Breaking the vicious cycle: Multifunctional nanomaterials targeting Tumor metabolic reprogramming to overcome T cell exhaustion and bone repair failure in bone tumors

Bone tumors establish a self-perpetuating vicious cycle wherein metabolic reprogramming (e.g., aerobic glycolysis, glutamine addiction) drives both T cell exhaustion and osteolytic damage. Tumor-derived lactate and nutrient depletion suppress T cell function while promoting osteoclast activation and inhibiting osteoblast differentiation. Reciprocally, bone damage releases immunosuppressive factors (e.g., TGF-β, and calcium) that further exacerbate T cell exhaustion, creating a pathological feedback loop. This review proposes the "Metabolic-Immune-Bone Network" (MIBN) as a framework for understanding this interplay. Crucially, multifunctional nanomaterials offer a promising strategy to disrupt this cycle. By precisely targeting metabolic pathways, they simultaneously suppress tumor growth and alleviate microenvironmental immunosuppression/acidosis. Their multifunctional design enables co-delivery of metabolic inhibitors, immune modulators, and osteogenic agents, thereby restoring T cell cytotoxicity and promoting bone regeneration. This dual "anti-tumor and osseous-preserving" functionality addresses the limitations of conventional therapies, shifting the paradigm from lesion-focused treatment toward holistic rehabilitation. This aligns with the "3R" strategy-Remodel, Repair, and Remove-highlighting microenvironment modulation, bone regeneration, and immune-mediated tumor clearance. Future advances in stimulus-responsive and metabolically targeted nanomaterials hold significant potential for breaking the MIBN-driven vicious cycle in bone oncology.