NEOPLASIA
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2021
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IF 5.715
Yihui Ma,Peiyi Xia,Zhengyang Wang,Jingjing Xu,Lan Zhang,Yanan Jiang
Protein Disulfide Isomerase Family A Member 6 (PDIA6) is an endoplasmic reticulum protein that is capable of catalyzing protein folding and disulfide bond formation. Abnormally elevated expression of PDIA6 has been reported to predict poor outcomes in various cancers. Herein, gain-of- and loss-of-function experiments were performed to investigate how PDIA6 participated in the carcinogenesis of pancreatic cancer (PC). By analyzing the protein expression of PDIA6 in 28 paired PC and para carcinoma specimens, we first found that PDIA6 expression was higher in PC samples. Both the overall survival and disease-free survival rates of PC patients with higher PDIA6 expression were poorer than those with lower PDIA6 ( n = 178). Furthermore, knockdown of PDIA6 impaired the malignancies of PC cells — suppressed cell proliferation, invasion, migration, cisplatin resistance, and xenografted tumor growth. PDIA6-silenced PC cells were more sensitive to cytotoxic natural killer (NK) cells. Overexpression of PDIA6 had opposite effects on PC cells. Interestingly, COP9 signalosome subunit 5 (CSN5), a regulator of E3 ubiquitin ligases known to promote deubiquitination of its downstream targets, was demonstrated to interact with PDIA6, and its expression was increased in PC cells overexpressing PDIA6. Additionally, PDIA6 overexpression promoted deubiquitination of β-catenin and PD-L1 and subsequently upregulated their expression in PC cells. These alterations were partly reversed by CSN5 shRNA. Collectively, the above results demonstrate that PDIA6 contributes to PC progression, which may be associated with CSN5-regulated deubiquitination of β-catenin and PD-L1. Our findings suggest PDIA6 as a potential target for the treatment of PC.
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Cell Death & Disease
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2023
·Vol. 14
·期 2
·1-13
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IF 9
Liu Nian,Zhang Jianglin,Yan Mingjie,Chen Lihui,Wu Jie,Tao Qian,Yan Bei,Chen Xiang,Peng Cong
Patients with advanced melanoma have shown an improved outlook after anti-PD1 therapy, but the low response rate restricts clinical benefit; therefore, enhancing anti-PD1 therapeutic efficacy remains a major challenge. Here, our findings showed a significantly increased abundance of α-KG in healthy controls, anti-PD1-sensitive melanoma-bearing mice, and anti-PD1-sensitive melanoma patients; moreover, supplementation with α-KG enhanced the efficacy of anti-PD1 immunotherapy and increased PD-L1 expression in melanoma tumors via STAT1/3. We also found that supplementation with α-KG significantly increased the activity of the methylcytosine dioxygenases TET2/3, which led to an increased 5-hydroxymethylcytosine (5-hmC) level in the PD-L1 promoter. As a consequence, STAT1/3 binding to the PD-L1 promoter was stabilized to upregulate PD-L1 expression. Importantly, single-cell sequencing of preclinical samples and analysis of clinical data revealed that TET2/3-STAT1/3-CD274 signaling was associated with sensitivity to anti-PD1 treatment in melanoma. Taken together, our results provide novel insight into α-KG’s function in anti-PD1 treatment of melanoma and suggest supplementation with α-KG as a novel promising strategy to improve the efficacy of anti-PD1 therapy.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2022
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IF 8.025
Mengya Ma,Xiaobin Liu,Chaoqun Ma,Ruyue Guo,Xueling Zhang,Zhenzhong Zhang,Xueling Ren
Improved curative effects with reduced toxicity has always been the ultimate goal of gene delivery vectors for tumor immunotherapy. Panax notoginseng polysaccharide (PNP), a natural plant-derived macromolecule, not only has antitumor immune activity but also has the typical structural characteristics useful for gene delivery. In this work, positively charged polyethyleneimine (PEI) was directly grafted to the backbone of PNP to induced its charge reversal and generate a functional gene vector (PNP-PEI). Moreover, a short hairpin RNA targeting the programmed death-ligand 1 (PD-L1) was loaded into PNP-PEI to generate a potentially therapeutic nanoparticle (PNP-PEI/shPD-L1). In vitro and in vivo experiments demonstrated that PNP-PEI could efficiently carry the therapeutic shPD-L1 into tumor cells and that PNP-PEI/shPD-L1 could significantly inhibit the expression of PD-L1 and growth of B16-F10 cells. Noteworthily, treatment with PNP-PEI reversed the phenotype of macrophages from M2 to M1 subtype and promoted dendritic cell maturation, which encouraged the host immunity and enhanced the therapeutic antitumor effects. In summary, this study describes a PNP-based gene delivery vector and highlights the beneficial immunopotentiating therapeutic outcomes of PNP-PEI for tumor immunotherapy.
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BIOMATERIALS
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2022
·
IF 15.304
Yan Gao,Zilin Song,Li Jia,Yi Tang,Chengcheng Wang,Xiuli Zhao,Haiyang Hu,Dawei Chen,Mingxi Qiao
Despite the important role of reactive oxygen species (ROS) in battling cancer, ROS production with current approaches has been severely limited by the deficiency of oxy-substrates in tumor microenvironment . Herein, an atorvastatin (Ato)-catalytic self-amplified approach was utilized for sustainable ROS production and enhancing anti-tumor efficacy of PD-L1 silencing. A C 18 -pArg 8 -ss-pHis 10 lipopeptide based self-assembled nanoplexes was developed to co-encapsulate AMP-activated protein kinase (AMPK) activator of Ato and PD-L1 siRNA. Efficient delivery of payloads was achieved because of the acidic pH triggered the protonation of pHis 10 , disulfide-bond exposure for cleavage and subsequent cytosolic translocation. Ato was found to activate AMPK, boosting the highly restrained mitochondrial fatty acid oxidation (FAO) in cancer cells for ROS production. The ROS derived from FAO further activated AMPK, creating a positive-feedback mechanism of sustainable ROS production. The self-amplified ROS production from cellular mitochondrial FAO was maintained by the sufficient intracellular fatty acid substrates arising from the dysregulated lipid metabolism and Ato inhibited triglyceride synthesis in cancer cells. The excessive ROS level was found to successfully induce immunogenic cell death effect, boosting the anti-tumor efficacy of PD-L1 silencing. Overall, the Ato catalyzed self-amplified ROS production has been demonstrated as a promising alternative for cancer therapy.
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mSystems
·
2024
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IF 5
Lei Tang,Xizhong Yang,Mengting Zhou,Lingxin Feng,Cuijie Ji,Jie Liang,Bei Zhang,Ruowu Shen,Luoyang Wang
Growing evidence indicates that gut microbiota is involved in the regulation of the host’s sex hormone levels, such as through interfering with the sex hormone metabolism in the intestine. However, if gut microbiota or its metabolites directly influence the sex hormone biosynthesis in the gonad remains largely unknown. Our previous study showed that colistin, as a narrow-spectrum antibiotic, can significantly downregulate the serum testosterone levels and thus enhance the antitumor efficiency of anti-PD-L1 in male mice; however, the underlying mechanism for the regulation of the host’s testosterone levels remains uninvestigated. In the present study, we analyzed the impact of colistin on the immune microenvironment of the testis as well as the composition and metabolism of gut microbiota in male mice. Our results showed that colistin has an impact on the immune microenvironment of the testis and can downregulate serum testosterone levels in male mice through inhibition of Akkermansia, leading to destroyed inosine metabolism. Supplement with inosine can restore testosterone secretion probably by prompting the recovery of the intestinal mucus barrier and the serum lipopolysaccharides levels. All these findings reveal a new pathway for the regulation of the host’s sex hormone levels by gut microbiota.
研究领域:
微生物学
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免疫学
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内分泌学
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药理学
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JOURNAL OF FLUORESCENCE
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2024
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IF 2.6
Li Ling,Li Zheng-Ling,Wang Wei,Long Xin-Xin,Liu Ping,Wang Guo-Tian,Sun Shi-Qing,Du Rong-Lian
The rapid and accurate detection of programmed death-ligand 1 (PD-L1) expression is of great value in the diagnosis and treatment of tumors. ELISA-based traditional method is the gold standard for protein detection, but there are still some shortcomings, especially the antigen-antibody dependence, greatly increased the detection time and cost. This work constructed a label-free fluorescent probe for rapid and sensitive detection of PD-L1 using a truncated aptamer as recognition molecules and double-stranded DNA specific dyes (SYBR Green I) as signal units. After a series of optimization conditions, this probe has good detection capability for PD-L1 in buffer solution with the detection limit as low as 0.68 ng/mL. Due to the specific recognition ability of aptamer and target, this method also has good selectivity for PD-L1 detection. The recovery of PD-L1 in human serum samples ranges from 86.20 to 96.36%. Compared with other methods, this strategy does not need to be marked, and does not need other complex design and purification process, but simple operation process and strong anti-interference ability. The whole detection process can be completed within 20 min and has good application prospect. This work will provide reference for drug dosage and prognosis evaluation of specific tumor therapy.
研究领域:
癌症生物学
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分子诊断
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生物技术
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JOURNAL OF CELLULAR BIOCHEMISTRY
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2023
·Vol. 124
·期 4
·557-572
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IF 4
Juan Gu,Xu Chu,Yujia Huo,Chaoyi Liu,Qingge Chen,Shengnan Hu,Yanyan Pei,Pu Ding,Sen Pang,Ming Wang
Gastric cancer (GC) with pulmonary metastasis is one of the deadliest diseases in the world; however, the underlying pathological mechanisms and potential therapeutic targets remain to be elucidated. As exosomes play indispensable roles in the formation of premetastatic niches (PMN) and cancer metastasis. Therefore, investigating the underlying mechanisms of exosome-mediated pulmonary metastasis of GC may shed new light on identifying novel therapeutic targets for GC treatment. GC-derived exosomes were isolated from the conditioned medium of mouse forestomach carcinoma (MFC) cell line. The effects of MFC-derived exosomes on pulmonary macrophage polarization were analyzed by reverse- transcription polymerase chain reaction and flow cytometry. Expression of PD-L1 and other proteins was evaluated by Western blot. Exosomal microRNAs (miRNAs) were analyzed by microarray. GC-derived exosomes (GC-exo) accumulated in high numbers in the lungs and were ingested by macrophages. The extracellular-signal-regulated kinase (ERK) signaling pathway was activated by GC-exo, inducing macrophage immunosuppressive-phenotype differentiation and increased PD-L1 expression. miRNA-sequencing identified 130 enriched miRNAs in GC-exo. Among the enriched miRNAs, miR-92a-3p plays a major role in activating ERK signaling via inhibition of PTEN expression. In addition, inhibiting ERK signaling with PD98059 significantly reduced the expression of PD-L1 in macrophages and, therefore, reversed the immunosuppressive PMN and inhibited the colonization of GC cells in the lungs. This study identified a novel mechanism of GC-exo mediated PD-L1 expression in lung macrophages that facilitates lung PMN formation and GC pulmonary metastasis, which also provided a potential therapeutic target for GC with pulmonary metastasis treatment.
研究领域:
肿瘤学
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免疫学
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分子生物学
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癌症生物学
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JOURNAL OF CONTROLLED RELEASE
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2025
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IF 11.5
Hongxin Zhao,Fangxue Du,Jianbo Huang,Ruiqian Guo,Ziyan Feng,Ziyao Wang,Li Qiu
Sonodynamic therapy (SDT)-mediated immunogenic cell death and immune checkpoint blockade offer new opportunities for tumor treatment. However, challenges including immunosuppression, hypoxic tumor microenvironments, and inadequate drug delivery hinder therapeutic efficacy. Therefore, we developed a multifunctional biomimetic liposome microbubble named H-R@Lip@M, which is coated with melanoma cell membranes, contains perfluoropentane as its core, and is loaded with the sonosensitizer hematoporphyrin monomethyl ether and the immune adjuvant resiquimod. The targeting properties of melanoma cell membranes enable effective accumulation of nanoparticles (NPs) at tumor sites. Equipped with ultrasonic/photoacoustic imaging capabilities, these NPs allow precise control over the release of drugs and oxygen upon ultrasound stimulation. In vitro and in vivo results consistently showed that the NPs enhanced anti-tumor efficacy, halting primary tumor progression and preventing lung metastasis. Moreover, SDT increased reactive oxygen species levels within tumors, preferentially inducing apoptosis while maximizing immunogenic cell death. When combined with PD-L1 blockade, this synergy promotes dendritic cell maturation and alters various immune populations, boosting T-cell infiltration while enhancing M1 macrophage polarization and reducing regulatory T-cell presence. In summary, the proposed combination has the potential to synergistically enhance the efficacy of sono-immunotherapy by remodeling the immunosuppressive microenvironment, providing valuable insights for addressing challenges associated with SDT-based cancer therapy.
研究领域:
肿瘤学
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生物医学工程
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免疫治疗
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Journal of Pharmaceutical Analysis
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2025
·
IF 8.9
Chenqian Feng,Lingfeng Zhou,Bo Chen,Hui Li,Min Mu,Rangrang Fan,Haifeng Chen,Gang Guo
Melanoma, a common malignant skin tumor, faces challenges with multidrug resistance and high recurrence rates. Combining photodynamic therapy (PDT) and immunotherapy offers a promising personalized treatment approach. However, poor water solubility and significant side effects of photosensitizers and immune checkpoint inhibitors (ICIs) limit their application. Enhancing delivery efficiency while reducing adverse effects is crucial. Herein, we formulate BM@HSSC nanoparticles (NPs), which consist of a reduction-responsive hyaluronic acid (HA) backbone modified with photosensitizer Chlorin e6 (Ce6) and loaded with the programmed cell death-ligand 1 (PD-L1) inhibitor BMS-1. This system synergistically integrates PDT, immunogenic cell death (ICD), and immunotherapy for melanoma treatment. BM@HSSC NPs target and accumulate at the tumor site via the CD44 receptor. The disulfide bonds in the nanoparticles react with high GSH concentrations in tumor cells, rapidly releasing Ce6 and BMS-1. Under 660 nm laser irradiation, BM@HSSC NPs generate cytotoxic reactive oxygen species (ROS), inducing cell apoptosis and triggering ICD via. PDT Damage-associated molecular patterns (DAMPs) and tumor-associated antigens (TAAs) released from ICD promote dendritic cell (DC) maturation, enhancing antigen presentation and activating cytotoxic T lymphocytes (CTLs). Meanwhile, BMS-1 blocks the programmed cell death-1 (PD-1)/PD-L1 pathway, countering the immunosuppressive tumor microenvironment and inhibiting tumor cell immune escape. This strategy amplifies antitumor immune responses by enhancing immunogenicity and synergizing with ICIs, resulting in robust antitumor efficacy.
研究领域:
肿瘤学
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纳米医学
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免疫学
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MOLECULAR PHARMACEUTICS
·
2026
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IF 4.9
Jiale Wei,Ke Qian,Jingbin Shi,Kexin Chen,Hongyan Zhang,Mancang Gu,Chaofeng Mu,Lifei Chen,Yang Xiong
Abstract Triple-negative breast cancer (TNBC) therapy is limited by the poor efficacy of anti-programmed death-ligand 1 (aPD-L1) monotherapy, with dysregulated lipid metabolism in the tumor microenvironment (TME) driving immunosuppression. Herein, a nanoemulsion co-loaded with berberine (BBR) and rhein (RHE) (BBR-RHE-NE), two lipid-modulating bioactives from Dahuang Huanglian Xiexin Decoction, was fabricated to remodel the immunosuppressive TME and boost aPD-L1 efficacy in TNBC. BBR-RHE-NE was characterized with a small droplet size (185.8 ± 0.44 nm), narrow polydispersity (PDI: 0.12 ± 0.02), and good stability. In orthotopic 4T1Fluc TNBC mouse models, BBR-RHE-NE monotherapy inhibited tumor growth, and its combination with aPD-L1 exerted robust synergistic anti-tumor activity. Flow cytometry revealed that BBR-RHE-NE, as a monotherapy or in combination with aPD-L1, enhanced effector immune cell infiltration and reduced immunosuppressive subsets in both tumor tissues and spleens. Lipidomic analysis, Oil Red O staining, and enzymatic assays confirmed BBR-RHE-NE reduced intratumoral lipid droplet accumulation and downregulated intratumoral triacylglycerols and fatty acids (FAs) levels both in vitro and in vivo. Mechanistically, RNA sequencing and functional validation experiments demonstrated that BBR-RHE-NE potentiated aPD-L1 efficacy via PPARγ/FABP4-mediated lipid metabolic remodeling, a process that promoted dendritic cell maturation and was attenuated by the PPARγ agonist GW1929. Moreover, BBR-RHE-NE exhibited excellent biocompatibility with no detectable organ toxicity. Collectively, these findings demonstrate that BBR-RHE-NE effectively remodels the immunosuppressive TME through lipid metabolic reprogramming, offering a promising nanomedicine-based combinatorial strategy to enhance aPD-L1 immunotherapy for TNBC.
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CELLULAR SIGNALLING
·
2025
·
IF 3.7
Suli Chong,Yang Liu,Ziming Bian,Dongxue Hu,Shiqun Guo,Chenfei Dong,Jiayue Zeng,Sairong Fan,Xiaoming Chen
Despite significant advancements in immunotherapy for cancer treatment, its effectiveness in pancreatic ductal adenocarcinoma (PDAC) remains disappointing, which is greatly due to the unique immunosuppressive microenvironment of PDAC. Here, we focus on the involvement of GALNT6 in immune evasion mechanisms in PDAC. Our results reveal a negative relationship between GALNT6 expression and immune cell infiltration in PDAC. Knockdown of GALNT6 enhances PDAC cells sensitivity to cytotoxic T cells and macrophages. Mechanistically, GALNT6-mediated glycosylation blocks the translocation of STING (stimulator of interferon genes) and accelerates its degradation in a cGAS-independent manner, leading to reduced levels of type I interferon (IFN-β) and CCL5 and CXCL10, thus promoting PDAC immune evasion by inhibiting cytotoxic CD8 + T cell and macrophage infiltration. Furthermore, GALNT6 stabilizes PD-L1 by blocking its ubiquitin-proteasome degradation, thereby promoting tumor immune evasion. Notably, the combination of an O-glycosylation inhibitor with PD-1/PD-L1 inhibitors synergistically enhances the anti-cancer immune response. In summary, these findings highlight GALNT6 as a critical player in immune evasion, and targeting GALNT6 could serve as a valuable approach to boost anti-tumor immunity in PDAC patients.
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International Journal of Nanomedicine
·
2026
·
IF 6.5
Zhiqiang Lin,Hui Jiang,Yingying Zhou,Li Xu,Lixin Jiang,Jing Du
Purpose Triple-negative breast cancer (TNBC) is prone to relapse and metastasis due to the immunosuppressive state of the tumor microenvironment and limited exposure to relevant antigens, and chemotherapy alone has poor efficacy. We have developed a novel theranostic nanoplatform to address these problems: multifunctional nanocapsules (NCs) with a PD-L1-mediated gold shell induce immunogenic cell death (ICD) to remodel the immune microenvironment. PD-L1 and NLG919 dual immune checkpoints are programmed to synergistically sensitize photothermal therapy and chemotherapy, and photoacoustic imaging (PAI) is used to visualize and localize TNBC tissues for identification.Methods DOX-NLG919@PLGA@Au-antiPD-L1 NCs (DNPA-aPD-L1 NCs) were prepared using an improved single emulsion water-in-oil (O/W) solvent evaporation method, electrostatic adsorption, gold seed surface-induced crystallization reduction method, and carbodiimide method. A series of animal models were established to focus on the in vivo PAI of NCs, the effects of photochemotherapy combined with immunotherapy and antitumor therapy, ICD induced by NCs, the metabolic distribution of NCs, and toxicity tests.Results This project successfully constructed gold nanoshell-PLGA core NCs with PD-L1 antibody co-loaded with chemotherapeutic drugs doxorubicin and indoleamine 2,3-dioxygenase inhibitor NLG919. Laser-triggered release of DOX, NLG919, and photothermal therapy can synergistically induce immunogenic cell death (ICD), thereby enhancing tumor immunogenicity, inhibiting IDO, and reshaping the tumor immune microenvironment. This can effectively eliminate the primary TNBC lesions, inhibit recurrence and metastasis, significantly prolong the survival of tumor-bearing mice, and NCs have good in vivo biosafety. This diagnostic and therapeutic agent can be used for photochemotherapy, immunotherapy, and PAI to visualize and identify TNBC.Conclusion The photochemotherapy mediated by the DNPA-aPD-L1 NCs we developed, combined with tumor microenvironment remodeling and immune activation, shows great promise for the diagnosis and treatment of TNBC.
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