Targeting the crosstalk of metabolism reprogramming and replication stress: novel strategy to combat cancer.

The induction of replication stress has emerged as a potent strategy for cancer therapy, with alkylating agents, nucleoside analogs, and inhibitors of cyclin and cyclin-dependent kinase remaining prominent drugs. As mechanistic insights into responses to replication stress are evolving, novel therapeutic agents targeting replication stress response pathways have been progressively developed. Despite the demonstrated pharmacological and clinical efficacy of certain agents, the therapeutic landscape remains characterized by suboptimal patient prognoses. Mounting evidence implicates cancer cell metabolic reprogramming as a critical determinant in both modulating replication stress and attenuating genotoxic drug efficacy. In addition, some metabolic enzymes demonstrate non-canonical functions that potentiate DNA damage response, while some metabolic pathways contribute vulnerability to replication stress in malignant cells. Therefore, this review seeks to elucidate the mechanisms by which metabolic reprogramming modulates replication stress in cancer cells and to provide an overview of the latest advancements in therapeutic regimens development.