Effects of macrophages in OSCC progression

Abstract

Macrophages are crucial immune cells within the tumor microenvironment (TME), involved in regulating tumor proliferation, invasion, metastasis, ECM remodeling, angiogenesis, and immunosuppression. Although more and more experimental evidence and clinical data indicate that macrophages are involved in the onset and progression of oral squamous cell carcinoma (OSCC), the exact pathogenesis of OSCC associated with macrophages has not been fully elucidated. Enhanced knowledge of the molecular mechanisms involving macrophages in OSCC will aid in the creation of treatments targeted specifically at macrophages. This review outlines the pro-tumoral and anti-tumoral effects of macrophages in OSCC, emphasizing the interaction between OSCC cells and macrophages. It can provide theoretical basis for the establishment of complex regulatory network centered on macrophages and explore novel therapeutic strategies for OSCC.

Keywords: interaction; loop; macrophages; oral squamous cell carcinoma; polarization.

Figure 1

Role of macrophages in OSCC. The role of macrophages in OSCC is mainly divided into the pro-tumoral and anti-tumoral effects. The pro-tumoral effects include promoting tumor cells proliferation, invasion and migration, angiogenesis and immune escape. The anti-tumoral effect is mainly manifested in anti-tumor immunity. Moreover, macrophages are polarized into M1 and M2 phenotypes with anti-tumoral and pro-tumoral effects. M2 macrophages further subdivided into four subtypes according to different microenvironmental stimuli.

Figure 2

Pro-tumoral functions of TAMs. TAMs could promote tumor growth or metastasis, tissue remodelling and immunosuppression. Recent studies show that TAMs produce mediators such as IL-6, MSF et al. to promote tumor invasion, produce IL-1, CCL13 et al. to promote tumor metastasis, produce IL-6, IL-17 et al. to promote tumor proliferation, produce ROI and NO to promote tumor genetic instability. TAMs also produce TGF-β and proteases to promote ECM remodelling/fibrosis, produce IL-1, HIF-1α et al. to promote tumor angiogenesis. TAMs play a critical role of immunosuppression in the TME, such as promoting the irregular skewing of dendritic cells towards immaturity and toleration, promoting Treg cells expansion, T cell metabolic starvation and converting Th1 into Th2 cells to promote tumor immune escape.

Figure 3

Loops related to interactions between tumor cells and macrophages. Tumor cell-derived RNAs, proteins and metabolites increase the secretion of cytokines in TAMs. In turn, the above TAM-derived cytokines promote OSCC proliferation, invasion and migration. Fn/CXCL2/CXCL2 loop and THBS1/IL-6 loop facilitate the proliferation, migration and invasion of OSCC. PAI-1 and IL-8/EGF loop facilitate the proliferation and invasion of OSCC. CXCL1/EGF loop, Lactic acid/GPNMB loop, MIF/IL-1β loop, ENO1 and Latic acid/IL-6 loop and HMGB1/IL-6 loop facilitate the invasion and migration of OSCC.

Figure 4

Activation of STAT3 and NF-κB/p65 signaling pathways in tumor cells promote OSCC progression. PLOD2-driven IL-6/STAT3 signaling promotes the invasion and metastasis of OSCC via activation of integrin β1. IL-6 released by M1-like TAMs activates the STAT3 signaling to produce exosome-THBS1 in OSCC cells, promoting tumor proliferation, invasion and migration. EGF produced by CD206⁺ TAMs increase the progression of OSCC by activating the STAT3 pathway. HMGB1 in both macrophages and OSCC cells might regulate the IL-6/NF-κB pathway to increase MMP-9 expression and further promote tumor growth and invasion.

Figure 5

Specific cell signaling related to polarization and cytokine expression of macrophages in OSCC. HMGB1 promotes M1 polarization and IL-6 secretion via TLR4/NF-κB pathway and M2 polarization via IL-10/TGF-β. Endoplasmic reticulum stress promotes the release of exosomal PD-L1 and upregulates PD-L1 expression in macrophages to drive M2 macrophages polarization. GABA promotes M2 macrophages polarization by activating GABBR1/ERK/Ca²⁺. Elevated stress granule formation in stressed M2 TAMs enhances the expression of CCL13 by improving DDX3Y/hnRNPF-mediated CCL13 mRNA stability. HMGB1 increases MMP-9 expression via IL-6/NF-κB pathway and PD-L1 expression via IL-6/STAT3 signaling. GM-CSF upregulates PD-L1 expression via JAK2/STAT3 signaling. IL-4 increases VEGF-C secretion via STAT6 signaling.