Macrophage polarization in Sjögren's syndrome: from mechanisms to therapeutic translation.

Sjögren's syndrome (SS) is a chronic systemic autoimmune disease characterized by damage to exocrine glands, and no effective treatment is currently available to reverse glandular fibrosis. As core effector cells of innate immunity, macrophages play a pivotal role in the dynamic imbalance of polarization states, which critically influences inflammation initiation, tissue injury, and irreversible fibrosis in SS. This review systematically delineates the heterogeneity of M1/M2 macrophage subsets, their spatiotemporal dynamics, and their functional transitions across different pathological stages of SS: M1 predominance drives early pro-inflammatory damage, M1/M2 interplay sustains chronic inflammation in the middle stage, and aberrant M2 polarization promotes late-stage glandular fibrosis. We further dissect the multi-level regulatory network underlying macrophage polarization imbalance, including immune cell crosstalk, core signaling pathways, non-coding RNA epigenetic regulation, and immunometabolic reprogramming. The in-depth mechanisms by which M2 macrophages drive the progression of glandular fibrosis are also summarized. In this context, we describe how certain traditional Chinese medicine (TCM) formulas and monomeric compounds can effectively restore the balance of macrophage polarization by targeting relevant pathways and molecular nodes. Moreover, we analyze the major bottlenecks currently hindering the clinical translation of macrophage-targeted strategies and propose innovative approaches, including tissue-specific delivery, spatiotemporally tailored modulation, integrated TCM-western medicine therapy, biomarker-guided patient stratification, and early-window intervention. Finally, we discuss the potential of cutting-edge technologies such as single-cell multi-omics, spatial transcriptomics, gene editing, and organoid models to decode the heterogeneity of macrophage subsets and their interactions with the microenvironment. Integration of these multidisciplinary tools will facilitate the development of safe, effective, and personalized therapeutic strategies targeting macrophage polarization for SS.