{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T20:18:05Z","timestamp":1789330685700,"version":"build-2803163510"},"reference-count":279,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Macrophages are highly plastic innate immune cells that adopt context-dependent phenotypes along a continuum, integrating developmental origin with local microenvironmental cues rather than conforming to discrete M1\/M2 states. This review delineates the molecular circuits shaping macrophage identity\u2014TLR\/cytokine signaling, microRNA networks, metabolic rewiring, and epigenetic mechanisms including histone lactylation\u2014and traces how circulating monocyte subsets contribute to tissue macrophage diversity. We examine macrophage plasticity across a broad disease spectrum\u2014oncology, autoimmune and rheumatic diseases, inflammatory bowel disease, infectious diseases, metabolic disorders, and neurological conditions\u2014showing that the pathogenic phenotype is strikingly context-dependent: for instance, M2-like tumor-associated macrophages promote immune evasion in solid tumors, whereas M1-skewed programs drive tissue damage in autoimmunity. Soluble markers (sCD163, sCD14, soluble mannose receptor) are emerging biomarkers of disease activity and prognosis. High-dimensional flow cytometry and mass cytometry (CyTOF) bridge molecular biology and clinical phenotyping, enabling integrated readouts of surface phenotype, intracellular signaling, and metabolic state. Therapeutic strategies discussed include selective tumor-associated macrophage (TAM) reprogramming, chimeric antigen receptor (CAR)-M cell therapies, and biomaterial-based platforms. Future priorities encompass spatially resolved multi-omics, epigenetic and metabolic targeting, and macrophage-centered vaccine approaches. Standardized cytometry panels will be essential for biomarker-guided stratification and context-specific interventions.<\/jats:p>","DOI":"10.3390\/ijms27125333","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T08:57:58Z","timestamp":1781513878000},"page":"5333","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Macrophage Plasticity: Phenotypic and Functional Profiles Across Pathological Microenvironments"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2922-4978","authenticated-orcid":false,"given":"Alessandra","family":"Falda","sequence":"first","affiliation":[{"name":"Laboratory Medicine Unit, Integrated Diagnostic Services-DIDAS, Padua University Hospital, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Mills, C.D. 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