Reprogramming tumor-associated macrophages in breast cancer: from myeloid plasticity and tumor-promoting programs to CAR-macrophage therapy.
5 affiliations
- 1Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Iranian Blood Transfusion Organization Building, Next to the Milad Tower, Hemmat Exp. Way, P.O.Box:14665-1157, Tehran, Iran.
- 2Cardiovascular Research Center, Rajaie Cardiovascular Institute, Iran University of Medical Sciences, Tehran, Iran.
- 3Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Iranian Blood Transfusion Organization Building, Next to the Milad Tower, Hemmat Exp. Way, P.O.Box:14665-1157, Tehran, Iran. [email protected].
- 4Department of Basic Medical Sciences, Khoy University of Medical Sciences, Khoy, Iran. [email protected].
- 5Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Mazandaran University of Medical Sciences, Sari, Iran. [email protected].
Abstract
Breast cancer develops within spatially organized, multicellular microenvironments in which particular tumor-associated macrophage (TAM) states can influence immune access and stromal remodeling. Conventional M1/M2 classification and total macrophage density fail to capture the developmental, transcriptional, metabolic, and spatial heterogeneity that determines TAM function. This macrophage-focused review examines breast cancer within its multicellular microenvironment, integrating lineage-tracing, single-cell, spatial, mechanistic, and clinical evidence while distinguishing breast-specific findings from hypotheses extrapolated from other tumors. We examine how tissue-resident and monocyte-derived macrophages are recruited, retained, expanded, and reprogrammed across primary and metastatic sites, emphasizing interactions with malignant cells, cancer-associated fibroblasts, extracellular matrix, vasculature, adipose tissue, and lymphoid populations. In defined breast-tumor contexts, TAM programs have been implicated in immune exclusion, invasion, metastatic dissemination, and adaptation to systemic treatment, although evidence strength varies across mechanisms and therapeutic modalities. Small and heterogeneous clinical studies have not established a benefit from broad CSF1/CSF1R-axis targeting in breast cancer, despite encouraging preclinical findings. Accordingly, we highlight a shift toward state-selective, spatially resolved, and temporally coordinated targeting. Emerging approaches include restoring phagocytosis, disrupting chemokine and fibrotic circuits, metabolic reprogramming, and converting suppressive TAMs into inflammatory, antigen-presenting effectors. A major focus is chimeric antigen receptor macrophage (CAR-M) therapy, which combines antigen-directed phagocytosis with tumor infiltration, matrix remodeling, antigen presentation, and recruitment of endogenous immunity. Although early clinical data support manufacturing feasibility, tumor trafficking, and acceptable initial safety, limited antitumor activity underscores challenges involving antigen heterogeneity, persistence, metabolic fitness, biodistribution, and scalable production. We propose a translational roadmap integrating spatial biomarkers, quantitative target selection, macrophage-adapted CAR design, checkpoint-resistant phagocytosis, metabolic engineering, safety switches, and biomarker-guided combination therapy. This framework positions macrophage reprogramming as a context-dependent strategy for modifying selected breast-tumor niches, with therapeutic targets chosen according to the macrophage program and its surrounding cellular architecture.
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BibTeX
@article{heydari2026reprogramming,
title = {{Reprogramming tumor-associated macrophages in breast cancer: from myeloid plasticity and tumor-promoting programs to CAR-macrophage therapy.}},
author = {Farshad Heydari and Mehdi Derakhshani and Jalal Naghinezhad},
journal = {Journal of hematology \& oncology},
year = {2026},
month = oct,
doi = {10.1186/s13045-026-01861-z},
url = {https://europepmc.org/article/MED/42907869},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Reprogramming tumor-associated macrophages in breast cancer: from myeloid plasticity and tumor-promoting programs to CAR-macrophage therapy.
AU - Farshad Heydari
AU - Mehdi Derakhshani
AU - Jalal Naghinezhad
PY - 2026
DA - 2026/10/21
JO - Journal of hematology & oncology
DO - 10.1186/s13045-026-01861-z
UR - https://europepmc.org/article/MED/42907869
AB - Breast cancer develops within spatially organized, multicellular microenvironments in which particular tumor-associated macrophage (TAM) states can influence immune access and stromal remodeling. Conventional M1/M2 classification and total macrophage density fail to capture the developmental, transcriptional, metabolic, and spatial heterogeneity that determines TAM function. This macrophage-focused review examines breast cancer within its multicellular microenvironment, integrating lineage-tracing, single-cell, spatial, mechanistic, and clinical evidence while distinguishing breast-specific findings from hypotheses extrapolated from other tumors. We examine how tissue-resident and monocyte-derived macrophages are recruited, retained, expanded, and reprogrammed across primary and metastatic sites, emphasizing interactions with malignant cells, cancer-associated fibroblasts, extracellular matrix, vasculature, adipose tissue, and lymphoid populations. In defined breast-tumor contexts, TAM programs have been implicated in immune exclusion, invasion, metastatic dissemination, and adaptation to systemic treatment, although evidence strength varies across mechanisms and therapeutic modalities. Small and heterogeneous clinical studies have not established a benefit from broad CSF1/CSF1R-axis targeting in breast cancer, despite encouraging preclinical findings. Accordingly, we highlight a shift toward state-selective, spatially resolved, and temporally coordinated targeting. Emerging approaches include restoring phagocytosis, disrupting chemokine and fibrotic circuits, metabolic reprogramming, and converting suppressive TAMs into inflammatory, antigen-presenting effectors. A major focus is chimeric antigen receptor macrophage (CAR-M) therapy, which combines antigen-directed phagocytosis with tumor infiltration, matrix remodeling, antigen presentation, and recruitment of endogenous immunity. Although early clinical data support manufacturing feasibility, tumor trafficking, and acceptable initial safety, limited antitumor activity underscores challenges involving antigen heterogeneity, persistence, metabolic fitness, biodistribution, and scalable production. We propose a translational roadmap integrating spatial biomarkers, quantitative target selection, macrophage-adapted CAR design, checkpoint-resistant phagocytosis, metabolic engineering, safety switches, and biomarker-guided combination therapy. This framework positions macrophage reprogramming as a context-dependent strategy for modifying selected breast-tumor niches, with therapeutic targets chosen according to the macrophage program and its surrounding cellular architecture.
SN - 1756-8722
ER -