The distinct pathological and molecular features of kidney cancer in adaptation to oxygen homeostasis render this malignancy an attractive model for investigating hypoxia signalling and potentially developing potent targeted therapies. Hypoxia signalling has a pivotal role in kidney cancer, particularly within the most prevalent subtype, known as renal cell carcinoma (RCC). Hypoxia promotes various crucial pathological processes, such as hypoxia-inducible factor (HIF) activation, angiogenesis, proliferation, metabolic reprogramming and drug resistance, all of which contribute to kidney cancer development, growth or metastasis formation. A substantial portion of kidney cancers, in particular clear cell RCC (ccRCC), are characterized by a loss of function of Von Hippel–Lindau tumour suppressor (VHL), leading to the accumulation of HIF proteins, especially HIF2α, a crucial driver of ccRCC. Thus, therapeutic strategies targeting pVHL–HIF signalling have been explored in ccRCC, culminating in the successful development of HIF2α-specific antagonists such as belzutifan (PT2977), an FDA-approved drug to treat VHL-associated diseases including advanced-stage ccRCC. An increased understanding of hypoxia signalling in kidney cancer came from the discovery of novel VHL protein (pVHL) targets, and mechanisms of synthetic lethality with VHL mutations. These breakthroughs can pave the way for the development of innovative and potent combination therapies in kidney cancer.

肾癌适应氧稳态的独特病理和分子特征使这种恶性肿瘤成为研究缺氧信号传导和可能开发有效靶向治疗的有吸引力的模型。缺氧信号在肾癌中起着关键作用，尤其是在最普遍的亚型中，称为肾细胞癌 （RCC）。缺氧促进各种关键的病理过程，例如缺氧诱导因子 （HIF） 激活、血管生成、增殖、代谢重编程和耐药性，所有这些都有助于肾癌的发展、生长或转移形成。很大一部分肾癌，尤其是透明细胞 RCC （ccRCC），其特征是 Von Hippel-Lindau 抑瘤基因 （VHL） 功能丧失，导致 HIF 蛋白积累，尤其是 HIF2α，这是 ccRCC 的关键驱动因素。因此，在 ccRCC 中探索了靶向 pVHL-HIF 信号传导的治疗策略，最终成功开发了 HIF2α 特异性拮抗剂，例如 belzutifan （PT2977），一种 FDA 批准的用于治疗 VHL 相关疾病（包括晚期 ccRCC）的药物。新型 VHL 蛋白 （pVHL） 靶标的发现以及 VHL 突变的合成致死机制使人们对肾癌中缺氧信号的理解增加。这些突破可以为肾癌创新和强效联合疗法的开发铺平道路。