Intercellular...ing in cancer_Qirou Wu.pdf

Cancer Biol Med 2023.doi:10.20892/j.issn.2095-3941.2022.0750PERSPECTIVEIntercellular transmission of cGAS-STING signaling in cancerQirou Wu1,2,3,Xiaohong Leng1,Pinglong Xu1,2,31MOE Laboratory of Biosystems Homeostasis and Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology,Life Sciences Institute,Zhejiang University,Hangzhou 310058,China;2Institute of Intelligent Medicine,Hangzhou Global Scientific and Technological Innovation Center,Zhejiang University(HIC-ZJU),Hangzhou 310058,China;3Cancer Center,Zhejiang University,Hangzhou 310058,ChinaCellular communication is necessary for organizing mul-ticellular organisms,and is critical in tumorigenesis and progression.Immune and tumor cells use the cGAS-STING mechanism to sense and respond to genomic instability,DNA damage,and mitochondrial dysfunction induced by extra-and intracellular stresses.As an essential component of innate nucleic acid sensing,cGAS-STING signaling is critical in various pathological processes,including micro-bial infection,autoimmunity,inflammation,organ degen-eration,and malignancy.The cytosolic DNA sensor cyclic GMP-AMP synthase(cGAS)senses aberrant or displaced dsDNA in the cytosol and synthesizes 23-cyclic GMP-AMP(cGAMP).Endoplasmic reticulum(ER)-resident adaptor stimulator of interferon genes(STING),mobilized by this second messenger,is trafficked among the ER,ER-Golgi intermediate compartment,and Golgi apparatus,and forms distinct STING signalosomes,which in turn trigger various molecular programs controlling mRNA transla-tion,autophagy,organelle reorganization,and interferon(IFN)production1.The non-canonical functions of cGAS-STING signaling have recently gained extensive attention.These functions occur in various cellular processes,includ-ing senescence,autophagy,and cap-dependent mRNA translation1,2.Notably,the complexity of cGAS-STING signaling is fur-ther enhanced by an intriguing feature of intercellular trans-mission(Figure 1)that has recently been established in several seminal discoveries.The effective intercellular transfer of cGAS-STING signaling enables the sharing of critical infor-mation arising from infected,injured,or cancerous cells and the activation of multiple bystander cells in innate immune responses.In cancers,intercellular communication of cGAS-STING signaling connects the tumor microenvironment and pathogenic,immune,and stromal cells,thus promoting or compromising various immune responses and substantially altering disease progression.Understanding this intercellular interplay would greatly aid in developing therapeutics against malignancy.In this perspective,we discuss current knowledge,effects on cancer biology,and implications of in cancer pro-gression and therapeutics.Intercellular transmission of dsDNAUnlike normal cells,free cytoplasmic dsDNA commonly arises in tumor cells because of chromatin instability and altered metabolism.These dsDNAs are derived from multiple sources,including genomic,mitochondrial,apoptotic,and transpos-able elements,all of which activate cGAS-STING signaling and subsequently induce innate immune responses3.The modes of dsDNA transmission include phagocytosis,facilitated inter-nalization,and extracellular vesicles(EVs).PhagocytosisdsDNA transfer between cancer cells and immune cells typi-cally occurs through phagocytosis in the tumor microenviron-ment.Tumor cell-derived DNA accumulates in the cytoplasm of phagocytes,such as dendritic cells and macrophages,and triggers the activation of cGAS-STING signaling,thus facili-tating antigen presentation and promoting acquired immune responses4.Correspondence to:Pinglong XuE-mail:Received January 2,2023;accepted January 3,2023Available at www.cancerbiomed.org2023 Cancer Biology&Medicine.Creative Commons Attribution-NonCommercial 4.0 International License94 Wu et al.Intercellular transmission of cGAS-STING signaling in cancerFacilitated internalizationHigh levels of dsDNA are released into extracellular space after cell death.This DNA is typically non-immunogenic because of its rapid degradation.However,some antimicro-bial peptides,such as LL37,bind extracellular dsDNA and facilitate its internalization into monocytes,which produce type I IFNs5.Extracellular vesiclesdsDNA associated with small EVs(200 nm in diameter)has been found to mediate intercellular communication in scenar-ios including infection,inflammation,and malignancy.EVs are lipid bilayer-bound vesicles in biological fluids and are released and captured by cells.EV-mediated delivery of for-eign DNA to bystander cells is frequently detected in pathogen Figure 1 Intercellular communication in cGAS-STING signaling.(A)Schematic diagram of canonical cGAS-STING signaling.The DNA sensor cyclic GMP-AMP synthase(cGAS)recognizes a wide range of double-strand DNA(dsDNA)and is activated,thus generating the second messenger 23-cyclic GMP-AMP(cGAMP),which in turn activates membrane-bound stimulator of interferon genes(STING)and induces interferons(IFNs).(B-E