Macrophage plasticity in the osteosarcoma tumor microenvironment: opportunities and challenges for immunotherapy

Osteosarcoma is an aggressive primary malignancy bone tumor, characterized by a complex immune microenvironment, which poses significant challenges for immunotherapy. Tumor-associated macrophages (TAMs) are pivotal immune cells in the tumor microenvironment (TME), exhibiting remarkable plasticity, enabling them to switch between pro-tumorigenic and anti-tumorigenic phenotypes. Their functional polarization critically influences tumor progression and therapeutic response. This comprehensive review outlines the immune environment of osteosarcoma and the underlying mechanisms of macrophage plasticity. In this paper, we discuss the therapeutic possibilities through modulation of macrophages, their reprogramming and depletion, and the issues related to clinical translation. We describe how recent advances create an opportunity to target tumor-associated macrophages to improve patient responses. By synthesizing current knowledge on macrophage phenotypes, macrophage polarization, and preclinical-to-clinical therapeutic interventions, we present a strategic framework for development of macrophage-centric immunotherapies, highlighting a promising yet challenging avenue in improving patient outcome in osteosarcoma.