Exosomes: A Potential Therapeutic Tool Targeting Communications between Tumor Cells and Macrophages

Exosomes comprise extracellular vesicles (EVs) with diameters between 30 and 150 nm. They transfer proteins, RNA, and other molecules from cell to cell, playing an important role in the interactions between cells. The tumor microenvironment (TME) has been found to contain various cells and molecules that have an important impact on tumor development. In the TME, macrophages have been found to have an important relationship with tumor cells, with tumors recruiting and inducing macrophages to become tumor-associated macrophages (TAMs), which promote tumor development. Recently, exosomes have been found to play a critical role in the interaction between tumor cells and macrophages. Thus, in this review, we summarize the roles and mechanisms of exosomes in the interaction between tumor cells and macrophages and the potential methods by which exosomes are used to target the communication between tumor cells and macrophages to treat cancer. Exosomes comprise extracellular vesicles (EVs) with diameters between 30 and 150 nm. They transfer proteins, RNA, and other molecules from cell to cell, playing an important role in the interactions between cells. The tumor microenvironment (TME) has been found to contain various cells and molecules that have an important impact on tumor development. In the TME, macrophages have been found to have an important relationship with tumor cells, with tumors recruiting and inducing macrophages to become tumor-associated macrophages (TAMs), which promote tumor development. Recently, exosomes have been found to play a critical role in the interaction between tumor cells and macrophages. Thus, in this review, we summarize the roles and mechanisms of exosomes in the interaction between tumor cells and macrophages and the potential methods by which exosomes are used to target the communication between tumor cells and macrophages to treat cancer. Exosomes are the smallest extracellular vesicles (EVs) with diameters between 30 and 150 nm and play an important role in the interactions between cells.1Pegtel D.M. Gould S.J. Exosomes.Annu. Rev. Biochem. 2019; 88: 487-514Crossref PubMed Scopus (80) Google Scholar,2Farooqi A.A. Desai N.N. Qureshi M.Z. Librelotto D.R.N. Gasparri M.L. Bishayee A. Nabavi S.M. Curti V. Daglia M. Exosome biogenesis, bioactivities and functions as new delivery systems of natural compounds.Biotechnol. Adv. 2018; 36: 328-334Crossref PubMed Scopus (49) Google Scholar Exosomes mainly contain proteins and RNAs and can also include glycoconjugates, lipids, and DNAs. Exosomal proteins include integral exosomal membrane proteins, lipid-anchored outer membrane proteins, peripheral surface proteins, lipid-anchored inner membrane proteins, inner peripheral membrane proteins, exosomal enzymes, and soluble proteins.1Pegtel D.M. Gould S.J. Exosomes.Annu. Rev. Biochem. 2019; 88: 487-514Crossref PubMed Scopus (80) Google Scholar Exosomal RNAs consist of mRNA and noncoding RNAs such as microRNAs and long noncoding RNAs (lncRNAs).3Sato-Kuwabara Y. Melo S.A. Soares F.A. Calin G.A. The fusion of two worlds: non-coding RNAs and extracellular vesicles—diagnostic and therapeutic implications (Review).Int. J. Oncol. 2015; 46: 17-27Crossref PubMed Scopus (0) Google Scholar Regarding the biogenesis of exosomes, it is generally thought that vesicles bud into endosomes, which then mature into multivesicular bodies (MVBs) and fuse with the plasma membrane (PM), from which the exosomes are released.1Pegtel D.M. Gould S.J. Exosomes.Annu. Rev. Biochem. 2019; 88: 487-514Crossref PubMed Scopus (80) Google Scholar The specific process is as follows. During the process of maturation of early endosomes into late endosomes, the early endosomal membrane encapsulates specific proteins, lipids, and cytosol to form MVBs. Most MVBs fuse with lysosomes, which degrade their contents, while some MVBs fuse with the PM, through which their contents are released into the extracellular environment.4Colombo M. Raposo G. Théry C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles.Annu. Rev. Cell Dev. Biol. 2014; 30: 255-289Crossref PubMed Scopus (1869) Google Scholar Early endosomes form MVBs through many pathways, and the most common pathway depends on endosomal sorting complexes required for transport (ESCRT).2Farooqi A.A. Desai N.N. Qureshi M.Z. Librelotto D.R.N. Gasparri M.L. Bishayee A. Nabavi S.M. Curti V. Daglia M. Exosome biogenesis, bioactivities and functions as new delivery systems of natural compounds.Biotechnol. Adv. 2018; 36: 328-334Crossref PubMed Scopus (49) Google Scholar In recent years, the tumor microenvironment (TME) has been found to have an important impact on tumor development. The TME is generated by tumor cells, containing a variety of molecules and cells that promote tumor metastasis, angiogenesis, drug resistance, and so on.5Nagarsheth N. Wicha M.S. Zou W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy.Nat. Rev. Immunol. 2017; 17: 559-572Crossref PubMed Scopus (359) Google Scholar In the TME, macrophages have been found to have an important relationship with tumors, with tumors recruiting and inducing macrophages to become tumor-associated macrophages (TAMs) that promote tumor development. Macrophages are immune cells that play an important role in tissue hemostasis, inflammation, and pathology.6Lee C.Z.W. Kozaki T. Ginhoux F. Studying tissue macrophages in vitro: are iPSC-derived cells the answer?.Nat. Rev. Immunol. 2018; 18: 716-725Crossref PubMed Scopus (17) Google Scholar Macrophage polarization is the process by which macrophages are activated into one of two different phenotypes at specific times and locations via multiple signals.7Murray P.J. Macrophage polarization.Annu. Rev. Physiol. 2017; 79: 541-566Crossref PubMed Scopus (381) Google Scholar Macrophages can be polarized into classically activated M1 macrophages or alternatively activated M2 macrophages.8Sica A. Erreni M. Allavena P. Porta C. Macrophage polarization in pathology.Cell. Mol. Life Sci. 2015; 72: 4111-4126Crossref PubMed Scopus (208) Google Scholar These phenotypes have different molecular characteristics and different functions. M1 macrophages appear in an inflammatory environment dominated by Toll-like receptors (TLRs) and interferon (IFN) signaling pathways and are often associated with immune responses to bacterial and intracellular pathogens. 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Exosomes derived from hypoxic epithelial ovarian cancer cells deliver microRNAs to macrophages and elicit a tumor-promoted phenotype.Cancer Lett. 2018; 435: 80-91Crossref PubMed Google Scholar In this review, we summarize the roles and mechanisms of exosomes in the interaction between tumor cells and macrophages as well as the potential methods that use exosomes to target the communication between tumor cells and macrophages to treat cancer. Studies have shown that, in a variety of cancers, such as gastric cancer, breast cancer, hepatocellular carcinoma (HCC), and nasopharyngeal carcinoma, exosomes can be secreted into the TME to regulate the function of neighboring cells, thus creating an environment conducive to tumor development.18Zhang X. Shi H. Yuan X. Jiang P. Qian H. Xu W. Tumor-derived exosomes induce N2 polarization of neutrophils to promote gastric cancer cell migration.Mol. Cancer. 2018; 17: 146Crossref PubMed Scopus (6) Google Scholar, 19Luga V. Zhang L. Viloria-Petit A.M. 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Ceder S. et al.Tumour exosome integrins determine organotropic metastasis.Nature. 2015; 527: 329-335Crossref PubMed Scopus (1541) Google Scholar For example, intercellular cell adhesion molecule-1 (ICAM-1) is enriched in exosomes derived from pancreatic ductal adenocarcinoma (PDAC) and interacts with CD11c exposed on the surface of macrophages to mediate exosomes docking to macrophages,23Linton S.S. Abraham T. Liao J. Clawson G.A. Butler P.J. Fox T. Kester M. Matters G.L. Tumor-promoting effects of pancreatic cancer cell exosomes on THP-1-derived macrophages.PLoS ONE. 2018; 13: e0206759Crossref PubMed Scopus (9) Google Scholar while regenerating islet-derived protein 3β (REG3β), released by paracarcinoma tissue, binds to the glycoproteins exposed on the surface of EVs, interfering with macrophage uptake of these EVs.24Bonjoch L. Gironella M. Iovanna J.L. Closa D. REG3β modifies cell tumor function by impairing extracellular vesicle uptake.Sci. Rep. 2017; 7: 3143Crossref PubMed Scopus (0) Google Scholar After macrophages internalize exosomes derived from cancer cells, molecules enriched in the exosomes enter the macrophages and regulate their polarization, thereby influencing metastasis, angiogenesis, drug resistance, and immune evasion (Figure 1; Table 1).Table 1The Functions and Mechanisms of Cancer-Derived Exosomes on MacrophagesCancerMoleculeMechanismFunctionReferencesHepatocellular carcinomamiR-146a–promoting M2 polarization, immune evasion25Han Q. Zhao H. Jiang Y. Yin C. Zhang J. HCC-derived exosomes: critical player and target for cancer immune escape.Cells. 2019; 8: E558Crossref PubMed Google Scholar,26Yin C. Han Q. Xu D. Zheng B. Zhao X. Zhang J. SALL4-mediated upregulation of exosomal miR-146a-5p drives T-cell exhaustion by M2 tumor-associated macrophages in HCC.OncoImmunology. 2019; 8: 1601479Crossref PubMed Scopus (3) Google ScholarmiR-23a-3pPTEN/PI3Kpromoting M2 polarization, immune evasion27Liu J. Fan L. Yu H. Zhang J. He Y. Feng D. Wang F. Li X. Liu Q. Li Y. et al.Endoplasmic reticulum stress causes liver cancer cells to release exosomal miR-23a-3p and up-regulate programmed death ligand 1 expression in macrophages.Hepatology. 2019; 70: 241-258Crossref PubMed Scopus (223) Google ScholarOvarian cancermiR-222-3p–promoting M2 polarization28Ying X. Wu Q. Wu X. Zhu Q. Wang X. Jiang L. Chen X. Wang X. Epithelial ovarian cancer-secreted exosomal miR-222-3p induces polarization of tumor-associated macrophages.Oncotarget. 2016; 7: 43076-43087Crossref PubMed Scopus (102) Google ScholarmiR-1246Cav1/p-gppromoting M2 polarization, resistance against paclitaxel29Kanlikilicer P. Bayraktar R. Denizli M. Rashed M.H. Ivan C. Aslan B. Mitra R. Karagoz K. Bayraktar E. Zhang X. et al.Exosomal miRNA confers chemo resistance via targeting Cav1/p-gp/M2-type macrophage axis in ovarian cancer.EBioMedicine. 2018; 38: 100-112Abstract Full Text Full Text PDF PubMed Scopus (0) Google ScholarHead and neck cancermiR-21–promoting M2 polarization30Hsieh C.H. Tai S.K. Yang M.H. Snail-overexpressing cancer cells promote M2-like polarization of tumor-associated macrophages by delivering miR-21-abundant exosomes.Neoplasia. 2018; 20: 775-788Crossref PubMed Scopus (27) Google ScholarPancreatic cancermiR-301a-3pPTEN/PI3Kpromoting M2 polarization31Wang X. Luo G. Zhang K. Cao J. Huang C. Jiang T. Liu B. Su L. Qiu Z. Hypoxic tumor-derived exosomal miR-301a mediates M2 macrophage polarization via PTEN/PI3Kγ to promote pancreatic cancer metastasis.Cancer Res. 2018; 78: 4586-4598Crossref PubMed Scopus (25) Google ScholarMIF–promoting pre-metastatic niches formation and metastasis32Costa-Silva B. Aiello N.M. Ocean A.J. Singh S. Zhang H. Thakur B.K. Becker A. Hoshino A. Mark M.T. Molina H. et al.Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver.Nat. Cell Biol. 2015; 17: 816-826Crossref PubMed Scopus (953) Google ScholarProstate cancer–integrin signalingpromoting M2 polarization33Ferguson S. Kim S. Lee C. Deci M. Nguyen J. The phenotypic effects of exosomes secreted from distinct cellular sources: a comparative study based on miRNA composition.AAPS J. 2018; 20: 67Crossref PubMed Scopus (3) Google ScholarMFG-E8–promoting M2 polarization34Soki F.N. Koh A.J. Jones J.D. Kim Y.W. Dai J. Keller E.T. Pienta K.J. Atabai K. Roca H. McCauley L.K. Polarization of prostate cancer-associated macrophages is induced by milk fat globule-EGF factor 8 (MFG-E8)-mediated efferocytosis.J. Biol. Chem. 2014; 289: 24560-24572Crossref PubMed Scopus (79) Google ScholarOSCCmiR-29a-3pSOCS1/STAT6promoting M2 polarization35Cai J. Qiao B. Gao N. Lin N. He W. Oral squamous cell carcinoma-derived exosomes promote M2 subtype macrophage polarization mediated by exosome-enclosed miR-29a-3p.Am. J. Physiol. Cell Physiol. 2019; 316: C731-C740Crossref PubMed Scopus (7) Google ScholarColon cancermiR-1246–promoting M2 polarization36Cooks T. Pateras I.S. Jenkins L.M. Patel K.M. Robles A.I. Morris J. Forshew T. Appella E. Gorgoulis V.G. Harris C.C. Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246.Nat. Commun. 2018; 9: 771Crossref PubMed Scopus (92) Google ScholarColorectal cancerIRF-2inducing macrophage-releasing VEGFCpromoting lymphatic metastasis37Sun B. Zhou Y. Fang Y. Li Z. Gu X. Xiang J. Colorectal cancer exosomes induce lymphatic network remodeling in lymph nodes.Int. J. Cancer. 2019; 145: 1648-1659Crossref PubMed Scopus (10) Google ScholarLarge B cell lymphomaNSEinhibiting NF-κB activitypromoting M2 polarization38Zhu M.Y. Liu W.J. Wang H. Wang W.D. Liu N.W. Lu Y. NSE from diffuse large B-cell lymphoma cells regulates macrophage polarization.Cancer Manag. Res. 2019; 11: 4577-4595Crossref PubMed Scopus (1) Google Scholaravβ5–promoting liver metastasis39Paolillo M. Schinelli S. Integrins and exosomes, a dangerous liaison in cancer progression.Cancers (Basel). 2017; 9: E95Crossref PubMed Scopus (17) Google ScholarLung adenocarcinomamiR-21targeting Pdcd4promoting bone metastasis40Xu Z. Liu X. Wang H. Li J. Dai L. Li J. Dong C. Lung adenocarcinoma cell-derived exosomal miR-21 facilitates osteoclastogenesis.Gene. 2018; 666: 116-122Crossref PubMed Scopus (19) Google ScholarNSCLCAREGEGFR pathwaypromoting bone metastasis41Taverna S. Pucci M. Giallombardo M. Di Bella M.A. Santarpia M. Reclusa P. Gil-Bazo I. Rolfo C. Alessandro R. Amphiregulin contained in NSCLC-exosomes induces osteoclast differentiation through the activation of EGFR pathway.Sci. Rep. 2017; 7: 3170Crossref PubMed Scopus (39) Google ScholarEsophageal squamous cell carcinomaHMGB1–promoting immune evasion42Li B. Song T.N. Wang F.R. Yin C. Li Z. Lin J.P. Meng Y.Q. Feng H.M. Jing T. Tumor-derived exosomal HMGB1 promotes esophageal squamous cell carcinoma progression through inducing PD1+ TAM expansion.Oncogenesis. 2019; 8: 17Crossref PubMed Scopus (15) Google ScholarMelanoma–inducing endothelial GM-CSF to induce HIF-1α in M1 or HIF-2α in M2promoting angiogenesis43Hood J.L. Melanoma exosome induction of endothelial cell GM-CSF in pre-metastatic lymph nodes may result in different M1 and M2 macrophage mediated angiogenic processes.Med. Hypotheses. 2016; 94: 118-122Crossref PubMed Google Scholar–, unknown. Open table in a new tab –, unknown. Exosomes derived from cancer cells can be internalized by macrophages where they regulate polarization. In most cases, exosomes induce M2 polarization,44Wang F. Li B. Wei Y. Zhao Y. Wang L. Zhang P. Yang J. He W. Chen H. Jiao Z. 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Exp. Clin. Cancer Res. 2018; 37: 143Crossref PubMed Scopus (26) Google Scholar The polarization induced may depend on the stage of the cancer.47Xiao M. Zhang J. Chen W. Chen W. M1-like tumor-associated macrophages activated by exosome-transferred THBS1 promote malignant migration in oral squamous cell carcinoma.J. Exp. Clin. Cancer Res. 2018; 37: 143Crossref PubMed Scopus (26) Google Scholar Different cell lines from the same type of tumor secrete different exosomes to activate macrophage polarization. In prostate cancer, for example, exosomes secreted by African-American prostate cancer (PCa) e006aa-ht cells strongly induce the pro-inflammatory M2 phenotype.48Panigrahi G.K. Praharaj P.P. Kittaka H. Mridha A.R. Black O.M. Singh R. Mercer R. van Bokhoven A. Torkko K.C. Agarwal C. et al.Exosome proteomic analyses identify inflammatory phenotype and novel biomarkers in African American prostate cancer patients.Cancer Med. 2019; 8: 1110-1123Crossref PubMed Scopus (7) Google Scholar Cancer cells deliver molecules such as microRNAs (miRNAs) and proteins to regulate macrophage polarization. Numerous studies have shown that exosomes secreted by tumors can carry miRNAs and transfer miRNAs into macrophages to regulate the polarization of macrophages. Different tumor-derived exosomes carry different miRNAs. In HCC, miR-146a enrichment in exosomes can promote M2 polarization and inhibit T cell function.25Han Q. Zhao H. Jiang Y. Yin C. Zhang J. HCC-derived exosomes: critical player and target for cancer immune escape.Cells. 2019; 8: E558Crossref PubMed Google Scholar In ovarian cancer, exosomal miR-222-3p derived from ovarian cancer cells is an effective regulator of M2 polarization that promotes cancer development.28Ying X. Wu Q. Wu X. Zhu Q. Wang X. Jiang L. 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Li Y. et al.Endoplasmic reticulum stress causes liver cancer cells to release exosomal miR-23a-3p and up-regulate programmed death ligand 1 expression in macrophages.Hepatology. 2019; 70: 241-258Crossref PubMed Scopus (223) Google Scholar In pancreatic cancer, hypoxia-related exosomal miR-301a-3p promotes M2 polarization by inhibiting PTEN and activating the PI3Kγ signaling pathway.31Wang X. Luo G. Zhang K. Cao J. Huang C. Jiang T. Liu B. Su L. Qiu Z. Hypoxic tumor-derived exosomal miR-301a mediates M2 macrophage polarization via PTEN/PI3Kγ to promote pancreatic cancer metastasis.Cancer Res. 2018; 78: 4586-4598Crossref PubMed Scopus (25) Google Scholar STAT1 is the main transcriptional factor that regulates M1 macrophage polarization, while STAT6 promotes M2 macrophage polarization.53Rahal O.M. Wolfe A.R. Mandal P.K. Larson R. Tin S. Jimenez C. Zhang D. Horton J. Reuben J.M. McMurray J.S. Woodward W.A. Blocking interleukin (IL)4- and IL13-mediated phosphorylation of STAT6 (Tyr641) decreases M2 polarization of macrophages and protects against macrophage-mediated radioresistance of inflammatory breast cancer.Int. J. Radiat. Oncol. Biol. Phys. 2018; 100: 1034-1043Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,54Gan Z.S. Wang Q.Q. Li J.H. Wang X.L. Wang Y.Z. Du H.H. Iron reduces M1 macrophage polarization in RAW264.7 macrophages associated with inhibition of STAT1.Mediators Inflamm. 2017; 2017: 8570818Crossref PubMed Scopus (27) Google Scholar Integrin β3 activates STAT1 signaling and suppresses STAT6 signaling, thereby promoting macrophage polarization into the M1 type. However, the expression of integrin β3 is promoted by STAT6 and inhibited by STAT1 to maintain a balance between STAT1 and STAT6 signal transduction. Thus, loss of integrin β3 disrupts this balance and promotes M2 polarization.55Su X. Esser A.K. Amend S.R. Xiang J. Xu Y. Ross M.H. Fox G.C. Kobayashi T. Steri V. Roomp K. et al.Antagonizing integrin β3 increases immunosuppression in cancer.Cancer Res. 2016; 76: 3484-3495Crossref PubMed Google Scholar In prostate cancer, the most abundant miRNAs in PC3 exosomes significantly downregulate integrin β3 expression, inducing macrophage M2 polarization.33Ferguson S. Kim S. Lee C. Deci M. Nguyen J. The phenotypic effects of exosomes secreted from distinct cellular sources: a comparative study based on miRNA composition.AAPS J. 2018; 20: 67Crossref PubMed Scopus (3) Google Scholar It is known that STAT6 signaling plays a critical role in promoting M2 polarization.53Rahal O.M. Wolfe A.R. Mandal P.K. Larson R. Tin S. Jimenez C. Zhang D. Horton J. Reuben J.M. McMurray J.S. Woodward W.A. Blocking interleukin (IL)4- and IL13-mediated phosphorylation of STAT6 (Tyr641) decreases M2 polarization of macrophages and protects against macrophage-mediated radioresistance of inflammatory breast cancer.Int. J. Radiat. Oncol. Biol. Phys. 2018; 100: 1034-1043Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar SOCS1 contains an SH2 domain that induces proteasomal degradation, which can suppress STAT6 signaling.56Ritz O. Guiter C. Dorsch K. Dusanter-Fourt I. Wegener S. Jouault H. Gaulard P. Castellano F. Möller P. Leroy K. STAT6 activity is regulated by SOCS-1 and modulates BCL-XL expression in primary mediastinal B-cell lymphoma.Leukemia. 2008; 22: 2106-2110Crossref PubMed Scopus (0) Google Scholar In oral squamous cell carcinoma (OSCC), OSCC-derived exosomes with captured miR-29a-3p directly target SOCS1 and downregulate its expression, thereby stimulating the STAT6 signal and promoting M2 macrophage polarization.35Cai J. Qiao B. Gao N. Lin N. He W. Oral squamous cell carcinoma-derived exosomes promote M2 subtype macrophage polarization mediated by exosome-enclosed miR-29a-3p.Am. J. Physiol. Cell Physiol. 2019; 316: C731-C740Crossref PubMed Scopus (7) Google Scholar The process by which cancer cells secrete exosomal miRNAs is regulated by many factors, including the physicochemical features of the TME and some transcriptional factors. One of the physicochemical features of the TME is hypoxia, and the harmful TME interferes with the ability of the endoplasmic reticulum (ER) to fold proteins, causing ER stress.57Wilson W.R. Hay M.P. Targeting hypoxia in cancer therapy.Nat. Rev. Cancer. 2011; 11: 393-410Crossref PubMed Scopus (1594) Google Scholar,58Cubillos-Ruiz J.R. Bettigole S.E. Glimcher L.H. Tumorigenic and immunosuppressive effects of endoplasmic reticulum stress in cancer.Cell. 2017; 168: 692-706Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar Both of them can promote cancer cells to secrete exosomal miRNAs. In epithelial ovarian cancer (EOC), hypoxia induces miRNAs in EOC cell-derived exosomes to promote M2 macrophage polarization via hypoxia-inducible factors (HIFs).17Chen X. Zhou J. Li X. Wang X. Lin Y. Wang X. Exosomes derived from hypoxic epithelial ovarian cancer cells deliver microRNAs to macrophages and elicit a tumor-promoted phenotype.Cancer Lett. 2018; 435: 80-91Crossref PubMed Google Scholar In HCC, ER-stressed HCC cells release exosomal miR-23a-3p to upregulate PD-L1 expression in macrophages.27Liu J. Fan L. Yu H. Zhang J. He Y. Feng D. Wang F. Li X. Liu Q. Li Y. et al.Endoplasmic reticulum stress causes liver cancer cells to release exosomal miR-23a-3p and up-regulate programmed death ligand 1 expression in macrophages.Hepatology. 2019; 70: 241-258Crossref PubMed Scopus (223) Google Scholar In addition, some transcription factors can affect the process of cancer cell secretion of exosomal miRNA, such as spalt-like transcription factor 4 (SALL4), epithelial-to-mesenchymal transition-activating transcription factors (EMT-TFs), and p53.26Yin C. Han Q. Xu D. Zheng B. Zhao X. Zhang J. SALL4-mediated upregulation of exosomal miR-146a-5p drives T-cell exhaustion by M2 tumor-associated macrophages in HCC.OncoImmu