Journal of Asthma and Allergy
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2022
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IF 3.027
Yang Sun,Tiancong Liu,Weiliang Bai
Purpose This work aimed to investigate the effects of MAF bZIP transcription factor B (MAFB) on the progression of allergic rhinitis (AR). Patients and Methods Nasal mucosa was isolated from AR patients and healthy individuals from Shengjing Hospital of China Medical University. The experimental procedures were approved by the Medical Ethics Committee of Shengjing Hospital of China Medical University (2019PS341K) in accordance with the Declaration of Helsinki. Informed consents were signed by participants or a parent/legal guardian of the participants under 18 years old of age. Then, an AR mouse model with MAFB overexpression was established with 25 μg ovalbumin (OVA) sensitization on day 0, 7, 14, followed by an injection with 1×10 7 TU/mL lentivirus MAFB on day 19 and a nasal challenge with 500 μg OVA from day 21 to 27. Results The results revealed that MAFB was down-regulated in the nasal mucosa of AR patients. The up-regulation of MAFB protected the AR mice against the OVA-induced allergic symptoms (sneezing and nasal rubbing) by alleviating the OVA-induced epithelial thicknesses, goblet cell hyperplasia, and inflammation including the eosinophil and mast cell infiltration. Moreover, MAFB facilitated the T helper (Th) 1 response and inhibited the Th2 and Th17 responses by the down-regulation of T-box transcription factor 21 and the up-regulation of GATA binding protein-3 as well as retinoid-related orphan receptor-γt in the splenocytes of AR mice. MAFB was found to repress the differentiation of naive CD4 + T cells into Th2 cells. Subsequently, MAFB overexpression reversed the OVA-induced enhancement of epithelial permeability, downregulation of tight junctions, and upregulation of cadherin-26, indicating the protective role of MAFB on epithelial barrier integrity. Conclusion MAFB protected against OVA-induced AR via the alleviation of inflammation by restoring the Th1/Th2/Th17 imbalance and epithelial barrier dysfunction.
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Cell Metabolism
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2022
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IF 31.373
Xie Li,Yinan Zhang,Lingyan Xu,Aoxue Wang,Yejun Zou,Ting Li,Li Huang,Weicai Chen,Shuning Liu,Kun Jiang,Xiuze Zhang,Dongmei Wang,Lijuan Zhang,Zhuo Zhang,Zeyi Zhang,Xianjun Chen,Wei Jia,Aihua Zhao,Xinfeng Yan,Haimeng Zhou,Linyong Zhu,Xinran Ma,Zhenyu Ju,Weiping Jia,Congrong Wang,Joseph Loscalzo,Yi Yang,Yuzheng Zhao
Summary Despite its central importance in cellular metabolism, many details remain to be determined regarding subcellular lactate metabolism and its regulation in physiology and disease, as there is sensitive spatiotemporal resolution of lactate distribution, and dynamics remains a technical challenge. Here, we develop and characterize an ultrasensitive, highly responsive, ratiometric lactate sensor, named FiLa, enabling the monitoring of subtle lactate fluctuations in living cells and animals. Utilizing FiLa, we demonstrate that lactate is highly enriched in mammalian mitochondria and compile an atlas of subcellular lactate metabolism that reveals lactate as a key hub sensing various metabolic activities. In addition, FiLa sensors also enable direct imaging of elevated lactate levels in diabetic mice and facilitate the establishment of a simple, rapid, and sensitive lactate assay for point-of-care clinical screening. Thus, FiLa sensors provide powerful, broadly applicable tools for defining the spatiotemporal landscape of lactate metabolism in health and disease.
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JOURNAL OF INTERNATIONAL MEDICAL RESEARCH
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2023
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IF 1.6
Fang Wang,Xiu-Li Zhang,Jing-Ya Yang,Gang Zhou
ObjectiveOral lichen planus (OLP) is a T cell-mediated inflammatory condition in the oral cavity. Mucosal-associated invariant T (MAIT) cells are gaining more relevance in immune diseases because they can be activated by cytokines without T cell receptor stimulation. Herein, we tested the effect of interleukin-23 (IL-23) on the activation status of OLP MAIT cells.MethodsPeripheral blood mononuclear cells (PBMCs) isolated from OLP patients were stimulated by IL-23 in the absence or presence of phorbol myristate acetate (PMA) and ionomycin. The activation status of MAIT cells was analyzed by flow cytometry after staining for CD3, CD4, CD8, CD161, TCR Vα7.2, and CD69.ResultsThe fraction of MAIT cells in OLP peripheral blood was approximately 0.38% to 3.97%, and CD8+ subpopulations overwhelmed CD4+ cells. The mean percentages of OLP MAIT cells in PBMCs and CD8+MAIT cells in MAIT cells were approximately 40%. PMA and ionomycin significantly increased CD69 expression on OLP T cells, MAIT cells, and CD8+MAIT cells. Cells with enhanced activation had different responsiveness to exogenous IL-23, showing increased CD69 expression on OLP T cells, decreased CD69 on OLP CD8+MAIT cells, and no significant change on OLP MAIT cells.ConclusionsIL-23 showed different effects on the activation status of OLP MAIT cells and CD8+MAIT cells.
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MOLECULAR IMMUNOLOGY
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2023
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IF 3.6
Wei Zhong,Leheng Feng,Wei Tian,Hongbo Qu,Haibo Xu,Ke Ning,Li Liu,Wei Liu,Xiaowei Gong,Hong Chen
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease . This study aimed to investigate the role of SMAD specific E3 ubiquitin protein ligase 1 (SMURF1) in the Th17 and Th17.1 differentiation and Treg/Th17 imbalance, which are major factors contributing to the pathogenesis of SLE. SLE patients and healthy individuals were recruited to detect the SMURF1 levels in naïve CD4 + cells from peripheral blood. Purified and expanded naïve CD4 + T cells were employed to evaluate the effects of SMURF1 on Th17 and Th17.1 polarization in vitro. MRL/lpr lupus model was employed to explore the disease phenotype as well as Treg/Th17 balance in vivo. The results showed that SMURF1 was down-regulated in naïve CD4 + T cells in peripheral blood of patients with SLE and in spleen of MRL/lpr mice. SMURF1 overexpression suppressed the polarization of naïve CD4 + T cells toward Th17 and Th17.1 phenotype and down-regulated the expression of retinoid-related orphan receptor-gammat (RORγt). Subsequently, SMURF1 down-regulation aggravated the disease phenotype, inflammation, and the Treg/Th17 imbalance in MRL/lpr mice. Furthermore, we found that SMURF overexpression promoted the ubiquitination and decreases the stability of RORγt. In conclusion, SMURF1 inhibited the polarization of Th17 and Th17.1 cells and improved the Treg/Th17 imbalance in SLE, which was mediated as least partly by the ubiquitination of RORγt.
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ENVIRONMENTAL POLLUTION
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2023
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IF 8.9
Jing Zhan,Qian S. Liu,Yuzhu Zhang,Zhendong Sun,Qunfang Zhou,Guibin Jiang
Silica nanoparticles (SiNPs) have attracted increasing attention for their health effects due to the increased risk of exposure to human bodies via diverse routes. Considering that SiNPs enter the circulatory system and inevitably encounter red blood cells (RBCs), it is necessary to investigate their risk of causing erythrocytotoxicity. In this study, three sizes of SiNPs (SiNP-60, SiNP-120, and SiNP-200) were tested for their effects on mouse RBCs. The results showed that SiNPs could induce hemolysis, morphological changes, and phosphatidylserine (PS) exposure in RBCs in a particulate size-related manner. Further investigations on the underlying mechanism indicated that SiNP-60 exposure increased intracellular reactive oxidative species (ROS) generation and subsequently caused the phosphorylation of p38 and ERK1/2 in RBCs. The addition of antioxidants or inhibitors of mitogen-activated protein kinase (MAPK) signaling significantly attenuated PS exposure in RBCs and ameliorated SiNP-induced erythrocytotoxicity. Moreover, ex vivo assays using platelet-rich plasma (PRP) showed that SiNP-60-induced PS exposure in RBCs could trigger thrombin-dependent platelet activation. The contrary evidence from the assays of PS blockage and thrombin inhibition further confirmed that SiNP-60-induced platelet activation was dependent on PS externalization in RBCs, concomitantly with thrombin formation. These findings revealed the procoagulant and prothrombotic effects of SiNPs through the regulation of PS externalization in RBCs, and may be of great help in bridging the knowledge gap on the potential cardiovascular hazards of particulate silica from both artificial and naturally occurring origins.
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Nature Protocols
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2024
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IF 13.1
Wang Aoxue,Zou Yejun,Liu Shuning,Zhang Xiuze,Li Ting,Zhang Lijuan,Wang Ruwen,Xia Yale,Li Xie,Zhang Zhuo,Liu Tiemin,Ju Zhenyu,Wang Ru,Loscalzo Joseph,Yang Yi,Zhao Yuzheng
As a key glycolytic metabolite, lactate has a central role in diverse physiological and pathological processes. However, comprehensive multiscale analysis of lactate metabolic dynamics in vitro and in vivo has remained an unsolved problem until now owing to the lack of a high-performance tool. We recently developed a series of genetically encoded fluorescent sensors for lactate, named FiLa, which illuminate lactate metabolism in cells, subcellular organelles, animals, and human serum and urine. In this protocol, we first describe the FiLa sensor-based strategies for real-time subcellular bioenergetic flux analysis by profiling the lactate metabolic response to different nutritional and pharmacological conditions, which provides a systematic-level view of cellular metabolic function at the subcellular scale for the first time. We also report detailed procedures for imaging lactate dynamics in live mice through a cell microcapsule system or recombinant adeno-associated virus and for the rapid and simple assay of lactate in human body fluids. This comprehensive multiscale metabolic analysis strategy may also be applied to other metabolite biosensors using various analytic platforms, further expanding its usability. The protocol is suited for users with expertise in biochemistry, molecular biology and cell biology. Typically, the preparation of FiLa-expressing cells or mice takes 2 days to 4 weeks, and live-cell and in vivo imaging can be performed within 1–2 hours. For the FiLa-based assay of body fluids, the whole measuring procedure generally takes ~1 min for one sample in a manual assay or ~3 min for 96 samples in an automatic microplate assay.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Dan Wang,Yimeng Zou,Tianqi Zhao,Weiyue Cao,Jiachi Han,Qing Wu,Zhitong Li,Xinyu Li,Peijing Liu,Lin Bai,Guiping Ren
Background The blood FGF21 expression has been previously suggested to increase in patients developing atopic dermatitis (AD) and asthma. However, its impact on atopic march is rarely analyzed. The present work focused on investigating the role of Fibroblast Growth Factor 21(FGF21) in atopic march mice and its underlying mechanisms. Methods The models were induced with Diisononyl phthalate (DINP) and OVA in wild-type C57BL/6 and FGF21 −/− mice. RAW264.7 cells were induced by LPS with/without FGF21 or KLB-SiRNA for in vitro analyses. Results The data indicated that there were more severe allergic reactions including IgE levels and the proportion of mast cells in the blood of FGF21 −/− mice in relative to WT model mice during the progression from AD to asthma. However, exogenous administration of FGF21 inhibited allergies. In this study, we reported that FGF21 mitigated AD-like lesions and Th1/2 or Th17/Treg cell imbalance in AD mice, and significantly decreased TSLP, IL-33, IL-4, IL-5, IL-13 and IL-17A expression on skin. During the asthma phase, FGF21 improved airway remodeling by downgrading inflammatory factors IL-4, IL-5, IL-13 and IL-17A; fibrotic markers α-SMA and Collagen I; and oxidative products MDA and ROS in wild-type model mice. Compared with WT model mice, the adverse consequences were aggravated in FGF21 −/− asthmatic mice. From the mechanistic perspective, FGF21 suppressed NF-κB/NLRP3, TGF-β1/Smad3 and JNK signaling pathways and increased Nrf2 expression in vivo and in vitro. In addition, β-Klotho knockdown attenuated the ameliorative impact of FGF21 on cellular damage. Blocking AMPKα in the LPS-treated RAW264.7 cells inhibited the reduction of FGF21 and the phosphorylation of JNK. Conclusions To conclude, FGF21 alleviated atopic march by inhibiting Th2/17 immune response, and reduced airway remodeling by regulating NF-κB/NLRP3, TGF-β1/Smad3 and AMPKα/JNK pathways. Moreover, this study provides a rationale and novel ideas for applying FGF21 in treating AD and asthma.
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ENVIRONMENTAL SCIENCE & TECHNOLOGY
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2024
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IF 10.8
Yuzhu Zhang,Laijin Zhong,Jing Zhan,Zhipeng Yin,Yao Pei,Dong Cao,Qian S. Liu,Qunfang Zhou,Qian Liu,Guibin Jiang
Atmospheric fine particulate matter (PM2.5) poses threats to the cardiovascular system. Red blood cells (RBCs) are the most abundant cells in blood, which are actively involved in multiple hematological diseases, such as blood clot formation and thrombosis. Exploring how PM2.5 with spatiotemporal heterogeneity influences the hematological system by targeting RBCs would help gain insights into the deleterious effects of PM2.5 and provide clues for finding the causative components therein. Herein, the PM2.5 samples collected from 3 urban sites in Beijing (i.e., Chaoyang, Shunyi, and Yanqing districts) during 4 seasons of 2022 were studied for their toxicities to mouse RBCs, and the main contributing components were further explored through chemical analysis and correlation measure. The results showed that exposure to PM2.5 samples decreased adenosine triphosphate (ATP) levels and increased phosphatidylserine (PS) externalization of RBCs, causing cell morphological deformity. The Pearson correlation analysis showed that the aromaticity of the dissolved organic matter (DOM) in PM2.5 samples was positively correlated with PS exposure of RBCs, showing that the lignin-like compounds were the potential contributors. The negative correlation of zeta potentials of PM2.5 samples with PS exposure of RBCs showed the particle-derived bioactivities of this airborne pollutant. The simulative test based on artificial nanomaterials of carbon black (CB) and oxidized CB (OCB) confirmed the crucial role of particulate carbon in PM2.5-induced effects on RBCs, and soot with a certain oxidation degree was, thus, recognized as another contributor, given its ubiquitous existence in PM2.5 samples. This study, for the first time, revealed PM2.5-induced PS exposure of RBCs, and the causative components of DOM and soot were unraveled. Considering the inevitable contact of airborne PM2.5 with RBCs in the blood circulatory system, the findings obtained herein would help bridge the gap between PM2.5 exposure and the risk of cardiovascular diseases, like thrombogenesis.
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Signal Transduction and Targeted Therapy
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2025
·Vol. 10
·期 1
·1-20
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IF 52.7
Ma Xiao,Chen Jiao,Wang Fang,Fan Xinzou,Li Zhenhong,Liang Hantian,Cheng Hao,Nan Fang,Lin Yubin,Song Xiaoshuang,Zhang Jianan,Gao Fan,Zhang Wei,Jin Wenwen,Zhang Huiyuan,Tong Jiyu,Jiang Hong,Zhou Xikun,Zou Qiang,Hu Hongbo,Tong Aiping,Chen WanJun,Zhang Dunfang
The intake of sugars, especially glucose and fructose, has significantly increased with the change of lifestyle. Excessive intake of sugar has been proven to be associated with tumors and inflammatory diseases. Fructose directly mediates innate immune responses; however, whether it can directly regulate T-cell immunity remains unknown. We show that high fructose consumption accelerates the development of inflammatory bowel disease (IBD) by promoting the generation of T helper 1 (Th1) and T helper 17 (Th17) cells. It was demonstrated that fructose promotes the differentiation of Th1 and Th17 cells directly by enhancing mechanistic target of rapamycin complex 1 (mTORC1) activation through the glutamine metabolism-dependent pathway. Reactive oxygen species (ROS)-induced activation of transforming growth factor-β (TGF-β) is also involved in fructose-induced Th17 cell generation. Moreover, metformin can reverse Th1 and Th17 cell generation induced by fructose by suppressing mTORC1 activation and reducing ROS-mediated TGF-β activation. Finally, we identified metformin as an in vivo therapeutic drug for relieving high fructose consumption-induced T-cell inflammation and colitis aggravation. Our study revealed a previously unknown adverse effect of high fructose consumption in disrupting immune homeostasis and exacerbating IBD by directly promoting T-cell immunity, and showed metformin is a potential therapeutic for reversing the T cell immune imbalance caused by long-term high fructose consumption.
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Nature Nanotechnology
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2025
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IF 34.9
Wu Yali,Chen Wenjuan,Deng Jingjing,Cao Xinghui,Yang Zimo,Chen Jiangbin,Tan Qi,Zhou E.,Li Minglei,Liu Jiatong,Guo Mengfei,Jin Yang
Tumour-derived microparticles (TMPs), extracellular vesicles traditionally obtained upon ultraviolet (UV) radiation of tumour cells, hold promise in tumour immunotherapies and vaccines and have demonstrated potential as drug delivery systems for tumour treatment. However, concerns remain regarding the limited efficacy and safety of UV-derived TMPs. Here we introduce a microwave (MW)-assisted method for preparing TMPs, termed MW-TMPs. Brief exposure of tumour cells to short-wavelength MW radiation promotes the release of TMPs showing superior in vivo antitumour activity and safety compared with UV-TMPs. MW-TMPs induce immunogenic cell death and reprogramme suppressive tumour immune microenvironments in different lung tumour models, enabling dual targeting of tumour cells by natural killer and T cells. We show that they can efficiently deliver methotrexate to tumours, synergistically boosting the efficacy of PD-L1 blockade. This MW-TMP development strategy is simpler, more efficient and safer than traditional UV-TMP methods.
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Journal of Extracellular Vesicles
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2025
·Vol. 14
·期 4
·e70068
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IF 14.5
Jiangbin Chen,Qi Tan,Zimo Yang,Wenjuan Chen,E. Zhou,Minglei Li,Jingjing Deng,Yali Wu,Jiatong Liu,Juanjuan Xu,Mengfei Guo,Yang Jin
Dendritic cell (DC)-derived extracellular vesicles (DEVs) are promising candidates for cancer vaccines, but their therapeutic effects still need further optimization. In this study, we utilized neoantigens, lipopolysaccharide and IFN-γ to induce the maturation of DCs, and then isolated DEVs derived from these mature DCs. We showed that the immune checkpoint inhibitor (anti-CTLA-4 antibody, aCTLA-4) can improve the immunostimulatory function of DEVs by directly activating T cells through immune checkpoint signal blockade. The cytokine interleukin-12 (IL-12), as one of the third signals for T cell activation, can also enhance the capability of DEVs to activate T cells directly. Based on these findings, we designed the engineered DEVs conjugated with IL-12 and aCTLA-4 (DEV@IL-12-aCTLA-4) to improve the therapeutic potential of DEVs by providing sufficient immune regulatory signals. Moreover, the carrier property of DEVs also contributes to the delivery of IL-12 and aCTLA-4 to lymph nodes. This indicates that the conjugation of DEVs with IL-12 and aCTLA-4 constitutes a complementary approach, where IL-12 and aCTLA-4 help to enhance the T cell activation effect of DEVs, and DEVs facilitate the delivery of IL-12 and aCTLA-4. Our results showed that DEV@IL-12-aCTLA-4 can enhance the Th1 immune response and reverse exhausted CD8 + T cells in the tumour microenvironment, effectively inducing robust T cell immune responses and inhibiting tumour growth in tumour-bearing mice. Overall, this study expands the theoretical foundation of DEVs and provides a universal strategy for optimizing cancer combination immunotherapy by reprogramming DEVs.
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JOURNAL OF CONTROLLED RELEASE
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2025
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IF 11.5
Yali Wu,Wenjuan Chen,Jingjing Deng,Xingyu Zhou,Jiangbin Chen,Zimo Yang,Xinghui Cao,Jiatong Liu,Qi Tan,E. Zhou,Minglei Li,Mengfei Guo,Yang Jin
Cancer immunotherapy has transformed cancer treatment, demonstrating the potential for lasting responses in multiple solid and hematologic malignancies and thus has revolutionized cancer treatment in clinic. However, the intricate tumor microenvironment (TME), characterized by a rigid extracellular matrix (ECM) and robust immunosuppressive environment, presents substantial hurdles to the effectiveness of cancer immunotherapy. Thus, cancer-associated fibroblasts (CAFs), the most abundant stromal cells that mediate ECM remodeling and participate in immune suppression, represent promising therapeutic targets for combination immunotherapy. In this study, by using and analyzing single-cell RNA-sequencing (scRNA-seq) in the public datasets, we have identified the elevated expression of glucose transporter 1 (GLUT1) in activated CAF subgroups within tumor sites compared to normal tissues. Moreover, the recent literature has also demonstrated that CAFs undergoing high metabolic levels have been identified to show a better response to immunotherapy. Furthermore, extracellular vesicles (EVs) secreted by CAFs remain unexplored, and their role in drug transport systems and targeting efficiency towards tumorous cells remains uninvestigated. Herein, we identified the elevated expression of glucose transporter 1 (GLUT1) as a prognostic indicator for cancer associated with poor prognosis and investigated the vulnerability of lung tumor cell lines and CAFs to pharmacological GLUT1 inhibition with BAY-876. Based on the possibility of targeting the intrinsic TME-associated metabolism by GLUT1 inhibition, we have firstly employed CAFs-derived extracellular vesicles (cEVs) as a carrier for targeted delivery of BAY-876 into GLUT1-high CAFs and tumor cells. The cEV-BAY-876 (cEV B6) treatment significantly resulted in glucose-rich, low-lactate TME, reversed the activated CAFs phenotype, enabled stromal reprogramming, decreased ECM stiffness and enhanced the infiltration of CD3 + CD8+ T cells in tumor core, thereby achieving an excellent anti-tumor efficiency. Moreover, cEV-B6 treatment synergized anti-programmed death ligand 1 (antiPD-L1) to reinvigorate the exhausted lymphocytes and exerted strong anticancer effects against mice lung tumors. Our study provides the first evidence that tumor stroma-specific therapies by targeting glucose metabolism present a promising strategy of remodeling the extracellular matrix to reverse CAFs into normal type and potentiate cytotoxic T lymphocytes (CTLs) infiltration thereby improving anticancer immunotherapy.
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