NGF/BDNF–Trk/p75NTR signaling in osteosarcoma immunity: biomarkers and therapeutic opportunities

Osteosarcoma is a primary bone malignancy in which outcomes for patients with metastatic or relapsed disease remain unsatisfactory despite optimized surgery–chemotherapy backbones. Recently, advances in cancer neuroscience have highlighted neurotrophins—nerve growth factor (NGF) and brain−derived neurotrophic factor (BDNF)—and their Trk/p75 NTR receptors as modulators of tumor behavior and immune tone, offering a new strategy to recondition the osteosarcoma microenvironment. Evidence has been accumulated with the real−world application of TRK inhibitors in fusion−positive cancers and anti−NGF biologics in bone pain, together with osteosarcoma specimens and functional models showing that NGF/BDNF signaling promotes invasion, angiogenesis, and immunosuppressive niches, while neuromodulatory agents may counter these programs. Notably, deployment of these agents as immunity enablers in an immunologically “cold” sarcoma remains controversial, with uncertainties around biomarker selection, pharmacodynamic monitoring, and rational combinations with checkpoint or cellular therapies. In this review, we summarized NGF/BDNF expression and receptor activity in osteosarcoma and conducted a translational, efficacy− and safety−oriented appraisal of tissue/biofluid biomarker readouts and drugging opportunities targeting neurotrophin and co−regulatory neural circuits. In addition, we further discussed the potential mechanisms by which neurotrophin and adrenergic pathways regulate the balance between microenvironmental immunosuppression and lasting anti−tumor immunity. The purpose of this article is to define NGF/BDNF as shapers of the osteosarcoma immune microenvironment and to delineate biomarker−guided therapeutic opportunities for clinical testing.