Tumor-associated macrophage reprogramming in cancer: recent advances in resistance mechanisms and therapy
- 1Department of Internal Medicine, University of Michigan
- 2Department of Pathology, University of Lahore
- 3Department of Biological Sciences, Superior University
Abstract
Tumor-associated macrophages (TAMs) are abundant, heterogeneous, and spatially organized immune cells that regulate cancer progression, immune evasion, metastasis, and therapeutic resistance. Single-cell and spatial technologies have revealed diverse TAM states shaped by ontogeny, tumor type, disease stage, cytokines, hypoxia, metabolism, epigenetic remodeling, extracellular matrix architecture, stromal interactions, extracellular vesicles, microbiome-derived signals, and therapy-induced damage. Bidirectional cancer-TAM crosstalk evolves from tumor initiation through progression and recurrence, generating tumor-specific resistance programs that suppress lymphocytes, impair antigen presentation and phagocytosis, promote angiogenesis and metabolic restriction, remodel stroma, mediate tolerogenic efferocytosis, and sustain stem-cell, metastatic, dormancy, and regenerative niches. Therapeutic strategies include blocking macrophage recruitment or survival, activating CD40/TLR/STING signaling, targeting PI3Kγ and STAT pathways, restoring phagocytosis, modulating efferocytosis, and applying metabolic, epigenetic, stromal, vascular, nanoparticle, RNA-based, microbiome-directed, and engineered-macrophage approaches. Randomized trials have established the efficacy of CSF1R inhibition in selected CSF1-driven, macrophage-dependent tumors, whereas most other TAM- or myeloid-directed strategies in conventional solid tumors have demonstrated only preliminary clinical activity or pharmacodynamic modulation without consistent durable benefit. Off-target toxicity, spatial heterogeneity, dynamic plasticity, preclinical-clinical discordance, and combination-treatment optimization remain major barriers. Biomarker-guided patient selection, longitudinal monitoring, tumor-specific targeting, and rationally sequenced combinations will be essential for converting tumor-supportive TAMs into durable antitumor effectors.
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BibTeX
@article{saeed2026tumorassociated,
title = {{Tumor-associated macrophage reprogramming in cancer: recent advances in resistance mechanisms and therapy}},
author = {Abdullah Farhan Saeed and Muhammad Naim Ashraf and Muhammad Zaheer Iqbal},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1920004},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1920004/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Tumor-associated macrophage reprogramming in cancer: recent advances in resistance mechanisms and therapy
AU - Abdullah Farhan Saeed
AU - Muhammad Naim Ashraf
AU - Muhammad Zaheer Iqbal
PY - 2026
DA - 2026/10/28
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1920004
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1920004/full
AB - Tumor-associated macrophages (TAMs) are abundant, heterogeneous, and spatially organized immune cells that regulate cancer progression, immune evasion, metastasis, and therapeutic resistance. Single-cell and spatial technologies have revealed diverse TAM states shaped by ontogeny, tumor type, disease stage, cytokines, hypoxia, metabolism, epigenetic remodeling, extracellular matrix architecture, stromal interactions, extracellular vesicles, microbiome-derived signals, and therapy-induced damage. Bidirectional cancer-TAM crosstalk evolves from tumor initiation through progression and recurrence, generating tumor-specific resistance programs that suppress lymphocytes, impair antigen presentation and phagocytosis, promote angiogenesis and metabolic restriction, remodel stroma, mediate tolerogenic efferocytosis, and sustain stem-cell, metastatic, dormancy, and regenerative niches. Therapeutic strategies include blocking macrophage recruitment or survival, activating CD40/TLR/STING signaling, targeting PI3Kγ and STAT pathways, restoring phagocytosis, modulating efferocytosis, and applying metabolic, epigenetic, stromal, vascular, nanoparticle, RNA-based, microbiome-directed, and engineered-macrophage approaches. Randomized trials have established the efficacy of CSF1R inhibition in selected CSF1-driven, macrophage-dependent tumors, whereas most other TAM- or myeloid-directed strategies in conventional solid tumors have demonstrated only preliminary clinical activity or pharmacodynamic modulation without consistent durable benefit. Off-target toxicity, spatial heterogeneity, dynamic plasticity, preclinical-clinical discordance, and combination-treatment optimization remain major barriers. Biomarker-guided patient selection, longitudinal monitoring, tumor-specific targeting, and rationally sequenced combinations will be essential for converting tumor-supportive TAMs into durable antitumor effectors.
SN - 1664-3224
ER -