Prostaglandin E3 attenuates macrophage-associated inflammation and prostate tumour growth by modulating polarization

Alternative polarization of macrophages regulates multiple biological processes. While M1-polarized macrophages generally mediate rapid immune responses, M2-polarized macrophages induce chronic and mild immune responses. In either case, polyunsaturated fatty acid (PUFA)-derived lipid mediators act as both products and regulators of macrophages. Prostaglandin E₃ (PGE₃) is an eicosanoid derived from eicosapentaenoic acid, which is converted by cyclooxygenase, followed by prostaglandin E synthase successively. We found that PGE₃ played an anti-inflammatory role by inhibiting LPS and interferon-γ-induced M1 polarization and promoting interleukin-4-mediated M2 polarization (M2a). Further, we found that although PGE₃ had no direct effect on the growth of prostate cancer cells in vitro, PGE₃ could inhibit prostate cancer in vivo in a nude mouse model of neoplasia. Notably, we found that PGE₃ significantly inhibited prostate cancer cell growth in a cancer cell-macrophage co-culture system. Experimental results showed that PGE₃ inhibited the polarization of tumour-associated M2 macrophages (TAM), consequently producing indirect anti-tumour activity. Mechanistically, we identified that PGE₃ regulated the expression and activation of protein kinase A, which is critical for macrophage polarization. In summary, this study indicates that PGE₃ can selectively promote M2a polarization, while inhibiting M1 and TAM polarization, thus exerting an anti-inflammatory effect and anti-tumour effect in prostate cancer.     

Dioscin elicits anti‐tumour immunity by inhibiting macrophage M2 polarization via JNK and STAT3 pathways in lung cancer

Tumour‐associated macrophage (TAM) is an important component in tumour microenvironment. Generally, TAM exhibits the function of M2‐like macrophage, which was closely related to angiogenesis and tumour progression. Dioscin, a natural steroidal saponin, has shown its powerful anti‐tumour activity recently. However, the mechanism of dioscin involved in immune regulation is still obscure. Here, we observed dioscin induced macrophage M2‐to‐M1 phenotype transition in vitro and inhibited IL‐10 secretion. Meanwhile, the phagocytosis of macrophages was enhanced. In subcutaneous lung tumour models, dioscin inhibited the augmentation of M2 macrophage populations. Furthermore, dioscin down‐regulated STAT3 and JNK signalling pathways in macrophages in vitro. In BMDMs, activating JNK and inhibiting STAT3 induce macrophages to M1 polarization while inhibiting JNK and activating STAT3 to M2 polarization. Additionally, condition mediums from dioscin‐pre‐treated macrophages inhibited the migration of 3LL cells and the tube‐formation capacity of HUVECs. What's more, dioscin‐mediated macrophage polarization inhibited the in vivo metastasis of 3LL cells. In conclusion, dioscin may act as a new anti‐tumour agent by inhibiting TAMs via JNK and STAT3 pathways in lung cancer.     

SNAIL Induces EMT and Lung Metastasis of Tumours Secreting CXCL2 to Promote the Invasion of M2-Type Immunosuppressed Macrophages in Colorectal Cancer

Background: There is increasing evidence that tumour-associated macrophages (TAMs) are critical in the formation of lung metastases. However, the molecular mechanisms of tumour interactions with TAMs via EMT are largely unknown.Methods: The mechanism of lung metastasis was studied in patient tissues. The mechanism of SNAIL regulation of the interaction between mesenchymal cells and M2 macrophages was elucidated using coculture of M2 macrophages and Transwell assays in vitro and in vivo in nude mice and NOD-SCID mice.Results: We demonstrated for the first time that SNAIL and CXCL2 were abnormally overexpressed in colorectal cancer, especially lung metastasis, and were associated with poor prognosis in colorectal cancer patients. We demonstrated that SNAIL promoted the secretion of CXCL2 by mesenchymal cells and induced the activation of M2 macrophages. We found that CXCL2 attracted M2-type macrophages to infiltrate and promote tumour metastasis.Conclusion: These findings suggest that SNAIL promotes epithelial tumour transformation, and that transformed mesenchymal cells secrete CXCL2, which promotes M2 macrophage infiltration and tumour cell metastasis. These findings elucidate the tumour-TAM interaction in the metastatic microenvironment, which is mediated by tumour-derived CXCL2 and affects lung metastasis. This study also provides a theoretical basis for the occurrence of secondary lung cancer.     

即早基因c-fos在THP-1单核巨噬细胞亚型极化中的差异表达*

目的:探讨即早基因c-fos在THP-1巨噬细胞亚型极化过程中的表达变化。方法:运用PMA刺激诱导THP-1单核细胞极化为巨噬细胞,观察c-fos在单核细胞极化过程中的表达变化;在PMA刺激的基础上,分别运用LPS和IL-4诱导THP-1巨噬细胞向M1及M2亚型极化,实时定量PCR及Western blot技术分析刺激24 h时,细胞亚型标记物CD274、CD86和CD163的表达变化,并动态观察诱导极化过程中,c-fos的表达情况。结果:c-fos在PMA刺激THP-1单核细胞分化为巨噬细胞过程中蛋白和mRNA水平显示上调;LPS诱导THP-1巨噬细胞极化为M1型过程中,c-fos蛋白和mRNA水平表达降低,其特异性标记物在24 h呈现出M1型极化的特点(CD86蛋白表达升高,CD274、CD163蛋白表达降低);IL-4诱导THP-1巨噬细胞极化为M2型过程中,c-fos蛋白和mRNA水平表达升高,其特异性标记物在24 h表现出M2型极化的特点(CD86蛋白表达降低,CD274、CD163蛋白表达升高)。结论:c-fos参与了THP-1单核细胞向巨噬细胞极化的过程,并且可能通过抑制巨噬细胞M1亚型形成,促进巨噬细胞向M2亚型极化的作用参与巨噬细胞的亚型极化及其功能调节中。     

CXC趋化因子配体8促进结直肠癌微环境中M2型巨噬细胞趋化及浸润

CXC趋化因子配体8(CXC chemokine ligand 8,CXCL8)在结直肠癌等多种肿瘤中高表达,并促进肿瘤恶性进展。研究发现,结直肠癌微环境中有大量M2型巨噬细胞浸润,但CXCL8是否影响M2型巨噬细胞的浸润及其潜在机制尚未可知。本文旨在探讨CXCL8对结直肠癌中M2型巨噬细胞浸润及趋化作用的影响。本研究首先分析了TCGA数据库结直肠癌样本中CXCL8表达水平及免疫细胞浸润情况,并在临床组织中进行验证。随后Western 印迹及qRT-PCR检测5种结直肠癌细胞株CXCL8的表达情况。佛波酯(PMA)及IL-4诱导THP-1至M2型巨噬细胞后,与HCT116、SW480细胞及过表达CXCL8的HCT116(CXCL8/HCT116)、SW480(CXCL8/SW480)共培养,检测M2型巨噬细胞趋化情况。白细胞介素1β(IL-1β)处理HCT116、SW480细胞,检测CXCL8表达情况,与M2型巨噬细胞共培养,分析趋化结果。结果显示,患者癌组织CXCL8表达高于癌旁组织,CXCL8高表达癌组织中存在更多M2型巨噬细胞浸润;IL-1β作用于HCT116或SW480后,CXCL8的mRNA及蛋白质表达水平升高(P<0.05)。Transwell实验证实,CXCL8趋化M2型巨噬细胞(P<0.05)。综上所述,结直肠癌细胞中CXCL8可由IL-1β诱导产生,CXCL8表达增加能够促进M2型巨噬细胞的趋化,结直肠癌微环境中M2型巨噬细胞大量浸润可能与CXCL8表达升高有关。     

Oesophageal squamous cell carcinoma–associated IL‐33 rewires macrophage polarization towards M2 via activating ornithine decarboxylase

BackgroundThe tumour microenvironment primarily constitutes macrophages in the form of an immunosuppressive M2 phenotype, which promotes tumour growth. Thus, the development of methodologies to rewire M2‐like tumour‐associated macrophages (TAMs) into the M1 phenotype, which inhibits tumour growth, might be a critical advancement in cancer immunotherapy research.MethodsThe expressions of IL‐33 and indicators related to macrophage polarization in oesophageal squamous cell carcinoma (ESCC) tissues and peripheral blood mononuclear cell (PBMC)–derived macrophages were determined. Inhibition of ornithine decarboxylase (ODC) with small interfering RNA was used to analyse the phenotype of macrophage polarization and polyamine secretory signals. CCK‐8, wound‐healing and Transwell assays were used to detect the proliferation and migration of ECA109 cells in vitro. The tumour xenograft assay in nude mice was used to examine the role of IL‐33 in ESCC development in vivo.ResultsThis study showed the substantially elevated IL‐33 expression in ESCC tissues compared with the normal tissues. Additionally, enhanced infiltration of M2‐like macrophages into the ESCC tumour tissue was also observed. We observed a strong correlation between the IL‐33 levels and the infiltration of M2‐like macrophages in ESCC tumours locally. Mechanistically, IL‐33 induces M2‐like macrophage polarization by activating ODC, a key enzyme that catalyses the synthesis of polyamines. Inhibition of ODC suppressed M2‐like macrophage polarization. Finally, in vivo, we confirmed that IL‐33 promotes tumour progression.ConclusionsThis study revealed an oncogenic role of IL‐33 by actively inducing M2‐like macrophage differentiation; thus, contributing to the formation of an immunosuppressive ESCC tumour microenvironment. Thus, IL‐33 could act as a novel target for cancer immunotherapies.     

The mechanism of lncRNA-CRNDE in regulating tumour-associated macrophage M2 polarization and promoting tumour angiogenesis

M2 macrophages can promote liver cancer metastasis by promoting tumour angiogenesis; however, the mechanism underlying macrophage polarization has not been completely revealed. In this study, we mainly explored the mechanism underlying long non-coding RNA-CRNDE (lncRNA-CRNDE) in regulating M2 macrophage polarization and promoting liver cancer angiogenesis. The expression of CRNDE was up-regulated or down-regulated in THP-1 cells (CRNDE^-/--THP-1 cells and pcDNA3.1-CRNDE-THP-1). THP-1 cells were co-cultured with liver cancer cell line H22, and M2 polarization was induced in THP-1 by IL-4/13 to simulate tumour-induced macrophage polarization. As a result, after CRNDE overexpression, THP-1 cell viability was up-regulated, the expression of M2 membrane marker CD163 was up-regulated, and the proportion of F4/80 + CD163+ cells was also up-regulated. ELISA assay showed that the expression of M2 markers (including TGF-β1 and IL-10) and chemokines (including CCl22 and CCL22) was up-regulated, and the expression of key signals (including STAT6, JAK-1, p-AKT1, and Arg-1) was also up-regulated, which were significantly different compared with the control group (Con). In addition, the intervention effect of CRNDE on THP-1 was consistent between co-culture with H22 cells and IL-4/13 induction assay. The induced M2 THP-1 cells were co-cultured with HUVEC. As a result, THP-1 cells with CRNDE overexpression can promote the migration and angiogenesis of HUVEC cells in vitro and simultaneously up-regulate the expression of Notch1, Dll4 and VEGFR2, indicating that THP-1 M2 polarization induced by CRNDE could further promote angiogenesis. The H22 cell tumour-bearing mouse model was constructed, followed by injection of CRNDE anti-oligosense nucleotides and overexpression plasmids to interfere CRNDE expression in tumour-bearing tissues. Consequently, down-regulation of CRNDE could down-regulate tumour volume, simultaneously down-regulate the expression of CD163 and CD31 in tissues, decrease the expression of key proteins (including JAK-1, STAT-6, p-STAT6 and p-AKT1), and down-regulate the expression of key angiogenesis-related proteins (including VEGF, Notch1, Dll4 and VEGFR2). In this study, we found that CENDE could indirectly regulate tumour angiogenesis by promoting M2 polarization of macrophages, which is also one of the mechanisms of microenvironmental immune regulation in liver cancer.     

Pentraxin 3 regulated by miR-224-5p modulates macrophage reprogramming and exacerbates osteoarthritis associated synovitis by targeting CD32

Emerging evidence has shown an imbalance in M1/M2 macrophage polarization to play an essential role in osteoarthritis (OA) progression. However, the underlying mechanistic basis for this polarization is unknown. RNA sequencing of OA M1-polarized macrophages found highly expressed levels of pentraxin 3 (PTX3), suggesting a role for PTX3 in OA occurrence and development. Herein, PTX3 was found to be increased in the synovium and articular cartilage of OA patients and OA mice. Intra-articular injection of PTX3 aggravated, while PTX3 neutralization reversed synovitis and cartilage degeneration. No metabolic disorder or proteoglycan loss were observed in cartilage explants when treated with PTX3 alone. However, cartilage explants exhibited an OA phenotype when treated with culture supernatants of macrophages stimulated with PTX3, suggesting that PTX3 did not have a direct effect on chondrocytes. Therefore, the OA anti-chondrogenic effects of PTX3 are primarily mediated through macrophages. Mechanistically, PTX3 was upregulated by miR-224-5p deficiency, which activated the p65/NF-κB pathway to promote M1 macrophage polarization by targeting CD32. CD32 was expressed by macrophages, that when stimulated with PTX3, secreted abundant pro-inflammation cytokines that induced severe articular cartilage damage. The paracrine interaction between macrophages and chondrocytes produced a feedback loop that enhanced synovitis and cartilage damage. The findings of this study identified a functional pathway important to OA development. Blockade of this pathway and PTX3 may prevent and treat OA.Subject terms: Osteoarthritis, Extracellular signalling molecules     

Lipotoxic hepatocytes promote nonalcoholic fatty liver disease progression by delivering microRNA-9-5p and activating macrophages

M1-polarized macrophages are involved in chronic inflammatory diseases, including nonalcoholic fatty liver disease (NAFLD). However, the mechanisms responsible for the activation of macrophages in NAFLD have not been fully elucidated. This study aimed at investigating the physiological mechanisms by which extracellular vesicles (EVs)-encapsulated microRNA-9-5p (miR-9-5p) derived from lipotoxic hepatocytes might activate macrophages in NALFD. After blood sample and cell collection, EVs were isolated and identified followed by co-culture with macrophages. Next, the palmitic acid-induced cell and high fat diet-induced mouse NALFD models were established to explore the in vitro and in vivo effects of EVs-loaded miR-9-5p on NAFLD as evidenced by inflammatory cell infiltration and inflammatory reactions in macrophages. Additionally, the targeting relationship between miR-9-5p and transglutaminase 2 (TGM2) was identified using dual-luciferase reporter gene assay. miR-9-5p was upregulated in the NAFLD-EVs, which promoted M1 polarization of THP-1 macrophages. Furthermore, miR-9-5p could target TGM2 to inhibit its expression. Downregulated miR-9-5p in NAFLD-EVs alleviated macrophage inflammation and M1 polarization as evidenced by reduced levels of macrophage inflammatory factors, positive rates of CD86⁺ CD11b⁺, and levels of macrophage surface markers in vitro. Moreover, the effect of silencing of miR-9-5p was replicated in vivo, supported by reductions in TG, TC, AST and ALT levels and attenuated pathological changes. Collectively, lipotoxic hepatocytes-derived EVs-loaded miR-9-5p downregulated the expression of TGM2 and facilitated M1 polarization of macrophages, thereby promoting the progression of NAFLD. This highlights a potential therapeutic target for treating NAFLD.     

CD73 Activity is Dispensable for the Polarization of M2 Macrophages

The ectoenzyme CD73 catalyzes the hydrolysis of AMP, and is one of the most important producers of extracellular adenosine. On regulatory T cells, CD73 is necessary for immunosuppressive functions, and on Th17 cells CD73-generated adenosine exerts anti-inflammatory effects. However, the expression and function of CD73 in pro-inflammatory M1 and in immunosuppressive M2 macrophages is largely unknown. Here we show that CD73 expression and enzyme activity were induced in in vitro polarized pro-inflammatory human M(LPS+TNF) monocytes/macrophages, while CD73 was absent from immunosuppressive M(IL-4+M-CSF)-polarized macrophages. Inhibition of CD73 activity with the inhibitor AMPCP did not affect the polarization of human monocytes. In mice, CD73 was present on resident peritoneal macrophages. In striking contrast, elicited peritoneal macrophages remained CD73 negative regardless of their polarization towards either a pro-inflammatory M(LPS) or anti-inflammatory M(IL-4c) direction. Finally, the ability of peritoneal macrophages to polarize to pro- and anti-inflammatory cells was perfectly normal in CD73-deficient mice in vivo. These data indicate that, in contrast to other major leukocyte subpopulations, CD73 activity on macrophages does not play a major role in their polarization and that in mice host CD73 on any cell type is not required in vivo for peritoneal macrophage polarization towards either a pro- or an anti-inflammatory direction.     

ω-Alkynyl arachidonic acid promotes anti-inflammatory macrophage M2 polarization against acute myocardial infarction via regulating the cross-talk between PKM2, HIF-1α and iNOS

Macrophage polarization determines the timing for the switch from the inflammation phase to the inflammation resolution phase after acute myocardial infarction. The aim of the present study was to investigate whether ω-alkynyl arachidonic acid could mitigate the inflammatory lipid mediators in the regulation of macrophage phenotypes and functions with a special regard to myocardial infarction. We initially discovered that ω-alkynyl arachidonic acid selectively suppressed the up-regulation of inducible nitric oxide synthase (iNOS) over cyclooxygenase-2 (COX-2) in LPS-stimulated macrophages. ω-Alkynyl arachidonic acid also reduced the expression of macrophage M1 biomarkers (e.g., TNF-α, CXCL10, iNOS and IL-6) but increased the expression of macrophage M2 biomarkers (e.g., IL-10 and arginase-1) in LPS-stimulated macrophages. Moreover, ω-alkynyl arachidonic acid markedly enhanced the phagocytotic activity of macrophages against fluorescently-labeled beads or apoptotic H9c2 cardiac cells. We further investigated the in vivo cardioprotective activities of ω-alkynyl arachidonic acid in a mouse model of myocardial infarction. ω-Alkynyl arachidonic acid indeed reduced infarct size, cardiac damage and the leakage of myocardial enzymes CK-MB. Mechanistic studies revealed that ω-alkynyl arachidonic acid suppressed the overexpression and nuclear translocation of glycolytic enzyme PKM2 in LPS-stimulated macrophages. Furthermore, co-immunoprecipitation assay suggested that ω-alkynyl arachidonic acid disrupted the interaction between PKM2 and HIF-1α. Consequently, ω-alkynyl arachidonic acid diminished HIF-1α binding to the HRE sequence in iNOS promoter in response to LPS stimulation. Collectively, ω-alkynyl arachidonic acid may promote the anti-inflammatory M2 polarization of macrophages in acute myocardial infarction via regulating the cross-talk between PKM2, HIF-1α and iNOS.     

A Meaningful Attempt: Applying Dielectric Barrier Discharge Plasma to Induce Polarization of Macrophages

Macrophage polarization plays an important role in many macrophage-related diseases. This study was designed to preliminarily explore the effects of dielectric barrier discharge (DBD) plasma on the polarization direction and cell activity of macrophages with different phenotypes (ie, M0, M1, and M2). The M1 macrophage marker inducible nitric oxide synthase (iNOS) and M2 macrophage marker cluster of differentiation 206 (CD206) were detected by western blot (WB). The effects of DBD plasma on macrophage viability were analyzed by using a cell counting kit-8 detection kit. M0, M1, and M2 macrophages exhibited a decrease in iNOS expression and an increase in CD206 expression after the DBD plasma intervention. Additionally, the decrease in macrophage viability remained non-significant after initiating the intervention. DBD plasma can promote the transformation of M0 and M1 macrophages to M2 macrophages, and can further enhance the expression of the M2 macrophage phenotype marker CD206. Our study not only demonstrates the potential therapeutic value of DBD plasma for macrophage-related diseases, but it also provides a new direction for research to improve the treatment of macrophage-related diseases. © 2023 Bioelectromagnetics Society.     

前列腺癌细胞来源的外泌体诱导巨噬细胞极化

外泌体(exosome)是直径约30～150 nm的由细胞分泌的一种具有生物学活性的囊泡。有些来自癌细胞的外泌体可以将巨噬细胞(macrophages,Mφ)极化为M2亚型,但前列腺癌细胞来源的外泌体在巨噬细胞极化中的作用仍缺乏研究。本研究采用超滤法提取前列腺癌细胞PC-3M-2B4和PC-3M-IE8条件培养基中的外泌体(PCa-exo)。分别用透射电子显微镜、纳米粒径分析及Western印迹对外泌体形态、颗粒大小和表面的特异性分子标志进行分析鉴定。用PKH67标记外泌体,观察PCa-exo能否被巨噬细胞吸收。免疫荧光分析PCa-exo处理巨噬细胞后,M2型巨噬细胞表面分子标志CD206的表达差异。用q-PCR观察PCa-exo诱导后的巨噬细胞中IL-10、IL-1β等细胞因子的表达。电镜、Western印迹和纳米粒径分析的结果显示,PCa-exo形态多为圆形,直径约为40～150 nm,PCa-exo能被巨噬细胞大量吸收。PCa-exo诱导后,巨噬细胞中CD206荧光表达显著增高,IL-10、IL-1β及IL-12等炎症因子的表达水平与M2/TAM亚型巨噬细胞的表达谱一致。本研究表明,前列腺癌细胞来源的外泌体能诱导巨噬细胞极化为M2表型。     

Pomalidomide Shows Significant Therapeutic Activity against CNS Lymphoma with a Major Impact on the Tumor Microenvironment in Murine Models

Primary CNS lymphoma carries a poor prognosis. Novel therapeutic agents are urgently needed. Pomalidomide (POM) is a novel immunomodulatory drug with anti-lymphoma activity. CNS pharmacokinetic analysis was performed in rats to assess the CNS penetration of POM. Preclinical evaluation of POM was performed in two murine models to assess its therapeutic activity against CNS lymphoma. The impact of POM on the CNS lymphoma immune microenvironment was evaluated by immunohistochemistry and immunofluorescence. In vitro cell culture experiments were carried out to further investigate the impact of POM on the biology of macrophages. POM crosses the blood brain barrier with CNS penetration of ~ 39%. Preclinical evaluations showed that it had significant therapeutic activity against CNS lymphoma with significant reduction in tumor growth rate and prolongation of survival, that it had a major impact on the tumor microenvironment with an increase in macrophages and natural killer cells, and that it decreased M2-polarized tumor-associated macrophages and increased M1-polarized macrophages when macrophages were evaluated based on polarization status. In vitro studies using various macrophage models showed that POM converted the polarization status of IL4-stimulated macrophages from M2 to M1, that M2 to M1 conversion by POM in the polarization status of lymphoma-associated macrophages is dependent on the presence of NK cells, that POM induced M2 to M1 conversion in the polarization of macrophages by inactivating STAT6 signaling and activating STAT1 signaling, and that POM functionally increased the phagocytic activity of macrophages. Based on our findings, POM is a promising therapeutic agent for CNS lymphoma with excellent CNS penetration, significant preclinical therapeutic activity, and a major impact on the tumor microenvironment. It can induce significant biological changes in tumor-associated macrophages, which likely play a major role in its therapeutic activity against CNS lymphoma. POM should be further evaluated in clinical trials.     

The regulatory peptide pidotimod facilitates M2 macrophage polarization and its function

Pidotimod is a synthetic dipeptide with biological and immunological activity in innate immune responses. It has been reported that pidotimod could promote functional maturation of dendritic cells, but little is known about the regulation of macrophages. Recent studies have demonstrated that M1 or M2 polarized macrophages are of great importance for responses to microorganism infection or host mediators. The aim of this study was to determine the effectiveness of pidotimod on mouse bone marrow-derived macrophage polarization and its function. The results showed that pidotimod had no influence on M1-polarized macrophage. While interestingly, a significant increase of M2 marker gene expression (Arg1, Fizz1, Ym1, MR) was observed (p < 0.01) in IL-4-induced M2 macrophage treated with pidotimod. In addition, cell surface expression of mannose receptor was dramatically enhanced using fluorescence activated cell sorter (FACS) analysis. Furthermore, the function of M2 macrophage was also determinated. The results showed that the supernatant of pidotimod-treated M2 macrophage could increase the migration (p < 0.05) and enhance the wound closure rate (p < 0.05) of MLE-12 cells. Collectively, it could be concluded that pidotimod significantly facilitated IL-4-induced M2 macrophage polarization and improves its function.     

Renal cell carcinoma-derived exosomes deliver lncARSR to induce macrophage polarization and promote tumor progression via STAT3 pathway

Tumor-derived exosomes play a pivotal role in regulating tumor progression by mediating crosstalk between tumor cells and immune cells such as macrophages within the tumor microenvironment. Macrophages can adopt two distinct polarization statuses and switch between M1 or M2 activation phenotypes in response to the different external stimuli. However, the role of tumor derived exosomes in the macrophage phenotypic switch and tumor development have not been elucidated in renal cell carcinoma (RCC). Here we found that high macrophage infiltration was associated with worse prognosis in RCC patients, therefore we propose our hypothesis that RCC derived exosomes might directly influence macrophage polarization and thus promote tumor progression. Both cell-based in vitro models and orthotopic transplantation in vivo tumor models were constructed and ELISA, flow cytometry, and macrophage functional studies were performed to investigate whether and how RCC-derived exosomes regulate macrophage polarization and tumor growth. The results found that these exosomes promote macrophage polarization, cytokine release, phagocytosis, angiogenesis, and tumor development. Further study revealed high amount of a recently discovered lncRNA called lncARSR in RCC-derived exosomes. Overexpression of lncARSR induced phenotypic and functional changes of macrophages in vitro and promoted tumor growth in vivo, while knockdown of lncARSR by siRNA disrupted the exosomes-mediated macrophage polarization. LncARSR interacts directly with miR-34/miR- 449 to increase STAT3 expression and mediate macrophage polarization in RCC cells. Together, RCC-derived exosomes facilitate the development of tumor through inducing macrophage polarization via transferring lncARSR, suggesting that RCC-derived exosomes, lncARSR and STAT3 are the potential therapeutic targets for treatment of RCC.