The Osteosarcoma Tumor Microenvironment: Supportive of Tumor Progression, Hostile to Immunity, but Therapeutically Targetable.

Osteosarcoma (OSA) remains the most common primary malignant bone tumor of children and young adults, with limited survival improvements in patients with relapsed or metastatic disease despite multimodal chemotherapeutic treatment. Beyond the intrinsic heterogeneity and malignancy of tumor cells, OSA progression and therapeutic resistance are strongly influenced by the specialized bone tumor microenvironment (TME). Interactions among tumor, immune and stromal cells generate a complex ecosystem characterized by immune suppression, hypoxia and metabolic adaptation, representing a major challenge for effective (immune) therapeutic approaches. In this review, we discuss how the OSA microenvironment shapes tumor evolution and therapeutic response, with particular emphasis on the mechanisms that limit effective immune-mediated tumor control. We further examine the rationale for combining tumor-directed and microenvironment-directed immunotherapies. Within this context, B7-H3/CD276 represents a relevant example of a multifunctional molecule at the interface between tumor biology and immune regulation. B7-H3 is associated with aggressive tumor features and therapy resistance, while its immunoregulatory activities contribute to the establishment of an immune-restrictive TME. Consequently, B7-H3-targeted therapies may exert complementary mechanisms of action, either by directly eliminating B7-H3-expressing tumor cells or by modulating the TME to overcome immunosuppressive barriers. This dual activity provides rationale for combination strategies integrating B7-H3-targeting with antigen-directed immunotherapies, including those targeting the novel OSA-associated antigen, chondroitin sulfate proteoglycan 4, where effective antitumor immunity may require simultaneous modulation of the local immune context. We then discuss how advanced preclinical models, comparative oncology, and emerging biomarker-guided approaches may accelerate the clinical translation of more effective immunotherapeutic strategies for OSA.