Abstract
Simple SummaryAs the most abundant cell in the tumor microenvironment (TME), tumor-associated macrophages (TAMs) drive tumor progress by inducing angiogenesis, fibrosis, invasion, metastasis, and immunosuppression, which makes these cells an important target for tumor treatment. Recently, the role of free mitochondrial DNA (mtDNA) has attracted increased attention in the regulation of immune cells in the TME. In this review, we first summarize the functional characteristics of macrophages in tumor progression. The release and regulation mechanisms of tumor cell-derived mtDNA in TME are also introduced. Then, the biological effects of endogenous and exogenous mtDNA on macrophages are discussed. Finally, we propose that the effect of mtDNA on macrophages is worthy of attention in the process of tumor treatment, especially in immunotherapy. Our review provides a systematic summary of the effects of mtDNA on the survival, function, and phenotypes of TAMs in the TME.As the richest immune cells in most tumor microenvironments (TMEs), tumor-associated macrophages (TAMs) play an important role in tumor development and treatment sensitivity. The phenotypes and functions of TAMs vary according to their sources and tumor progression. Different TAM phenotypes display distinct behaviors in terms of tumor immunity and are regulated by intracellular and exogenous molecules. Additionally, dysfunctional and oxidatively stressed mitochondrial-derived mitochondrial DNA (mtDNA) plays an important role in remodeling the phenotypes and functions of TAMs. This article reviews the interactions between mtDNA and TAMs in the TME and further discusses the influence of their performance on tumor genesis and development.
Highlights
In response to harmful stimulation and tissue damage, macrophages are involved in tissue homeostasis and immune defense against pathogens by removing dead cells and foreign substances [1]
Several studies have reported that activated neutrophils expelled extracellular traps (NETs) containing mitochondrial DNA (mtDNA), which promoted the release of interferons and other pro-inflammatory cytokines to form a chronic inflammatory environment, which contributed to cancer cell growth and metastasis [99–103]
Cunning cancer cells disguise themselves to avoid being recognized by immune cells and provoke macrophages by secreting cytokines transforming growth factor-β (TGF-β), CSF 1, and vascular endothelial growth factor (VEGF) and tumor-derived exosomes (TDEs) or acidifying the tumor microenvironments (TMEs) generated by the special metabolic patterns of cancer cells [154,155]
Summary
In response to harmful stimulation and tissue damage, macrophages are involved in tissue homeostasis and immune defense against pathogens by removing dead cells and foreign substances [1]. The phenotypes and functions of TAMs are highly heterogeneous and closely regulated by tumor processes as well as many small molecules in the TME, including various cytokines, interleukins, nucleic acid, and other pathogen-associated molecular patterns (PAMPs), in addition to damage-associated molecular patterns (DAMPs), mitochondrial metabolism, and lactic acid [6]. DNA (mtDNA) is an important DAMP released by damaged mitochondria after infection and stress and can induce inflammatory responses through a variety of pattern recognition receptors (PRRs) [7]. We discuss how various derived free mtDNA accumulate in macrophages; regulate macrophage recruitment, survival, polarization, and function; and determine the immunity of the tumor microenvironment
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