Macrophages Are a Double-Edged Sword: Molecular Crosstalk between Tumor-Associated Macrophages and Cancer Stem Cells

Abstract

Cancer stem cells (CSCs) are a subset of highly tumorigenic cells in tumors. They have enhanced self-renewal properties, are usually chemo-radioresistant, and can promote tumor recurrence and metastasis. They can recruit macrophages into the tumor microenvironment and differentiate them into tumor-associated macrophages (TAMs). TAMs maintain CSC stemness and construct niches that are favorable for CSC survival. However, how CSCs and TAMs interact is not completely understood. An understanding on these mechanisms can provide additional targeting strategies for eliminating CSCs. In this review, we comprehensively summarize the reported mechanisms of crosstalk between CSCs and TAMs and update the related signaling pathways involved in tumor progression. In addition, we discuss potential therapies targeting CSC-TAM interaction, including targeting macrophage recruitment and polarization by CSCs and inhibiting the TAM-induced promotion of CSC stemness. This review also provides the perspective on the major challenge for developing potential therapeutic strategies to overcome CSC-TAM crosstalk.

Keywords: cancer immunotherapy; cancer stem cells; tumor microenvironment; tumor-associated macrophages.

Figure 1

Molecular crosstalk between TAMs and CSCs. CSCs promote macrophage recruitment by secreting CCL2, CCL3, CCL5, CCL8, CCL9, CXCL5, CXCL12, CXCL14, IL-10, IL-33, CSF-1, IGF-β, MIC-1, LOX, VEGF, OLFML3, Sdf1, POSTN, CX3CL1, HGF, MIF, and FGL2. CSCs promote macrophage polarization by secreting CCL2, IL-4, IL-6, IL-8, IL-10, IL-13, IL-33, IL-34, CSF1, CSF2, WISP1, TGF-β1, MIC-1, PGE2, Osteoactivin, and exosomes. TAMs produce factors to support CSC-like features, including CCL2, CCL5, CCL7, CCL8, CCL17, CCL22, CXCL1, CXCL7, CXCL8, IL-1β, IL-6, IL-8, IL-10, IL-18, IL-35, TGF-β, EGF, GPNMB, TNF-α, PTN, IGF, PDGF-BB, hCAP-18, S100A9, HMGB1, MFG-E8, and extracellular vesicles.

Figure 2

Targeting strategies of CSCs and TAMs in cancer therapy. Key pathways regulating CSC and TAM properties during tumorigenesis and progression have been identified, including TAM survival, recruitment, polarization, and phagocytosis and maintenance of CSC stemness. Targeting these pathways can help regulate CSC properties and TAMs and interfere with the interaction between them, thereby inhibiting the development of CSCs and providing more effective therapeutic strategies.