<p>Mesenchymal stromal cells (MSCs) have gained significant attention in regenerative medicine for their potential in treating a variety of diseases even intractable ones, due to their ability to differentiate into various cell types and promote tissue repair. In addition to their regenerative properties, MSCs possess potent immunomodulatory effects, which make them particularly promising for treating orthopedic conditions and musculoskeletal disorders complicated by chronic inflammation, infection, or other comorbidities. This review explores the immunomodulatory mechanisms of MSCs and their role in facilitating bone and cartilage repair in conditions such as fractures, osteoarthritis, and tendon injuries. We examine the key mechanisms by which MSCs regulate the immune responses, including the paracrine activity by secreting cytokines, growth factors and extracellular vesicles on one hand, and modulation of immune cell activities through direct cell-cell contact. Furthermore, this review examines how comorbidities impact MSC function and quality and explores the potential of MSCs in treating orthopedic conditions complicated by diabetes, obesity, smoking, and infections, which can hinder the healing process. The challenges of translating MSC-based therapies into orthopaedic clinical practice are also discussed, particularly concerning MSC source selection, optimal dosing strategies and long-term safety and efficacy. Finally, we highlight emerging strategies aimed at enhancing the immunomodulatory effects of MSCs, such as preconditioning, genetic modifications, biomaterial-based delivery systems and combination therapies. A profound understanding of MSC immunomodulatory mechanisms can pave the way toward optimizing their application in orthopedic cell therapy and tissue engineering and enhancing clinical outcomes for patients with complex healing conditions.</p> Graphical Abstract <p>MSC Therapy in Orthopedic Conditions and Comorbidities. A schematic representation of MSC-based therapy in orthopedic conditions, including bone fractures, osteoarthritis and tendon injuries, particularly in the presence of comorbidities such as diabetes, obesity, infection, and smoking. Comorbid conditions not only impair tissue repair in orthopedics but also diminish the functional efficacy of MSCs. MSCs exhibit regenerative, immunomodulatory, and homing capabilities, making them a promising therapeutic approach for compromised healing environments. Through cell-cell interactions and paracrine signaling, MSCs modulate the immune response and promote tissue repair and regeneration (Created with BioRender.com).</p> <p></p>