Advancing osteosarcoma treatment: the impact of intratumoral metabolic reprogramming on immunotherapy

Osteosarcoma (OS) remains difficult to cure once it becomes metastatic, recurrent, or resistant to chemotherapy, and immune checkpoint blockade has provided limited clinical benefit. The metabolic-immune tumor microenvironment (TME) is one barrier to effective immunity because malignant, stromal, and immune cells compete for nutrients and adapt to hypoxia, acidosis, and matrix-related constraints. This review examines how cancer-associated fibroblasts, extracellular matrix, myeloid and lymphoid populations interact with glucose/lactate, glutamine, arginine, and lipid metabolism in OS. Public OS single-cell RNA sequencing datasets are used to illustrate cellular heterogeneity and are interpreted alongside published experimental evidence. OS-specific evidence is most developed for glycolysis and acidosis, glutamine dependence, myeloid regulation, and selected stromal and lipid-related pathways. Arginine-directed approaches, NK-cell immunometabolism, and most metabolism-ICB combinations remain preclinical or are supported mainly by mechanistic evidence from other tumor types. Together, these findings highlight the mechanisms with the strongest current support and the major gaps that remain before clinical translation.