Targeting the Tumor Microenvironment in Osteosarcoma: A Pathway to Overcome Therapeutic Resistance

Osteosarcoma is the most common primary malignant bone tumor, predominantly affecting children and adolescents. Despite advances in conventional therapies like chemotherapy and surgical resection, the survival rate has remained stagnant due to therapeutic resistance and high rates of metastasis. The tumor microenvironment (TME), a complex network of cellular and non-cellular components, plays a pivotal role in osteosarcoma progression, metastasis, and treatment resistance. Understanding the dynamics within the TME is crucial for developing novel therapeutic strategies that can overcome these challenges. This review explores the key elements of the osteosarcoma TME, including immune cells, endothelial cells, cancer-associated fibroblasts (CAFs), and extracellular matrix (ECM). It examines the roles of cytokines, growth factors, and exosomes secreted by osteosarcoma cells in modifying the TME to foster tumor growth, evade immune surveillance, and promote angiogenesis. Furthermore, the review critically assesses current therapeutic approaches that target TME components, with a focus on disrupting the interactions between the tumor and its microenvironment. This analysis includes a review of clinical trials and preclinical studies evaluating TME-targeting therapies. The findings highlight that the TME actively contributes to osteosarcoma progression by promoting immunosuppression, angiogenesis, and metastasis, while also enhancing resistance to standard treatments such as chemotherapy and immune checkpoint inhibitors. Various therapeutic strategies targeting the TME, such as inhibiting angiogenesis, modulating immune responses, and disrupting CAF and ECM interactions, have shown promise in preclinical models. However, clinical outcomes remain variable, underscoring the complexity of the TME and the need for more comprehensive approaches. Targeting the TME represents a promising pathway to overcome therapeutic resistance in osteosarcoma. While significant progress has been made in understanding the role of the TME in tumor development and resistance mechanisms, further research is required to optimize TME-targeting therapies. A deeper comprehension of the intricate interactions between osteosarcoma cells and their microenvironment may lead to more effective, personalized treatments, improving clinical outcomes for patients with osteosarcoma.