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潜在开发有效靶向治疗的有吸引力的模型。缺氧信号在肾癌中发挥着关键作用，特别是在最常见的亚型肾细胞癌 (RCC) 中。缺氧促进各种重要的病理过程，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生、生长或转移形成。很大一部分肾癌，特别是透明细胞肾细胞癌 (ccRCC)，其特点是 Von Hippel-Lindau 肿瘤抑制因子 ( 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，针对 ccRCC 的 pVHL-HIF 信号传导治疗策略已得到探索，最终成功开发了 HIF2α 特异性拮抗剂，例如 belzutifan (PT2977)，这是一种 FDA 批准的药物，用于治疗包括晚期 ccRCC 在内的VHL相关疾病。随着新型 VHL 蛋白 (pVHL) 靶点的发现以及VHL突变的综合致死机制的发现，人们对肾癌缺氧信号传导有了更多的了解。这些突破可以为肾癌创新和有效的联合疗法的开发铺平道路。