Reframing macrophage polarization through cholesterol efflux: an organelle-coupled immunometabolic model.

Macrophages reside at the interface of immunity and metabolism, where their functional states are traditionally described by the M1/M2 polarization paradigm. However, this binary framework fails to capture the dynamic integration between inflammatory signaling and lipid metabolism that underlies macrophage behavior in chronic diseases. A central unresolved question is why macrophages, under sustained inflammatory and metabolic stress, progressively lose their capacity to maintain cholesterol homeostasis. Here, we propose a conceptual framework that is not merely a reinterpretation of existing data but a testable model: the macrophage polarization-efflux coupling axis, in which macrophage functional states are governed by the coordinated integration of lipid metabolism and organellar homeostasis, particularly the mitochondria-lysosome axis. Current evidence suggests that impaired cholesterol efflux may function as an active driver, rather than merely a downstream consequence, of macrophage dysfunction, based on evidence showing that genetic or pharmacological restoration of efflux actively repolarizes inflammatory macrophages toward a resolving phenotype. Lipid accumulation is reframed as a consequence of system-level failure arising from mismatched mitochondrial energy metabolism and lysosomal processing capacity. We further synthesize evidence demonstrating how transcriptional regulators, microRNA networks, epigenetic memory, and post-translational modifications converge to stabilize this dysfunctional state across diseases such as atherosclerosis and diabetic kidney disease. Importantly, emerging therapeutic strategies that restore organellar integrity and metabolic coordination show greater promise than approaches solely targeting inflammatory polarization. This integrative perspective shifts the focus from static phenotypic classification toward dynamic metabolic-organelle coupling, providing a unifying framework for understanding macrophage dysfunction and identifying novel therapeutic opportunities.