Advances in the study of macrophage polarization in intervertebral disc degeneration.

Intervertebral disc degeneration (IDD) is a major contributor to chronic low back pain, with its pathological mechanisms closely linked to an imbalance in macrophage polarization within the immune microenvironment. Macrophages are broadly categorized into two phenotypes: pro-inflammatory M1 and anti-inflammatory/restorative M2. The dynamic equilibrium between these subsets profoundly influences IDD progression. M1 macrophages exacerbate disc degeneration by secreting pro-inflammatory cytokines (e.g., TNF-α, IL-1β) and activating NF-κB and MAPK signaling pathways, thereby amplifying inflammatory responses, apoptosis, matrix degradation, and oxidative stress. Conversely, M2 macrophages promote tissue repair and extracellular matrix (ECM) remodeling through anti-inflammatory mediators such as IL-10 and TGF-β. Emerging therapeutic strategies, including pharmacological interventions (e.g., ROS scavengers, COX-2 inhibitors), biomaterials (e.g., smart hydrogels, engineered exosomes), and multimodal therapies (e.g., gene editing combined with immune-metabolic modulation), demonstrate significant translational potential. However, challenges persist, including the impact of the disc-specific microenvironment (hypoxia, nutrient deprivation, mechanical stress) on polarization efficiency, drug delivery limitations, and fibrosis risks. Future research should focus on resolving macrophage subpopulation heterogeneity, achieving precise polarization regulation, and optimizing clinical translation to advance immunometabolic therapies for IDD.