Targeting stemness pathways modulates macrophage polarization and reprograms the tumor microenvironment

Area of Science:

• Oncology
• Immunology
• Cancer Biology

Background:

• The tumor microenvironment (TME) is crucial for cancer progression and treatment resistance.
• Tumor-associated macrophages (TAMs) often promote immune suppression and tumor growth.
• Mesenchymal-like cancers, such as Consensus Molecular Subtype 4 (CMS4) colorectal cancer (CRC) and triple-negative breast cancer, exhibit immune exclusion and high macrophage infiltration.

Purpose of the Study:

• To investigate if targeting cancer cell stemness can modulate macrophage polarization.
• To shift the immune balance from pro-tumor M2-like macrophages to anti-tumor M1-like macrophages.
• To evaluate the effects of stemness inhibitors on CRC in vitro and breast cancer in vivo.

Main Methods:

• Four stemness inhibitors (salinomycin, SB-431542, JIB-04, napabucasin) targeting Wnt/β-catenin, TGF-β, histone demethylation, and STAT3 pathways were used.
• Effects were evaluated on CMS4 CRC cell lines (HCT116, SW620) and human peripheral blood-derived macrophages in an indirect co-culture model.
• In vivo studies utilized the syngeneic immunocompetent EO771 breast cancer mouse model.

Main Results:

• CMS4 CRC cell lines induced distinct macrophage polarization: HCT116 promoted M2-like, SW620 promoted M1-like macrophages.
• Combination stemness inhibitors reduced stemness markers (CD133, CD44) in CRC cells.
• Stemness inhibitors shifted macrophage polarization toward an M1-like phenotype, especially with HCT116, and increased the M1/M2 macrophage ratio in vivo.

Conclusions:

• Stemness inhibitors possess a dual role in targeting cancer cells and modulating the immune microenvironment.
• These findings suggest promising strategies for enhancing anti-tumor immunity in mesenchymal-like tumors.
• Targeting cancer stemness offers a novel approach to immunomodulation in challenging cancer subtypes.