Macrophage polarization in hematologic cancers: mechanisms and therapeutic strategies

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.

Keywords: CAR-M Therapy; CD47-SIRPα Blockade; CSF-1R Inhibitors; Leukemia Stem Cells; Macrophage Polarization; Tumor Microenvironment.

Fig. 1

The Polarization Mechanism of Macrophages in Hematologic Cancers. M1 Macrophages: Induced by TNF-α and IL-17A, M1 macrophages secrete inflammatory cytokines, devour cancer cells, and activate T/NK cells. They are associated with a pro-inflammatory immune response and immune activation, contributing to the inhibition of leukemia cell lysis and cancer cell proliferation. M2 Macrophages: Induced by IL-4, IL-13, and TGF-β, M2 macrophages exhibit immunosuppressive properties, promote angiogenesis, and are chemotherapy-resistant. They are linked to VEGF production, Treg cell activation, and the inhibition of natural killer cell function, ultimately supporting the survival and proliferation of leukemia cells