Adaptive Rewiring of Nucleotide Metabolism in Therapeutic Resistance

Therapeutic resistance remains a major barrier to durable cancer control and is increasingly recognized as a dynamic process shaped not only by genetic evolution but also by metabolic adaptation. Nucleotide metabolism is uniquely positioned at this interface, supporting DNA and RNA synthesis while also regulating signaling, energy homeostasis, redox balance, genome maintenance, and cellular stress responses. In this Review, we examine emerging evidence that cancer cells in solid tumors adapt nucleotide metabolism in response to therapeutic pressure through coordinated remodeling of de novo biosynthesis, nucleotide salvage, metabolite transport, and pathway-specific feedback mechanisms. We discuss how cytotoxic chemotherapy, targeted therapies, immunotherapies, and radiation impose distinct but convergent pressures on nucleotide homeostasis and how restoration or redistribution of nucleotide pools can promote survival, DNA repair, persistent oncogenic signaling, and immune evasion. We further highlight the reciprocal relationship between oncogenic signaling and nucleotide metabolism, as well as the contribution of tumor suppressor loss and the tumor microenvironment to context-specific metabolic dependencies. Rather than functioning only as a biosynthetic requirement of proliferating cells, nucleotide metabolism emerges as a flexible stress-response network that can facilitate adaptation to cancer therapy. Defining the mechanisms that maintain nucleotide balance in resistant tumors may reveal therapeutically actionable dependencies and inform rational combination strategies designed to prevent or overcome treatment resistance.