Metabolic reprogramming in tumor-associated cells of hematologic malignancies: mechanisms, crosstalk networks, and therapeutic implications in the tumor microenvironment.

Hematologic malignancies (HMs), which originate from hematopoietic or lymphoid tissues, pose a significant therapeutic challenge due to issues such as drug resistance, relapse, and treatment-related toxicity. The tumor microenvironment (TME), especially within the bone marrow niche, is now widely recognized as a critical determinant of disease progression and treatment response. A central mechanism within this specialized niche is the extensive metabolic reprogramming of key stromal and immune cells, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), and bone marrow adipocytes (BMAds). This review systematically elaborates on the alterations in glucose, lipid, and amino acid metabolism within these cellular compartments of the HM-TME. We detail how metabolites such as lactate, fatty acids, and itaconate function not merely as metabolic byproducts but as active signaling molecules that drive critical processes like immune cell polarization, stromal remodeling, and intricate metabolic crosstalk. This comprehensive reprogramming collectively fosters a profoundly immunosuppressive milieu, promotes tumor cell survival and proliferation, and confers resistance to conventional and novel therapies. Furthermore, we explore emerging therapeutic strategies designed to target these metabolic vulnerabilities. These include inhibitors of specific metabolic pathways, modulators of metabolite-driven signaling, and innovative approaches such as nanomedicine and metabolically enhanced immunotherapy. Finally, we outline the current challenges in the field-such as intra-tumoral metabolic heterogeneity and the pressing need for targeted delivery systems-and discuss future perspectives involving advanced technologies like single-cell metabolomics and rational combination strategies. In summary, this synthesis aims to provide a comprehensive and rational foundation for developing novel immunometabolic interventions against HMs, highlighting the therapeutic potential of disrupting the metabolic dialogue within the TME.