Harnessing the immune system against osteosarcoma: from tumor microenvironment modulation to combinatorial immunotherapies

Abstract Osteosarcoma (OS) is the most common primary malignant bone tumor, predominantly affecting adolescents and older adults with high metastatic potential and poor prognosis upon metastasis. Traditional surgical interventions combined with adjuvant therapies have significantly improved the prognosis of patients with localized primary tumors and have enabled limb preservation in most cases. However, these approaches remain limited in cases where the tumor is difficult to resect completely, recurs, or metastasizes. Over the past few decades, there has been no significant improvement in the therapeutic outcomes for OS. This persistent clinical challenge underscores the critical need to develop novel treatment strategies that demonstrate enhanced efficacy while minimizing adverse effects. Immunotherapy has emerged as a major research focus in recent years. This review synthesizes contemporary advances in immunotherapeutic strategies for OS, with emphasis on the tumor microenvironment (TME) as both a barrier and a target for intervention. We reviewed recent immunotherapeutic approaches, therapeutic targets, and efficient drug delivery systems that have demonstrated efficacy in preclinical and clinical studies, including strategies aimed at modulating the tumor microenvironment and enhancing immune activation. Furthermore, current challenges in the field of immunotherapy for OS are discussed, particularly those related to immune suppression, antigen heterogeneity, and limited therapeutic penetration. Despite the limitations posed by the unique TME and the current scope of research, immunotherapy holds significant potential and offers new hope for the treatment of OS through rational combination strategies and continued technological innovations.