Wavelength-Dependent Photobiomodulation Regulates Macrophage Polarization via Mitochondrial Dynamics and Metabolic Reprogramming.

Photobiomodulation (PBM) provides a non-invasive means to regulate immune function, yet its clinical translation is hindered by a lack of mechanistic links between light parameters and biological outcomes. Here, we demonstrate that specific wavelengths act as metabolic switches that direct macrophage polarization through the selective engagement of distinct immunometabolic pathways. In both in vitro and in vivo wound healing models, 850-nm light enhances fatty acid oxidation and lipid droplet-mitochondria interactions, driving anti-inflammatory M2 polarization and accelerating tissue repair. Conversely, 625 nm light increases glycolytic flux and lactate production, promoting a pro-inflammatory M1 state that delays healing. We identify mitochondrial dynamics as the key interface: 850 and 625 nm light promote mitochondrial fusion and fission, respectively, to dictate metabolic routing. Causality was confirmed via metabolic interventions, which reversed wavelength-specific polarization outcomes. Together, these findings define photo-immunometabolism as a wavelength-dependent framework in which light regulates macrophage fate through coordinated control of mitochondrial dynamics and metabolism. This framework provides a mechanistic basis for precision, wavelength-tailored PBM therapies for wound repair and other immune-mediated inflammatory disorders.