Work

Macrophage plasticity in inflammatory and tumor microenvironments: mechanisms, evidence, and therapeutic opportunities

Year: 2026

Type: review

Abstract: Macrophages are differentiated innate immune cells with niche-responsive plasticity and, in many resident populations, proliferative self-renewal. Single-cell omics, spatial profiling, lineage tracing, and epigenomic studies show that disease-associated macrophages can acquire collagen-producing, lipid-processing, vascular-construction, antigen-presentation, bone-resorptive, or fusion-associated functions. We use lineage-incongruent macrophage state as a descriptive umbrella for phenotypes that deploy a function or regulatory module conventionally associated with another cell type. Six phenomena are compared: functional adaptation, lineage-program borrowing, hybrid identity, intralineage differentiation, cell fusion, and candidate transdifferentiation. We distinguish state plasticity within the myeloid lineage, lineage-ambiguous or hybrid states with co-expression of different lineage programs, and transdifferentiation requiring established cellular origin, source-program attenuation, stable acquisition of a target-lineage network, and target-cell function. Evidence is graded from Level 1 marker observations, through Level 2 single-cell trajectory or spatial support and Level 3 lineage tracing, to Level 4 functional demonstration of the proposed converted identity. Under this framework, TREM2 + lipid-associated macrophages, osteoclasts, multinucleated giant cells, and most angiogenic macrophages represent specialization, intralineage differentiation, or fusion. TAM-to-CAF transitions are the strongest current candidates for cross-lineage conversion, but the evidence remains model- and organ-dependent, and causal human evidence is limited. A PU.1-anchored rewritable enhancer model provides a testable explanation for how macrophages retain a myeloid scaffold while deploying selected modules. Therapeutic proposals are therefore separated into mechanistic hypotheses, preclinical proof of concept, early clinical evidence, and established myeloid-niche therapies. State-selective targeting is promising, but clinical actionability requires validation of target stability, tissue-specific safety, biomarkers, and efficacy in adequately controlled human studies.

Source: Frontiers in Immunology

DOI: 10.3389/fimmu.2026.1949327

Authors: Jun Zhang, Zhiwei Wang, Shuang Wu, Tao Meng, Ming Lu

Institutions: University of Science and Technology of China, Anhui Medical University, Second Affiliated Hospital of Anhui Medical University

Language: English

Topic: Immune cells in cancer

Subfield: Immunology

Field: Immunology and Microbiology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,801