Bioelectrical signals, particularly endogenous direct-current electric fields (EFs), constitute a pivotal yet often underappreciated class of physical cues within the cellular microenvironment. Macrophages, as central effectors of the innate immune system, exhibit remarkable plasticity in response to physicochemical stimuli. Accumulating evidence indicates that both endogenous and applied direct current EFs can significantly modulate key macrophage behaviors, including electrotaxis, phenotypic polarization (M1/M2), and phagocytic activity. While the precise molecular architecture remains to be fully delineated, current research suggests a multi-layered regulatory network involving surface charge redistribution, polarized activation of growth factor receptors, and signal transduction mediated by voltage-gated or mechanosensitive ion channels, which subsequently converge on downstream pathways such as phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase (MAPK), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). A rigorous dissection of the biophysical and molecular mechanisms governing these responses is essential for elucidating the role of physical signaling in tissue repair, chronic inflammation, and the tumor microenvironment. Furthermore, distinguishing the mechanistic nuances between physiological endogenous fields and therapeutic applied fields provides a critical theoretical foundation for developing next-generation, bio-mimetic immunomodulatory strategies. Future efforts should focus on characterizing the in vivo spatiotemporal dynamics of EFs, unraveling cell-type-specific response mechanisms, and assessing the translational feasibility of these fundamental insights.
Keywords: Applied electric fields; Electro-immunomodulation; Electrotaxis; Endogenous electric fields; Macrophage polarization.