Macrophage plasticity in inflammatory and tumor microenvironments: mechanisms, evidence, and therapeutic opportunities
- 1Division of Life Science and Medicine, Department of Colorectal Surgery, The First Affiliated Hospital of USTC (Anhui Provincial Tumor Hospital), University of Science and Technology of China
- 2Department of Immunology, School of Basic Medical Sciences, Anhui Medical University
- 3Department of Rheumatology and Immunology, The Second Affiliated Hospital of Anhui Medical University
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.
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BibTeX
@article{zhang2026macrophage,
title = {{Macrophage plasticity in inflammatory and tumor microenvironments: mechanisms, evidence, and therapeutic opportunities}},
author = {Jun Zhang and Zhiwei Wang and Shuang Wu and Tao Meng and Ming Lu},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1949327},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1949327/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Macrophage plasticity in inflammatory and tumor microenvironments: mechanisms, evidence, and therapeutic opportunities
AU - Jun Zhang
AU - Zhiwei Wang
AU - Shuang Wu
AU - Tao Meng
AU - Ming Lu
PY - 2026
DA - 2026/10/22
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1949327
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1949327/full
AB - 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.
SN - 1664-3224
ER -