unlimited proliferation. In addition, abnormalities in the aerobic glycolytic pathway have been associated with poor prognosis. Dysregulated glycolytic signaling promotes tumor progression and interacts with immune cells within the TME in ccRCC, resulting in an imbalance between pro and antitumor immunity, creating a suppressive immune microenvironment, promoting tumor immune escape, and impairing antitumor effects of immunotherapy. Therefore, integrating the aerobic glycolytic pathway and the immune microenvironment as an entry point, limiting tumor progression by restricting aberrant glycolytic metabolism broadens therapeutic options for ccRCC and pan-cancer treatments. However, further research is required on maximizing the metabolic reprogramming that tumor cells harbor in the complex TME to convert it into a therapeutic target and apply it in clinical practice. Glycolytic inhibitors in combination with ICI or TKI might be a novel strategy that demonstrates synergistic antitumor effects and overcomes resistance in treating human cancers. This review analyzes the correlations between essential rate-limiting enzymes, transporters, glycolytic pathway inhibitors, and the tumor immune microenvironment in ccRCC. Then we summarize the effects of glycolytic inhibitors in human cancers and alterations in the tumor immune microenvironment. Along with the potential clinical translational value in combination with targeted therapy or immunotherapy, targeting glycolysis will provide new insights for the clinical treatment of ccRCC and bring clinical benefits to patients in the future.