The Osteosarcoma Tumor Microenvironment: Supportive of Tumor Progression, Hostile to Immunity, but Therapeutically Targetable.
4 affiliations
- 1Laboratory of OncoImmunology, Molecular Biotechnology Center "Guido Tarone", Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy.
- 2Pediatric Onco-Hematology Department, Regina Margherita Children's Hospital, 10126 Turin, Italy.
- 3Department of Public Health and Pediatrics, University of Turin, 10124 Turin, Italy.
- 4Department of Veterinary Sciences, University of Turin, 10095 Grugliasco, Italy.
Abstract
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.
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BibTeX
@article{tarone2026osteosarcoma,
title = {{The Osteosarcoma Tumor Microenvironment: Supportive of Tumor Progression, Hostile to Immunity, but Therapeutically Targetable.}},
author = {Lidia Tarone and Irene Fiore Merighi and Elisa Tirtei and Davide Giacobino and Emanuela Maria Morello and Federica Cavallo and Federica Riccardo},
journal = {Cancers},
year = {2026},
month = oct,
doi = {10.3390/cancers18193239},
url = {https://europepmc.org/article/MED/42882933},
note = {CC BY},
}
RIS
TY - JOUR
TI - The Osteosarcoma Tumor Microenvironment: Supportive of Tumor Progression, Hostile to Immunity, but Therapeutically Targetable.
AU - Lidia Tarone
AU - Irene Fiore Merighi
AU - Elisa Tirtei
AU - Davide Giacobino
AU - Emanuela Maria Morello
AU - Federica Cavallo
AU - Federica Riccardo
PY - 2026
DA - 2026/10/08
JO - Cancers
DO - 10.3390/cancers18193239
UR - https://europepmc.org/article/MED/42882933
AB - 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.
SN - 2072-6694
ER -