Musculoskeletal Diseases: Mechanisms and Therapeutic Advances.

Musculoskeletal diseases encompass a broad spectrum of inflammatory, degenerative, and neoplastic disorders that compromise bone and joint function across the lifespan. Increasing evidence highlights the central role of immune regulation in their pathogenesis, driven by complex interactions among immune, bone, and stromal cells. Inflammatory conditions such as rheumatoid arthritis, ankylosing spondylitis, and dermatomyositis are marked by persistent immune activation and progressive tissue destruction. Degenerative diseases like osteoarthritis, osteoporosis, and intervertebral disc degeneration involve immune senescence, dysregulated tissue remodeling, and inflammation-driven structural damage. Bone and soft tissue tumors-including osteosarcoma, chondrosarcoma, Ewing sarcoma, and soft tissue sarcoma-develop within immunosuppressive niches that hinder antitumor immunity. Notably, these immune environments are not strictly dichotomous but exhibit dynamic, context-dependent states of immune stimulation and suppression. This review delineates both shared and disease-specific immune mechanisms, spanning cytokine networks, signaling pathways, and cellular interactions. It further discusses current and emerging therapeutic strategies, including cytokine modulators, bone-regulatory agents, immune checkpoint inhibitors, and cell-based therapies. Despite recent advances, key challenges persist in translating immunological insights into durable, disease-modifying treatments. By bridging mechanisms across inflammation, degeneration, and malignancy, this review provides an integrated framework for understanding immune contributions to musculoskeletal diseases and identifies promising directions for precision immunotherapy.