The complex tumor microenvironment (TME) in osteosarcoma is emerging as a critical factor in disease progression and treatment resistance. Recent insights highlight the intricate interplay between cancer cells, immune components, stromal elements, and extracellular matrix, revealing new opportunities for therapeutic intervention. Osteosarcoma, the most common primary bone cancer in adolescents, has long posed significant treatment challenges due to its high metastatic potential and limited response to conventional therapies.

The immune landscape within the osteosarcoma microenvironment plays a pivotal role in tumor progression. Tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells create an immunosuppressive niche, allowing cancer cells to evade immune surveillance. The presence of pro-inflammatory cytokines and immunosuppressive factors further complicates the immune response, contributing to drug resistance and metastatic spread. Strategies aimed at reprogramming immune cells and enhancing anti-tumor immunity are now being explored as promising therapeutic avenues.

The extracellular matrix (ECM) and stromal components provide structural and biochemical support to osteosarcoma cells, influencing their behavior and response to treatment. Fibroblasts, mesenchymal stem cells, and endothelial cells within the TME contribute to tumor growth by secreting growth factors, cytokines, and angiogenic signals. These interactions create a pro-tumorigenic microenvironment, promoting invasion, metastasis, and resistance to chemotherapy. Targeting the cross-talk between stromal and cancer cells is a growing area of research, with the goal of disrupting tumor-promoting pathways.

Hypoxia is another defining feature of the osteosarcoma TME, leading to genetic instability, increased angiogenesis, and therapy resistance. The activation of hypoxia-inducible factors (HIFs) drives tumor adaptation and survival in low-oxygen conditions. Emerging therapeutic approaches focus on inhibiting HIF signaling, thereby reducing the aggressive nature of osteosarcoma cells and sensitizing them to treatment.

Recent advances in targeted therapies and immunotherapy are reshaping the osteosarcoma treatment landscape. The use of immune checkpoint inhibitors, CAR-T cell therapy, and monoclonal antibodies is gaining momentum, aiming to harness the body's immune system to fight cancer. Additionally, precision medicine approaches targeting tumor-specific genetic alterations and signaling pathways offer new hope for patients with metastatic or recurrent osteosarcoma.

Understanding the dynamic interactions within the osteosarcoma microenvironment is crucial for developing more effective and personalized treatment strategies. By targeting key components of the TME, researchers aim to overcome drug resistance, improve patient outcomes, and pave the way for innovative therapies that transform the management of this aggressive bone cancer.

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Reference
Yihan Yu, Kanglu Li, Yizhong Peng, Zhicai Zhang, Feifei Pu, Zengwu Shao, Wei Wu, Tumor microenvironment in osteosarcoma: From cellular mechanism to clinical therapy, Genes & Diseases, Volume 12, Issue 5, 2025, 101569, https://doi.org/10.1016/j.gendis.2025.101569
Funding
National Natural Science Foundation of China 82274559
National Natural Science Foundation of China 81904231