Plain-language summary
Rotator cuff tears are one of the most common causes of shoulder pain and disability, yet surgical repair fails far too often because the tendon does not reattach firmly to bone. This review focuses on macrophages, the immune cells that clear debris and coordinate tissue repair, and on their role in the healing enthesis. Drawing on single-cell and spatial transcriptomics, the authors show that macrophages do not simply switch from a pro-inflammatory to an anti-inflammatory state. Instead they adopt several context-dependent programs, inflammatory, resolving, remodelling and profibrotic, that differ by injury stage and by tissue compartment. Persistent inflammatory or profibrotic activity is linked to matrix breakdown, fatty infiltration and muscle wasting, whereas resolving and reparative programs may support inflammation resolution and fibrocartilaginous regeneration. The review also examines how mechanical loading shapes crosstalk between macrophages and resident stem cells, and how dysregulated macrophage function contributes to cuff tear arthropathy. Among the advanced strategies described are stem cell-derived exosomes, immuno-engineered scaffolds and targeted immunomodulation. All have shown therapeutic potential in preclinical studies, but the authors stress that clinical efficacy and translational applicability remain to be established.
Key findings
- Rotator cuff repair frequently fails because the tendon-to-bone enthesis heals poorly, and macrophages are central regulators of the inflammatory and regenerative microenvironment at that interface.
- Single-cell and spatial transcriptomics reveal that macrophages adopt distinct inflammatory, resolving, remodelling and profibrotic programs depending on injury stage and tissue compartment, rather than following a simple M1-to-M2 transition.
- Persistent inflammatory or profibrotic programs are associated with chronic inflammation, matrix degradation, fatty infiltration and muscle atrophy, while resolving and reparative programs may support fibrocartilaginous regeneration.
- 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.
Original abstract
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.
Frequently asked questions
What did this study find?
Rotator cuff tears are one of the most common causes of shoulder pain and disability, yet surgical repair fails far too often because the tendon does not reattach firmly to bone. This review focuses on macrophages, the immune cells that clear debris and coordinate tissue repair, and on their role in the healing enthesis. Drawing on single-cell and spatial transcriptomics, the authors show that macrophages do not simply switch from a pro-inflammatory to an anti-inflammatory state. Instead they adopt several context-dependent programs, inflammatory, resolving, remodelling and profibrotic, that differ by injury stage and by tissue compartment. Persistent inflammatory or profibrotic activity is linked to matrix breakdown, fatty infiltration and muscle wasting, whereas resolving and reparative programs may support inflammation resolution and fibrocartilaginous regeneration. The review also examines how mechanical loading shapes crosstalk between macrophages and resident stem cells, and how dysregulated macrophage function contributes to cuff tear arthropathy. Among the advanced strategies described are stem cell-derived exosomes, immuno-engineered scaffolds and targeted immunomodulation. All have shown therapeutic potential in preclinical studies, but the authors stress that clinical efficacy and translational applicability remain to be established.
Was this tested in humans or in the laboratory?
This is a review: it summarises and weighs up previously published studies rather than presenting new experiments.
Where can I read the original paper?
The full text lives with the publisher: https://doi.org/10.1016/j.intimp.2026.117521
How to cite this paper
Ma Tingkun, Wang Zitong, Gao Xing, Wang Xin, Xu Jian, Wang Weikang et al.. Macrophages in rotator cuff injuries and tendon-to-bone healing: Heterogeneity, pathophysiology, and therapeutic strategies.. International immunopharmacology. 2026, 2026-10-10. DOI: 10.1016/j.intimp.2026.117521
Source & verification
- Journal: International immunopharmacology
- Published: 10 October 2026
- DOI: 10.1016/j.intimp.2026.117521
- PubMed ID: 42858730
- Indexed via: pubmed
- MeSH terms: —