Immune microenvironment in rotator cuff healing: from macrophage dynamics to immunomodulatory regenerative therapies

Abstract

Rotator cuff repair is increasingly limited by biology rather than fixation alone: the repaired tendon commonly heals through fibrovascular scar rather than recreating the graded tendon-fibrocartilage-bone enthesis, particularly in aging, metabolic disease, muscle degeneration, and poor bone quality. The immune microenvironment is a dynamic determinant of whether injury progresses toward persistent inflammation and fibrosis or toward resolution and regeneration. This Review synthesizes immune regulation across the rotator cuff muscle-tendon-enthesis-bone unit, with emphasis on macrophage heterogeneity, efferocytosis, autophagy, immunometabolism, mechanosensing, and immune-stromal crosstalk. Human single-cell studies identify pro-fibrotic macrophage, senescent tenocyte, osteopontin/TGF-beta, and endothelial programs in rotator cuff scar, while mechanistic studies nominate resolution pathways as therapeutic targets. We critically evaluate cytokine/chemokine modulation, extracellular vesicles, senomorphic strategies, bioactive ions, ROS-responsive materials, nanoengineered interfaces, and rehabilitation-based immunomodulation. Across these approaches, the key translational requirements are causal mechanism, validation in chronic or aged disease models and human tissue, integration of structural and mechanical outcomes, arthroscopic deployability, manufacturing feasibility, and biomarker-guided patient selection. Together, these data support a shift from nonspecific anti-inflammatory augmentation toward mechanism-based, pro-resolution strategies for durable tendon-to-bone repair.