Macrophage: Biological Functions, Diseases, and Therapeutic Targets.

Macrophages are sentinel innate immune cells that arise from embryonic precursors and bone marrow monocytes, displaying a functional continuum that transcends the classical M1 (pro-inflammatory)/M2 (anti-inflammatory) dichotomy. Under homeostatic conditions, balanced M1/M2 polarization preserves tissue integrity by coordinating immune surveillance, efferocytosis, and tissue repair. When this equilibrium is disrupted, however, M1-skewed responses drive chronic inflammation and autoimmunity, whereas M2-skewed polarization facilitates tumor immune evasion and organ fibrosis. Although diverse therapeutic strategies-including reprogramming, depletion, blockade of monocyte recruitment, CAR-M cells, and nanomedicine-are being explored to restore homeostasis, clinical translation remains constrained by the lack of pathogenic subset-specific markers, insufficient predictive biomarkers for patient stratification, species divergence between mice and humans, and the temporal complexity of context-dependent intervention windows. In this Review, we systematically delineate macrophage plasticity and the molecular mechanisms underlying polarization imbalance, evaluate existing and emerging macrophage-directed interventions, and dissect these translational bottlenecks in depth, highlighting how single-cell multi-omics, humanized models, and dynamic biomarkers can overcome them. By providing a roadmap for precisely calibrating macrophage functional states and restoring M1/M2 balance, this framework will accelerate the development of precision immunotherapies aimed at re-establishing immune homeostasis across a broad spectrum of human pathologies.