Metabolic alterations are a key hallmark of cancer cells, and the augmented synthesis and use of nucleotide triphosphates is a critical and universal metabolic dependency of cancer cells across different cancer types and genetic backgrounds. Many of the aggressive behaviours of cancer cells, including uncontrolled proliferation, chemotherapy resistance, immune evasion and metastasis, rely heavily on augmented nucleotide metabolism. Furthermore, most of the known oncogenic drivers upregulate nucleotide biosynthetic capacity, suggesting that this phenotype is a prerequisite for cancer initiation and progression. Despite the wealth of data demonstrating the efficacy of nucleotide synthesis inhibitors in preclinical cancer models and the well-established clinical use of these drugs in certain cancer settings, the full potential of these agents remains unrealized. In this Review, we discuss recent studies that have generated mechanistic insights into the diverse biological roles of hyperactive cancer cell nucleotide metabolism. We explore opportunities for combination therapies that are highlighted by these recent advances and detail key questions that remain to be answered, with the goal of informing urgently warranted future studies.

代谢改变是癌细胞的一个关键标志，三磷酸核苷酸的增强合成和使用是不同癌症类型和遗传背景的癌细胞的关键和普遍的代谢依赖性。癌细胞的许多侵袭行为，包括不受控制的增殖、化疗耐药、免疫逃避和转移，在很大程度上依赖于增强的核苷酸代谢。此外，大多数已知的致癌驱动因素都会上调核苷酸生物合成能力，表明这种表型是癌症发生和进展的先决条件。尽管大量数据证明了核苷酸合成抑制剂在临床前癌症模型中的功效，并且这些药物在某些癌症环境中的临床应用已得到证实，但这些药物的全部潜力仍未实现。在这篇综述中，我们讨论了最近的研究，这些研究对过度活跃的癌细胞核苷酸代谢的多种生物学作用产生了机制见解。我们探索这些最新进展所强调的联合疗法的机会，并详细说明仍有待回答的关键问题，目的是为迫切需要的未来研究提供信息。