CANCER IMMUNOLOGY IMMUNOTHERAPY
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2025
·Vol. 74
·期 3
·1-17
·
IF 5.1
Han Tianci,Guo Xiaoqi,Xie Junwei,Tong Wei,Zhang Liang
Objective Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors with a high metastasis rate and a poor prognosis. ETS variant transcription factor 1 (ETV1) plays an important role in multiple malignancies. However, its function in ESCC progression and tumor microenvironment (TME) remains to be explored. In this study, we characterized the role of ETV1 in ESCC process and TME. Methods Gene expression and immune infiltration in ESCC samples from the Cancer Genome Atlas (TCGA) were analyzed. The expression of ETV1 in clinical samples was detected by real-time PCR, western blot and immunohistochemistry staining. Cell growth was detected by CCK-8 and colony formation assays. Macrophage phenotypes were determined using flow cytometry. Immunofluorescence double staining was used to detect the tumor-associated macrophage (TAM) infiltration. The tumor volume was recorded and weighed. Transcriptional activity was measured using dual-luciferase assay, chromatin immunoprecipitation (ChIP) assay and DNA pull-down assay. Results In this study, through analysis of ESCC samples from TCGA database and the clinic, we noticed that ETV1 was highly expressed in ESCC tumor tissues and was associated with TAM infiltration. Overexpression of ETV1 promoted ESCC cell proliferation in vitro and xenograft tumor growth in nude mice, while ETV1 knockdown elicited the opposite effects. Furthermore, ETV1 upregulation in tumor tissues was found to drive M2 macrophage infiltration both in vitro (transwell assays) and in vivo (xenograft tumor models). C–C motif chemokine ligand 2 (CCL2), a key factor inducing M2 macrophage polarization, was also found to be elevated in ESCC tumor tissues. Mechanism study demonstrated that ETV1 facilitated M2 macrophage infiltration via the transcriptional modulation of CCL2. In addition, the cause of the changes in ETV1 activity and expression was investigated. The E2 small ubiquitin-like modifier (SUMO) binding enzyme UBC9 increased ETV1 activity and expression, indicating the presence of SUMO modification in ETV1. Conclusions Our data deciphered the mechanism of ETV1-mediated M2 macrophage infiltration in the TME of ESCC, which has important implications for the development of novel prognostic and therapeutic targets to optimize current therapies against ESCC.
研究领域:
肿瘤学
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免疫学
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转录调控
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癌症生物学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Haisi Wu,Xianbao Sun,Kaiming Li,Jinyu Li,Hui Jiang,Dan Yan,Ya Lin,Yan Ding,Yawen Lu,Xiaole Zhu,Xufeng Chen,Xiaolin Li,Gaolin Liang,Huae Xu
Paclitaxel (PTX) is a first-line chemotherapeutic drug for non-small cell lung cancer (NSCLC) but it can induce indoleamine 2,3-dioxygenase (IDO) activation, which severely lowers down its immuno-chemotherapeutic effect. To address this issue, a smart peptide hydrogelator Nap–Phe–Phe–Phe–Lys–Ser–Thr–Gly–Gly–Lys–Ala–Pro–Arg–OH ( Nap-T ), which co-assembles with PTX and an IDO inhibitor GDC0919 to form a hydrogel GP@Gel Nap-T, is rationally designed. Upon specific phosphorylation by pyruvate kinase M2 (PKM2), an overexpressed biomarker of NSCLC, Nap-T is gradually converted to Nap–Phe–Phe–Phe–Lys–Ser–Thr(H 2 PO 3 )–Gly–Gly–Lys–Ala–Pro–Arg–OH ( Nap-Tp ), leading to dehydrogelation and sustained release of PTX and GDC0919 within NSCLC tissues. The released PTX exerts chemotherapy on NSCLC cells as well as immunogenic cell death induction, while GDC0919 promotes the immuno-chemotherapeutic effect of PTX through IDO inhibition. We find that GP@Gel Nap-T enhances the infiltration of tumor-infiltrating immune cells and reduces the number of immunosuppressive cells in either tumor tissues or tumor-draining lymph nodes, thus enhancing the immuno-chemotherapy of PTX toward NSCLC. With this PKM2-responsive drug release strategy, the smart peptide hydrogel platform might be applied for NSCLC treatment in clinic in near future.
研究领域:
肿瘤学
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药理学
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免疫学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2022
·
IF 6.51
Zhengjie Meng,Bowen Fu,Zheng Yang,Yuhua Xu,Haixiao Huang,Yunhao Bai,Xue Fang,Shuilin Shen,Jing Yang,Jiahui Yong,Xinyue Tao,Chenyu Ma,Wenjun Miao,Hao Ren,Yonglu Wang,Hao Xu,Xueming Li
High levels of proinflammatory cytokines, macrophage polarization status and immune-mediated angiogenesis play pivotal roles in the pathogenesis of inflammatory bowel disease (IBD). Thalidomide, an anti-inflammatory, immunomodulatory and antiangiogenic agent, is used off-label for treatment of IBD. The therapeutic potential of thalidomide is limited by its poor solubility and side effects associated with its systemic exposure. To address these issues and promote its therapeutic effects on IBD, thalidomide nanocrystals (Thali NCs) were prepared and coated with polydopamine (PDA), a potential macrophage polarization modulator, to form PDA coated Thali NCs ( [email protected] ). [email protected] possessed a high drug loading and displayed average particle size of 764.7 ± 50.30 nm. It showed a better anti-colitis effect than bare thalidomide nanocrystals at the same dose of thalidomide. Synergistic effects of polydopamine on anti-inflammatory and anti-angiogenic activities of thalidomide were observed. Furthermore, PDA coating could direct polarization of macrophages towards M2 phenotype, which boosted therapeutic effects of [email protected] on IBD. Upon repeated dosing of [email protected] for one week, symptoms of IBD in mice were significantly relieved, and histomorphology of the colitis colons were normalized. Key proinflammatory cytokine levels in the inflamed intestines were significantly decreased. Toxicity study also revealed that [email protected] is a safe formulation.
研究领域:
药理学
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免疫学
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纳米技术
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胃肠病学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Ke Wang,Xiaomin Xia,Nan Wang,Jie Liu,Xue Li
Macrophage extracellular traps (METs) are protein network structures released by macrophages during immune defense initiation and inflammation regulation. Evidence shows that these protein structures can help kill pathogens. However, overproduction of METs can harm organisms. Therefore, novel strategies to inhibit the excessive production of METs during immune reactions need to be developed. This study introduces a novel type of anti-inflammatory and antibacterial nanocomposites (i.e., ZIF-8/Ce@rutin NPs) developed by doping the nanozyme Ce into the antibacterial zeolitic imidazole framework-8 (ZIF-8) and then loading the reactive oxygen species (ROS) scavenger rutin via electrostatic adsorption. Results showed that ZIF-8/Ce@rutin exerted bactericidal effects on gram-positive and -negative bacteria, thereby inhibiting MET production from the source. Furthermore, ZIF-8/Ce@rutin scavenged ROS and induced macrophage polarization into the anti-inflammatory M2 type, thereby inhibiting MET progression. This research shows that ZIF-8/Ce@rutin can restrain MET overproduction, providing a theoretical basis for using ZIF-8/Ce@rutin to treat inflammatory and infectious diseases.
研究领域:
纳米技术
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免疫学
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炎症研究
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生物医学工程
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材料科学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2024
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IF 12.8
Guoquan Wu,Tianyu Su,Peng Zhou,Rongze Tang,Xu Zhu,Jin Wang,Minghao Chao,Liying Fan,Hanrong Yan,Peng Ye,Dehong Yu,Fenglei Gao,Hongliang Chen
Nanomedicines for immune modulation have made advancements in the treatment of rheumatoid arthritis (RA). However, due to aberrations in patients' immune systems, inducing antigen-specific immune tolerance while halting disease progression remains a significant challenge. Here, we develop a highly targeted multifunctional nanocomplex, termed M2Exo@CuS-CitP-Rapa (M2CPR), with the aim of selectively inhibiting inflammatory immune reactions while promoting immune tolerance towards specific antigens. M2CPR specifically targets inflammatory tissues in RA, delivering CuS NPs, CitP, Rapa, and endogenous anti-inflammatory factors, thereby ameliorating the inflammatory joint microenvironment. CuS NPs induce Cuproptosis of activated T cells, whose fragments are engulfed by resident or recruited macrophages, resulting in abundant production of TGF-β. TGF-β acts synergistically with Rapa to induce the iDCs into tDCs. tDCs present CitP to Naive T cells, promoting Tregs differentiation. Tregs, in turn, produce more TGF-β, inducing tDCs differentiation, thereby establishing a cycle of immune tolerance. Through in vitro and in vivo experiments, we validate that M2CPR can induce robust and durable antigen-specific immune tolerance, offering a new paradigm for RA therapy.
研究领域:
免疫学
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纳米技术
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风湿病学
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药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2025
·Vol. 23
·期 1
·1-21
·
IF 12.6
Lu Ermei,Zhou Kecheng,Miao Jiansen,Zhu Yanlin,Tang Jiyao,Du Siting,Feng Yanzhen,Jiang Linyuan,Jiang Tianyao,Huang Ting,Li Ping,Miao Xinjun,Han Qi,Xiao Jian
Recovery from spinal cord injury (SCI) is often impeded by neuroinflammation, scar formation, and limited axonal regeneration. To tackle these issues, we developed an innovative biomimetic drug delivery system using liquid nitrogen-treated M2 macrophages (LNT M2) which internalized paclitaxel (PTX) nanoparticles beforehand. These were incorporated into a gelatin methacryloyl (GelMA) scaffold, creating a multifunctional, injectable treatment for single-dose administration. The LNT M2 inherited the inflammatory factor/chemokine receptors from the living M2 macrophages and thus possessing significant inflammatory neutralizing effect. In addition, the scaffold provides slow, sustained release of PTX, promoting axonal regeneration and suppressing scar formation in SCI rats. The LNT M2-based dual-functional scaffold significantly enhances motor function, reduces neuroinflammation, and accelerates axonal regeneration by modulating the inflammatory microenvironment and preventing the formation of glial and fibrotic scars. This approach combines the regenerative effects of low-dose PTX with the immunoregulatory properties of LNT M2, leading to remarkable neurological recovery in SCI rats. Moreover, the scaffold’s straightforward preparation, ease of standardization, and “ready-to-use” nature make it a promising candidate for acute SCI intervention and future clinical applications. Graphical
研究领域:
神经科学
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生物材料
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药学
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再生医学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Reproductive Sciences
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2025
·
IF 2.5
Qiu Yingying,Wei Xinjun,Cao Jian,Wang Jindan,Dou Qianru,Zhou Fangfang,Chen Xi,Liu Yongli,Wan Guiping,Huang Meihua,Li Zhenli,Gui Tao
Adenomyosis (AM), a gynecological disorder that severely affects female reproductive health. AM-associated macrophage (AAM) polarization-induced epithelial–mesenchymal transition (EMT) is a key driver of AM progression. In this study, we investigated the role and underlying mechanisms of endometrial mesenchymal stem cell (eMSC)-derived exosomes in regulating AAM polarization and the subsequent EMT of endometrial epithelial cells (EECs). In vitro coculture studies revealed that AM eutopic eMSCs markedly induced M2 macrophage polarization via exosomes and promoted EMT of EECs. Differentially expressed microRNAs (DE-miRNAs) between exosomes derived from normal eMSCs (N-eMSCs) and AM eutopic eMSCs (A-eMSCs) were identified using miRNA sequencing and miR-4669 was found to be the most significantly upregulated miRNA. Internalization of exosomal miR-4669 by macrophages induced their polarization toward the M2 phenotype and promoted the EMT of EECs. Mechanistic analysis using luciferase assay, mRNA sequencing, and rescue experiments revealed that miR-4669 induced M2 macrophage polarization via downregulation of DUSP6 and activation of MAPK/ERK signaling. The polarized M2 macrophages promoted the EMT of ISK cells via TGF-β1 secretion. In an AM xenograft mouse model, miR-4669 depletion inhibited AM progression by targeting the DUSP6/ERK1/2 pathway in macrophages. Overall, AM A-eMSC-derived exosomal miR-4669 facilitates M2 macrophage polarization by targeting the DUSP6/ERK signaling pathway, thereby promoting EMT of EECs via TGF-β1 secretion. These findings open avenues for developing novel preventive and therapeutic strategies for AM. Graphical
研究领域:
妇科学
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干细胞生物学
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分子生物学
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细胞信号传导
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癌症生物学
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免疫学
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microRNA研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Translational Medicine
·
2025
·Vol. 23
·期 1
·1-19
·
IF 7.5
Xing Chunyang,Hu Wei,Zhao Liyuan
Background Osteosarcoma (OS) is one of the most common malignancies arising in bone. Hypoxia and immune regulation are pivotal in tumor biology. However, their combined effects and mechanisms in OS remain understudied. This study aimed to explore the role and mechanism of hypoxic-induced M2 macrophages in promoting the progression of OS.Methods Differentially expressed proteins in hypoxic macrophage supernatants were detected by antibody array. Cell functional experiments, siRNA-mediated gene silencing, and overexpression transfection were used to study osteopontin (OPN) and its supernatant effect. Bioinformatics analysis was applied to investigate downstream targets and pathways, and a xenograft model was established to assess in vivo effects.Results Our data revealed that hypoxic M2 macrophage supernatant enhanced OS malignancy and epithelial-mesenchymal transition, activating cancer pathways. Hypoxia upregulated OPN in M2 macrophages, and OPN inhibition reduced its tumor-promoting effect. Early growth response 3 (EGR3) was differentially expressed in OS cells treated with the supernatant, and its overexpression inhibited OS cell migration, reversing tumor promotion. Interferon-stimulated gene 15 (ISG15), a key differentially expressed gene related to OPN and EGR3 overexpression, inhibited OS cell proliferation and migration. Additionally, OPN increased retinoic acid-inducible gene I (RIG-I) expression and enhanced signal transducer and activator of transcription 3, nuclear factor kappa B, and extracellular signal-regulated kinase signaling, while EGR3 and ISG15 overexpression inhibited these effects. Silencing ISG15 restored pathway activation and reversed the inhibitory effect of EGR3 on OS cell migration. Dual-Luciferase reporter gene assay confirmed that EGR3 activates ISG15 transcription. OPN treatment upregulated DNA (cytosine-5)-methyltransferase 1 (DNMT1) expression, and ChIP assays demonstrated that EGR3 overexpression enhanced DNMT1 binding to the EGR3 promoter. These findings suggest that OPN promotes OS malignancy by downregulating EGR3 and ISG15, and by enhancing RIG-I expression, as validated in a xenograft model of OS.Conclusion Our findings demonstrate that hypoxic-induced M2 macrophages promote OS progression through OPN-dependent mechanisms, including inhibition of EGR3 and ISG15 expression and upregulation of RIG-I.Graphical abstract
研究领域:
癌症生物学
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免疫学
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分子生物学
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细胞生物学
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肿瘤微环境
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信号转导
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2023
·
IF 5.3
Li Liu,Rong Zhang,Chang Chen,Changbo Xia,Guangda Yao,Xiaogang He,Baomei Xia
It has been reported that Banxia-houpo decoction (BXHPD) serves as the anti-depressant treatment for a mild and severe depressive disease with limited side effects. The present study was performed to evaluate the protective effect of BXHPD on chronic unpredicted mild stress (CUMS)-induced depression and explore its effect on TrkA/Akt-mediated microglia polarization. The CUMS procedure was carried out, and the mice were intragastrically treated with BXHPD once daily. The selective TrkA inhibitor GW441756 was applied to further investigate the role of TrkA in BXHPD-mediated microglia polarization. The behaviour test including open field test (OFT), sucrose preference test (SPT), novelty-suppressed feeding test (NSFT), tail suspension test (TST) and forced swim test (FST) was performed. The concentrations of pro-inflammatory cytokines IL-6, TNF-α, IL-1β, IL-12 and anti-inflammatory cytokines IL-4, IL-10 were determined using Enzyme-linked immunosorbent assay. The population of Iba1+ cells and the length of microglia processes were observed under the fluorescence microscope. The mRNA expressions of Arg1, Ym1 and Fizzl1 were measured by PCR. The protein expressions of TrkA, p-Tyr490-TrkA, p-Ser473-Akt, p-Ser473-Akt1, p-Ser474-Akt2, p-CREB and Jmjd3 were detected by western blot. Our results showed that BXHPD attenuated CUMS-induced depressive-like behaviour, promoted anti-inflammatory cytokines, inhibited pro-inflammatory cytokines, suppressed microglia activation, promoted M2 phenotype-specific indices and upregulated the expressions of TrkA, p-Tyr490-TrkA, p-Ser473-Akt, p-Ser473-Akt1, p-Ser474-Akt2, p-CREB and Jmjd3. The above beneficial effect of BXHPD can be blocked by TrkA inhibitor GW441756. This work demonstrated that BXHPD exerted an anti-depressant effect by promoting M2 phenotype microglia polarization via TrkA/Akt pathway.
研究领域:
药理学
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神经科学
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精神病学
✓ 已验证
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2024
·
IF 10
Bei Wang,Hao Cheng,Zhongsheng Ji,Zijun Jiang,Rong Wang,Yang Ding,Jiang Ni
Collaboration of cancerous cells and microenvironment is the root for tumor spreading, leading to difficulty in complete metastasis blockage via mono-intervention. Herein, a triple-responsive nanoassembly is designed for orienting tumor cells and migration-driving M2 tumor associated macrophages (TAMs) in microenvironment for efficient anti-metastatic therapy. Structurally, a reactive oxygen species (ROS)-responsive crosslinked short-chain polyquaternium is synthesized to bridge graphene oxide (GO) scaffold with apolipoprotein A-I crown via borate-crosslinking, electrostatic adherence, and coordinative coupling. The protein-crowning polymeric GO nanoparticles could give multimodal shielding and triple-responsive release of doxorubicin and Snail-targeted siRNA. Tailor-made apolipoprotein A-I crown fulfills nanoparticles synergistically attacking tumor cells and M2 TAMs via binding with overexpressed scavenger receptors. The findings witness the targeted accumulation and potent cytotoxicity of the hybrid nanoparticles for M2 TAMs and tumor cells; especially, elimination of M2 TAMs in tumor microenvironment holds back Snail-enhancing transforming growth factor (TGF)-β signal pathway, which collaborates with Snail silencing in tumor cells to reverse epithelial mesenchymal transition (EMT) and metastasis-promoting niche. Collectively, the synergistic targeting therapeutic platform could provide a promising solution for metastatic tumor treatment.
研究领域:
肿瘤学
·
纳米技术
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药学
·
癌症生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2023
·
IF 8.2
Changcan Shi,Yinting Yu,Hongjuan Wu,Huanjin Liu,Mengyu Guo,Wenxin Wang,Dan Wang,Chenxu Wei,Hao Zhai,Guojun Yan,Zhipeng Chen,Ting Cai,Weidong Li
A coordinated interaction between osteogenesis and the osteoimmune microenvironment plays a vital role in regulating bone healing. However, disturbances in the pro- and anti-inflammatory balance hinder the therapeutic advantages of biomaterials. In this study, a novel composite hydrogel was successfully fabricated using graphene oxide (GO)-loaded processed pyritum (PP) in combination with poly(ethylene glycol) diacrylate (PEGDA) and carboxymethyl chitosan (CMC). Subsequently, the immunomodulatory effects and bone regenerative potential of PP/GO@PEGDA/CMC were investigated. The results demonstrated that the PP/GO@PEGDA/CMC hydrogel possessed excellent mechanical properties, swelling capacity, and stability. Moreover, PP/GO@PEGDA/CMC prominently promoted M2 polarization and increased the levels of anti-inflammatory factors (interleukin (IL)-4, IL-10, and transforming growth factor-β). These beneficial effects facilitated the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells in vitro. Additionally, the in vivo results further verified that the implantation of PP/GO@PEGDA/CMC markedly reduced local inflammation while enhancing bone regeneration at 8 weeks post-implantation. Therefore, the results of this study provide potential therapeutic strategies for bone tissue repair and regeneration by modulating the immune microenvironment.
研究领域:
材料科学
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生物材料
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组织工程
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免疫学
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骨再生
✓ 已验证
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2024
·
IF 10
Junjun Yang,Xiaoyuan Gong,Tao Li,Zengzilu Xia,Rui He,Xiongbo Song,Xin Wang,Jiangyi Wu,Jiajia Chen,Fangzheng Wang,Ran Xiong,Yangjing Lin,Guangxing Chen,Liu Yang,Kaiyong Cai
In this study, the regulatory role and mechanisms of tantalum (Ta) particles in the bone tissue microenvironment are explored. Ta particle deposition occurs in both clinical samples and animal tissues following porous Ta implantation. Unlike titanium (Ti) particles promoting M1 macrophage (Mϕ) polarization, Ta particles regulating calcium signaling pathways and promoting M2 Mϕ polarization. Ta-induced M2 Mϕ enhances bone marrow-derived mesenchymal stem cells (BMSCs) proliferation, migration, and osteogenic differentiation through exosomes (Exo) by upregulating miR-378a-3p/miR-221-5p and downregulating miR-155-5p/miR-212-5p. Ta particles suppress the pro-inflammatory and bone resorption effects of Ti particles in vivo and in vitro. In a rat femoral condyle bone defect model, artificial bone loaded with Ta particles promotes endogenous Mϕ polarization toward M2 differentiation at the defect site, accelerating bone repair. In conclusion, Ta particles modulate Mϕ polarization toward M2 and influence BMSCs osteogenic capacity through Exo secreted by M2 Mϕ, providing insights for potential bone repair applications.
研究领域:
生物材料
·
免疫学
·
骨生物学
·
干细胞研究
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再生医学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）