Unraveling the impact of chemoradiotherapy on hematopoietic function in cancer patients: a metabolomics-driven mechanistic investigation.

Myelosuppression, a dose-limiting toxicity affecting a substantial proportion of chemotherapy patients globally (Wilson et al in Lancet Oncol 20(6):769-780, 2019. https://doi.org/10.1016/S1470-20451930163-9) remains a major clinical barrier to curative intent therapies and long-term survival. It leads to treatment delays, dose reductions, infection-related morbidity, and mortality, thereby imposing substantial healthcare burdens and diminishing patient quality of life. Here, we integrate recent metabolomics-driven discoveries to characterize chemotherapy- and radiotherapy-induced metabolic dysregulation across glucose, amino acid, lipid, and mitochondrial pathways and delineate how these alterations impair hematopoietic stem cell (HSC) function and disrupt the bone marrow microenvironment. We further connect metabolic perturbations with functional consequences, including HSC quiescence loss, oxidative stress, stromal niche remodeling, and immune dysregulation. We highlight emerging metabolite-based biomarkers, metabolic checkpoints, and nutrient-targeted therapeutic strategies capable of preventing or mitigating myelosuppression. In addition, we discuss metabolic-pathway-specific interventions, such as amino acid deprivation therapy, ketone-mediated hematopoietic protection, and mitochondrial stress modulation, emphasizing the translational potential of precision metabolic monitoring. Our analysis underscores the central role of precision metabolomics in predicting, stratifying, and reducing treatment-related hematotoxicity, providing a mechanistic and clinically actionable framework for improving therapeutic tolerance. This metabolomics-centered perspective supports individualized intervention strategies that may ultimately enhance therapeutic index and reduce hematological complications.