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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\u2010driven structural damage. Bone and soft tissue tumors\u2014including osteosarcoma, chondrosarcoma, Ewing sarcoma, and soft tissue sarcoma\u2014develop within immunosuppressive niches that hinder antitumor immunity. Notably, these immune environments are not strictly dichotomous but exhibit dynamic, context\u2010dependent states of immune stimulation and suppression. This review delineates both shared and disease\u2010specific immune mechanisms, spanning cytokine networks, signaling pathways, and cellular interactions. It further discusses current and emerging therapeutic strategies, including cytokine modulators, bone\u2010regulatory agents, immune checkpoint inhibitors, and cell\u2010based therapies. Despite recent advances, key challenges persist in translating immunological insights into durable, disease\u2010modifying 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.<\/jats:p>","DOI":"10.1002\/mco2.70519","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T07:01:27Z","timestamp":1764918087000},"source":"Crossref","is-referenced-by-count":4,"title":["Musculoskeletal Diseases: Mechanisms and Therapeutic Advances"],"prefix":"10.1002","volume":"6","author":[{"given":"Xiao","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery The Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou City Zhejiang Province China"},{"name":"Orthopedics Research Institute of Zhejiang University  Hangzhou City Zhejiang Province China"},{"name":"Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province  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