Decoding the Impact of Tumor Microenvironment in Osteosarcoma Progression and Metastasis

Abstract

Osteosarcoma (OS) is a heterogeneous, highly metastatic bone malignancy in children and adolescents. Despite advancements in multimodal treatment strategies, the prognosis for patients with metastatic or recurrent disease has not improved significantly in the last four decades. OS is a highly heterogeneous tumor; its genetic background and the mechanism of oncogenesis are not well defined. Unfortunately, no effective molecular targeted therapy is currently available for this disease. Understanding osteosarcoma’s tumor microenvironment (TME) has recently gained much interest among scientists hoping to provide valuable insights into tumor heterogeneity, progression, metastasis, and the identification of novel therapeutic avenues. Here, we review the current understanding of the TME of OS, including different cellular and noncellular components, their crosstalk with OS tumor cells, and their involvement in tumor progression and metastasis. We also highlight past/current clinical trials targeting the TME of OS for effective therapies and potential future therapeutic strategies with negligible adverse effects.

Immunotherapy Innovations in the Fight against Osteosarcoma: Emerging Strategies and Promising Progress

“…Osteosarcoma is known for its high heterogenicity and low tumor immunogenicity. The extensive immune cell infiltration in the OS-TME leads to the formation of a niche for OS proliferation, metastasis, and resistance [ 17 , 49 ]. This immunosuppressive OS-TME is correlated with the presence of MDSCs (Myeloid-Derived Suppressor Cells), OS-Ms (osteosarcoma-associated macrophages), ECs (endothelial cells), and Tregs (regulatory T lymphocytes) [ 50 ].…”

“…OS cells release TGF-beta to increase the ratio of Treg in the OS-TME [ 17 ]. MDSCs release IL-10 and TNF-alpha, which decrease the activity of cytotoxic T lymphocytes (CTLs) [ 109 ].…”

“…Within the OS-TME, the prevailing majority of macrophages primarily display the pro-tumor Type-2 phenotype, lacking anti-tumor functionalities [ 16 ]. Osteosarcoma-associated neutrophils also participate in the OS-TME [ 17 ]. Initially, neutrophils are responsible for immune attack; however, the OS educates the neutrophils to become tumor-promoting neutrophils [ 18 ].…”

IL-1 Family Members in Bone Sarcomas

“…With some heterogeneity across different OS tumors, malignant osteoblastic cells and myeloid cells are the most represented elements [30][31][32][33]. The variegated cellular microenvironment is reflected by a complex network of factors and receptors.…”