What question did this study set out to answer?

The aim is to explore the role of macrophage polarization in hematologic cancers and identify therapeutic strategies to improve treatment outcomes.

February 9, 20260 citations

Macrophage polarization in hematologic cancers: mechanisms and therapeutic strategies.

ZCZhigang ChenArmy Medical University HYHuan YangArmy Medical University CYChen-Ming YangArmy Medical University

Key Points

The aim is to explore the role of macrophage polarization in hematologic cancers and identify therapeutic strategies to improve treatment outcomes.
Examine the dynamic shift between M1 and M2 macrophage phenotypes in the tumor microenvironment.
Analyze the role of cytokines and signaling pathways in macrophage polarization.
Evaluate therapeutic interventions including M2 depletion and pathway inhibitors.
M2-polarized tumor-associated macrophages are linked to poor prognosis in leukemia.
Therapeutic strategies show promise in disrupting tumor-associated macrophage interactions.
Preclinical studies indicate that CSF-1R inhibitors can enhance treatment efficacy against leukemia.

Abstract

Leukemia treatment faces persistent challenges, including chemotherapy resistance and relapse, highlighting macrophage polarization in the tumor microenvironment (TME) as a therapeutic target. Macrophages dynamically shift between antitumor M1 and protumor M2 phenotypes, with M2-polarized tumor-associated macrophages (TAMs) dominating leukemia TMEs. These cells secrete IL-10 and TGF-β, fostering immune evasion, angiogenesis, and leukemia stem cell (LSC) survival. In AML, M2 TAMs correlate with poor prognosis and chemoresistance via CSF-1/IL-10 signaling. Polarization is regulated by transcription factors (STAT6, PPARγ, KLF4), hypoxia, and metabolic reprogramming. Therapeutic strategies focus on: (1) M2 depletion (anti-CD163/CD206 antibodies); (2) Pathway inhibition (CCL2/CCR2 or IL-4/STAT6 blockade); (3) Metabolic modulation (glycolysis/OXPHOS targeting); and (4) Phagocytosis enhancement (CD47-SIRPα blockade, HDAC6 inhibition). Preclinical studies demonstrate CSF-1R inhibitors (e.g., pexidartinib) disrupt LSC-TAM crosstalk, while CAR-M therapy synergizes with phagocytosis-promoting agents. Despite challenges, macrophage-targeted therapies offer transformative potential by remodeling the TME, overcoming resistance, and augmenting immunotherapy. This review outlines mechanistic insights and translational strategies to harness macrophage plasticity for leukemia treatment.

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