Macrophage Polarization in Disc Herniation and Degeneration: Evidence and Perspectives on Metabolic Crosstalk and Precision Immunomodulation

Spontaneous resorption of herniated intervertebral disc material involves inflammatory responses, neovascularization, and macrophage-associated tissue clearance. This process should be distinguished from protection or regeneration of the remaining disc. This narrative review examines macrophage polarization in disc herniation and degeneration, focusing on phenotypic stability, metabolic-redox interactions, and emerging immunomodulatory delivery systems. Clinical imaging studies provide evidence of herniated-fragment regression, whereas most studies of extracellular vesicles, nanovesicles, and responsive hydrogels evaluate inflammatory activity, cellular injury, matrix homeostasis, or degeneration in experimental intradiscal models. These outcomes indicate potential protective or repair-associated effects but do not independently establish fragment resorption or functional disc regeneration. Experimental findings suggest that inflammatory and oxidative conditions can influence macrophage phenotypes; however, changes in marker-positive populations should not be equated with direct evidence of conversion of alternatively activated (M2-like) macrophages into classically activated (M1-like) macrophages, and altered metabolite abundance does not establish increased metabolic flux. These findings support a proposed framework in which clearance-associated inflammation and protection of the remaining disc may require spatially and temporally coordinated modulation. Whether such an approach can preserve spontaneous resorption while supporting subsequent repair remains to be demonstrated. Future studies should assess fragment clearance and residual disc outcomes separately and evaluate long-term structural, functional, and safety endpoints prior to clinical translation.