Macrophages in rotator cuff injuries and tendon-to-bone healing: Heterogeneity, pathophysiology, and therapeutic strategies.

Rotator cuff tears (RCTs) are a leading cause of shoulder disability, with high postoperative failure rates primarily attributed to poor tendon-to-bone healing. Macrophages act as central regulators of the inflammatory and regenerative microenvironment in the injured enthesis, tendon stump, subacromial bursa, and rotator cuff musculature. This review highlights the spatiotemporal heterogeneity and phenotypic plasticity of macrophages revealed by single-cell and spatial transcriptomics. Rather than following a simple M1-to-M2 transition, macrophages adopt context-dependent inflammatory, resolving, remodeling, and profibrotic programs across different stages and tissue compartments of rotator cuff injury. Persistent inflammatory programs are associated with chronic inflammation, matrix degradation, fatty infiltration, and muscle atrophy, whereas resolving and reparative programs may support inflammation resolution and fibrocartilaginous regeneration; sustained remodeling or profibrotic states may also contribute to pathological fibrosis. The review further explores macrophage-stem cell crosstalk under mechanical loading and the contribution of dysregulated macrophage function to the progression of cuff tear arthropathy. Advanced strategies including stem cell-derived exosomes, immuno-engineered scaffolds, and targeted immunomodulation, have shown therapeutic potential in preclinical studies, but their clinical efficacy and translational applicability remain to be established.