Spatiotemporal orchestration of macrophage heterogeneity by cell adhesion molecules.

Monocyte-derived macrophages (mo-macs) are central regulators of innate immunity and are essential for maintaining physiological homeostasis and host defense. Their functional efficacy relies on precisely coordinated transendothelial migration (TEM) and phenotypic polarization into classically activated (M1) or alternatively activated (M2) macrophages. This review delineates how cell adhesion molecules (CAMs), including integrins, selectins, the immunoglobulin superfamily (IgSF), and cadherins, act as pivotal sensors that orchestrate these spatiotemporal dynamics. CAMs facilitate the multi-step TEM of mo-macs and trigger intracellular signaling pathways, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription (STAT), to dictate macrophage plasticity in response to inflammation and the tumor microenvironment (TME). We highlight the dual role of CAMs in driving the pathogenesis of atherosclerosis and cancer while also exploring their potential in bioengineering for regenerative medicine. Elucidating these CAM-dependent regulatory networks not only helps to explain the intrinsic mechanisms underlying immune regulation but also provides a theoretical framework for designing next-generation targeted immunotherapies and personalized clinical interventions for inflammatory diseases and malignancies.