Cell Metabolism
·
2025
·
IF 30.9
Ming-Ming Wu,Yan-Chao Yang,Zhi-Qiang Hu,Jie-Yu Chang,Han Xiao,Chang Miao,Bo-Wen Zhang,Zhi-Xi He,Di Zhu,Yu-Ran Duan,Shuo Wang,Jian-Yu Liu,Zhan-Peng Guo,Yu Sun,Dan-Yang Liu,Miao Yu,Yue Zhang,Jian-Jun Mao,Shuai Jiang,Bing-Kun Zhang,Zhu Mei,Jun Gao,Chen Liang,Qiu-Shi Wang,Chang-Jiang Yu,Dan Zhao,Cheng-Hui Yan,Yue Li,Zhen-Wei Pan,Zheng Chen,Da-Qian Xu,Tong Liu,Yong Ji,Zhi-Ren Zhang
Immune checkpoint inhibitor (ICI) therapies increase the risk of metabolic syndrome; the underlying mechanisms remain elusive. We show that an anti-PD-1 antibody targets macrophage PD-1 to reduce energy expenditure without affecting food intake, augmenting the susceptibility of mice to high-fat diet (HFD)-induced obesity and systemic metabolic disorders. Mechanistically, lipopolysaccharide (LPS) activates Unc-51-like autophagy activating kinase 1 (ULK1) in a mammalian target of rapamycin (mTOR)-dependent manner. Activated ULK1 phosphorylates PD-1 at Thr250 to inhibit FBXO38-mediated PD-1 ubiquitination and degradation by disrupting FBXO38-PD-1 binding. Phosphorylated PD-1 interacts with inositol-requiring enzyme 1α (IRE1α) and attenuates IRE1α autophosphorylation to suppress endoplasmic reticulum (ER) stress-mediated inflammatory responses. Suppressing IRE1α alleviates HFD-induced metabolic disorders in macrophage-specific PD-1 knockout mice by rescuing the reduced energy expenditure. Our findings highlight the critical role of macrophage PD-1 at the intersection of immune checkpoint blockade, energy expenditure, and metabolic dysfunction. The underscored moonlighting function of macrophage PD-1 may provide a new rationale for combating ICI therapy- and HFD-induced metabolic diseases.
研究领域:
免疫学
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代谢学
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细胞生物学
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分子生物学
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肥胖研究
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产品关联
DOI
PubMed
高影响因子
IMMUNITY
·
2024
·
IF 25.5
Jiping Sun,Youqin Zhang,Qingbing Zhang,Lin Hu,Linfeng Zhao,Hongdong Wang,Yue Yuan,Hongshen Niu,Dongdi Wang,Huasheng Zhang,Jianyue Liu,Xujiao Feng,Xiaohui Su,Ju Qiu,Jing Sun,Heping Xu,Catherine Zhang,Kathleen Wang,Yan Bi,Edgar G. Engleman,Lei Shen
Adipose tissue group 2 innate lymphoid cells (ILC2s) help maintain metabolic homeostasis by sustaining type 2 immunity and promoting adipose beiging. Although impairment of the ILC2 compartment contributes to obesity-associated insulin resistance, the underlying mechanisms have not been elucidated. Here, we found that ILC2s in obese mice and humans exhibited impaired liver kinase B1 (LKB1) activation. Genetic ablation of LKB1 disrupted ILC2 mitochondrial metabolism and suppressed ILC2 responses, resulting in exacerbated insulin resistance. Mechanistically, LKB1 deficiency induced aberrant PD-1 expression through activation of NFAT, which in turn enhanced mitophagy by suppressing Bcl-xL expression. Blockade of PD-1 restored the normal functions of ILC2s and reversed obesity-induced insulin resistance in mice. Collectively, these data present the LKB1-PD-1 axis as a promising therapeutic target for the treatment of metabolic disease.
研究领域:
免疫学
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代谢生物学
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医学
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DOI
PubMed
高影响因子
PLoS One
·
2015
·Vol. 10
·期 7
·e0131450
·
IF 3.234
Hangjun Zhang,Xiaojun Jiang,Liping Lu,Wenfeng Xiao
Polychlorinated biphenyls (PCBs), a class of hazardous pollutants, are difficult to dissipate in the natural environment. In this study, a cyanobacterial strain Anabaena PD-1 showed good resistance against PCB congeners. Compared to a control group, chlorophyll a content decreased 3.7% and 11.7% when Anabaena PD-1 was exposed to 2 and 5 mg/L PCBs for 7 d. This cyanobacterial strain was capable of decomposing PCB congeners which was conclusively proved by determination of chloride ion concentrations in chlorine-free medium. After 7 d, the chloride ion concentrations in PCB-treated groups (1, 2, 5 mg/L) were 3.55, 3.05, and 2.25 mg/L, respectively. The genetic information of strain PD-1 was obtained through 16S rRNA sequencing analysis. The GenBank accession number of 16S rRNA of Anabaena PD-1 was KF201693.1. Phylogenetic tree analysis clearly indicated that Anabaena PD-1 belonged to the genus Anabaena . The degradation half-life of Aroclor 1254 by Anabaena PD-1 was 11.36 d; the total degradation rate for Aroclor 1254 was 84.4% after 25 d. Less chlorinated PCB congeners were more likely to be degraded by Anabaena PD-1 in comparison with highly chlorinated congeners. Meta - and para -chlorines in trichlorodiphenyls and tetrachlorobiphenyls were more susceptible to dechlorination than ortho -chlorines during the PCB-degradation process by Anabaena PD-1. Furthermore, Anabaena PD-1 can decompose dioxin-like PCBs. The percent biodegradation of 12 dioxin-like PCBs by strain PD-1 ranged from 37.4% to 68.4% after 25 days. Results above demonstrate that Anabaena PD-1 is a PCB-degrader with great potential for the in situ bioremediation of PCB-contaminated paddy soils.
研究领域:
环境科学
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微生物学
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产品关联
DOI
PubMed
高影响因子
ACS Synthetic Biology
·
2025
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IF 3.9
Hong-Rui Li,Ying Zhou,Bang-Ce Ye
Bacteriophages, leveraging phage display and chemical modification, have the potential to deliver large payloads of antitumor agents with precision and to advance vaccine development. However, systemic phage administration often induces neutralizing antibodies, which accelerate phage clearance and reduce accumulation at the target site. To address this limitation, we propose a genetically modified nonpathogenic bacterial strain that specifically targets tumors and releases programmed death ligand 1 (PD-L1)-specific M13 bacteriophage within tumor tissue. We assessed the antitumor efficacy of this phage-expressing strain as an adjunctive therapeutic strategy along with a therapeutic bacterial strain engineered for the controlled release of an immunotoxin. The combination of these strains demonstrated synergistic effects in eliciting antitumor immune responses and inhibiting tumor growth in a murine model of colorectal cancer (CRC). Moreover, when combined with Folfox, the phage-expressing strain significantly extended the survival. This strategy of in vivo expression and tumor-specific release mediated by nonpathogenic bacterial strains provides an effective and safe method for targeted therapeutic phage delivery to tumors.
研究领域:
肿瘤学
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免疫学
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微生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 6.8
Hang Zhang,Yujie Zhang,Yinping Geng,Xuanlong Zhen,Xiaodi Wang,Qiange Yin,Peng Zhang,Yuanyuan Li,Mengzhen Zhang,Yi-chao Zheng,Bing-rui Liu,Hui-min Liu,Hai-wei Xu
Gastric cancer is one of the major health threats to human beings and has a low response rate to emerging immunotherapy. We herein reported a novel indole-based LSD1-targeted antigastric agent 7ae, which was able to enhance the sensitivity of gastric cancer cells to a T-cell-mediated immune response. It exhibited potent LSD1 inhibitory activity (IC50 = 0.080 ± 0.002 μM) and reduced the expression of PD-L1, which in turn promoted the T-cell killing response in gastric cancer cells. As a result, 7ae acted as an active LSD1 inhibitor, exerting excellent anti-invasion and anti-migration effects in gastric cancer cells and leading to significant suppression of the growth of xenograft gastric tumors without obvious toxicity in vivo. Collectively, 7ae has been demonstrated to be a novel, potent LSD1 inhibitor with the potential to be used as an antigastric agent, as well as a useful tool compound for exploratory studies of T-cell-mediated immunity and/or immunotherapy in gastric cancer.
研究领域:
肿瘤学
·
药理学
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免疫学
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产品关联
DOI
PubMed
高影响因子
CELL RESEARCH
·
2023
·Vol. 33
·期 12
·923-939
·
IF 44.1
Liu Rui,Zeng Lin-Wen,Li Hui-Fang,Shi Jun-Ge,Zhong Bo,Shu Hong-Bing,Li Shu
Combination therapy with PD-1 blockade and IL-2 substantially improves anti-tumor efficacy comparing to monotherapy. The underlying mechanisms responsible for the synergistic effects of the combination therapy remain enigmatic. Here we show that PD-1 ligation results in BATF-dependent transcriptional induction of the membrane-associated E3 ubiquitin ligase MARCH5, which mediates K27-linked polyubiquitination and lysosomal degradation of the common cytokine receptor γ chain (γ c ). PD-1 ligation also activates SHP2, which dephosphorylates γ c Y357 , leading to impairment of γ c family cytokine-triggered signaling. Conversely, PD-1 blockade restores γ c level and activity, thereby sensitizing CD8 + T cells to IL-2. We also identified Pitavastatin Calcium as an inhibitor of MARCH5, which combined with PD-1 blockade and IL-2 significantly improves the efficacy of anti-tumor immunotherapy in mice. Our findings uncover the mechanisms by which PD-1 signaling antagonizes γ c family cytokine-triggered immune activation and demonstrate that the underlying mechanisms can be exploited for increased efficacy of combination immunotherapy of cancer.
研究领域:
免疫学
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肿瘤学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Science Advances
·
2020
·Vol. 6
·期 6
·
IF 13.117
Zecong Xiao,Zhenwei Su,Shisong Han,Jinsheng Huang,Liteng Lin,Xintao Shuai
The response to programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) blockade in cancer immunotherapy is limited because of multiple immune evasion mechanisms. Here, a previously unknown strategy is proposed to synergize the nuclear factor κB (NF-κB) inhibition and PD-1 blockade for antitumor immunotherapy. A dual pH-sensitive nanocarrier loading curcumin (CUR) and anti–PD-1 monoclonal antibody (aPD-1) may bind to circulating PD-1+ T cells and then follow their infiltration into the tumor. Furthermore, the nanodrug bound to PD-1+ T cells may be released in the tumor microenvironment, leaving aPD-1 to block PD-1 on T cells and generating a CUR-encapsulated cationic nanodrug that can be easily taken up by tumor cells/tumor associated macrophages (TAMs). Thus, not only the antitumor T cells mediate efficient CUR delivery to tumor but also the efficient CUR delivery promotes the tumor infiltration of antitumor T cells, thereby resulting in effective activation of antitumor immunity.
研究领域:
癌症免疫疗法
·
纳米技术
·
免疫学
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药理学
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产品关联
DOI
PubMed
高影响因子
Theranostics
·
2021
·
IF 11.556
Shi-Long Zhang,Yu-Qin Mao,Zheng-Yan Zhang,Zhan-Ming Li,Chao-Yue Kong,Hui-Ling Chen,Pei-Ran Cai,Bing Han,Tao Ye,Li-Shun Wang
Background: Anti-PD-1-based immunotherapy has emerged as a promising therapy for several cancers. However, it only benefits a small subset of colorectal cancer (CRC) patients. Mounting data supports the pivotal role of gut microbiota in shaping immune system. Pectin, a widely consumed soluble fiber, has been reported to ameliorate the imbalance of gut microbiota. Therefore, we aimed to explore the effect and the underlying mechanisms of pectin in improving anti-PD-1 mAb efficacy. Methods: The C57BL/6 mice were treated with a broad-spectrum antibiotic (ATB) cocktail to depleted endogenous gut microbiota and subsequently humanized with feces from healthy controls or newly diagnosed CRC patients. The antitumor efficacies of anti-PD-1 mAb combined with or without pectin were assessed using these mice. Flow cytometry and immunohistochemistry (IHC) were conducted to investigate the tumor immune microenvironment after treatment. The gut microbiota profiles and short-chain fatty acids (SCFAs) levels were determined by 16S ribosomal RNA (16S rRNA) gene sequencing and gas chromatography-mass spectrometry (GC-MS), respectively. The effect of gut microbiota on anti-PD-1 mAb efficacy after pectin supplement was further tested by fecal microbiota transplantation (FMT). Results: The anti-PD-1 mAb efficacy was largely impaired in the mice humanized with feces from newly diagnosed CRC patients compared to those from healthy controls. However, pectin significantly enhanced the anti-PD-1 mAb efficacy in the tumor-bearing mice humanized with CRC patient gut microbiota. Flow cytometry and IHC analysis revealed increased T cell infiltration and activation in the tumor microenvironment of mice treated with anti-PD-1 mAb plus pectin. In vivo depletion of CD8 + T cells diminished the anti-tumor effect of anti-PD-1 mAb combined with pectin. 16S rRNA gene sequencing showed that pectin significantly increased gut microbial diversity and beneficially regulated microbial composition. In addition, we identified unique bacterial modules that were significantly enriched in the anti-PD-1 mAb + pectin group, which composed of butyrate-producing bacteria indicative of good response to immunotherapy. Meanwhile, GC-MS showed that pectin altered the level of SCFA butyrate. Furthermore, butyrate, a main product of dietary fiber in gut microbial fermentation, was found to be sufficient to promote T cells infiltration and thus enhance the efficacy of anti-PD-1 mAb. In addition, FMT demonstrated the effects of pectin were dependent on gut microbiota. Importantly, the beneficial effects of pectin were confirmed in the mice humanized with gut microbiota from patient with resistance to anti-PD-1 mAb. Conclusion: Pectin facilitated the anti-PD-1 mAb efficacy in CRC via regulating the T cell infiltration in the tumor microenvironment, which was potentially mediated by the metabolite butyrate.
研究领域:
肿瘤学
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免疫学
·
微生物学
✓ 已验证
DOI
PubMed
高影响因子
Food Bioscience
·
2025
·
IF 5.9
Yixuan Wang,Songyu Yang,Shengbin Chen,Yingbing Zuo,Xiaoyu Mu,Hongmei Zhou,Yufei Yao,Xiaoping Peng,Wenjuan Li
This study aimed to explore the anti-tumor activity and mechanisms of the ethanol-soluble acidic components (ESAC) of Camellia oleifera cake through a combination of network pharmacology, in vitro and in vivo studies, and metabolomics based on UPLC-Q-TOF/MS. Additionally, the potential application of ESAC in combination with PD-1 inhibitors was explored. In this work, our results demonstrated that ESAC exhibited anti-tumor activities mediated by regulated cell death (RCD), which were associated with apoptosis, pyroptosis, and ferroptosis. UPLC-Q-TOF/MS-based serum metabolomics revealed that metabolic disorders were occurred in tumor group when compared to control group. In contrast, ESAC significantly inhibited abnormal energy metabolism including glycolysis, tricarboxylic acid cycle, and amino acid metabolism. Consequently, hexokinase and malate dehydrogenase, key enzymes of energy metabolism, were determined, and data showed that treatment of tumor mice with ESAC significantly suppressed activities of these metabolic enzymes when compared to tumor group, confirming that mitigating metabolic disorders contributed to the anti-tumor activities of ESAC. Moreover, ESAC could also reduced PD-L1 expression in tumor tissue, which was similar to the effect of PD-1 inhibitor. Furthermore, combination treatment with ESAC and PD-1 inhibitor was superior to either treatment alone, and it enhanced pyroptosis through the NLRP3/Caspase-1/GSDMD pathway. Together, we concluded that metabolic correction and PD-L1 inhibition were the critical mechanisms to exert anti-tumor activities of ESAC.
研究领域:
药理学
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肿瘤学
·
代谢组学
✓ 已验证
产品关联
DOI
高影响因子
Cancer Nanotechnology
·
2024
·Vol. 15
·期 1
·1-16
·
IF 4.5
Jiang Qiping,Yao Fengjiao,An Yacong,Lai Xialian,Li Xundou,Yu Zhen,Yang Xian-Da
Background PD-1/PD-L1 blockade plays a crucial role in cancer immunotherapy. Exploration of new technologies to further enhance the efficacy of PD-1/PD-L1 blockade is therefore of potential medical importance. Nanotherapeutics can accumulate in tumor tissues due to enhanced permeability and retention (EPR) effects. In this study, a novel nanotherapeutic for cancer immunotherapy was implemented with albumin nanoparticles functionalized by both PD-1 and PD-L1 aptamers.Results Albumin nanoparticles (NP) were functionalized with either PD-1 aptamers (PD1-NP), PD-L1 aptamers (PDL1-NP), or both types of aptamers (PD1-NP-PDL1). Average sizes of PD1-NP, PDL1-NP, and PD1-NP-PDL1 were 141.8 nm, 141.8 nm, and 164.2 nm, respectively. PD1-NP had good affinity for activated T cells that expresses PD-1. Similarly, PDL1-NP could bind with MDA-MB-231 or CT26 tumor cells that express PD-L1. Moreover, the bispecific PD1-NP-PDL1 could bind with both the activated T cells and the PD-L1-expressing tumor cells, and tether the two type of cells together. Functionally, aptamer-modified nanoparticles exhibited stronger immune-stimulating effects vs. free aptamers. Specifically, PD1-NP or PDL1-NP induced stronger lymphocyte-mediated cytotoxicity against PD-L1-expressing tumor cells in vitro vs. free PD-1 or PD-L1 aptamers. Animal studies also showed that PD1-NP or PDL1-NP significantly improved antitumor efficacy against CT26 colon cancer in vivo vs. free PD-1 or PD-L1 aptamers. Importantly, the bispecific PD1-NP-PDL1 further boosted the in vivo antitumor efficacy compared with PD1-NP or PDL1-NP, without raising systemic toxicity.Conclusion The results suggest that the bispecific PD1-NP-PDL1 is a promising nanotherapeutic to improve the efficacy of PD-1/PD-L1 blockade, and may have application potential in colon cancer treatment.
研究领域:
肿瘤学
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纳米医学
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免疫学
✓ 已验证
DOI
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Mengdan Shen,Xi Han,Xixi Li,Jiayun Ji,Shunyao Zhu,Beihua Xu,Senlin Shi,Ting Zhang
In this study, emodin (ED) and polysialic acid (PSA) were synthesized into a compound called PSA-ED. The PSA-ED self-assembled into nanoparticles (PE-NS) using a nano-precipitation method. According to the results of particle size analyzer, the particle size of PE-NS was 180.7 ± 1.60 nm, the polydispersity index (PDI) was 0.263 ± 0.090, and the ζ potential was −17.1 ± 0.9 mV. In vitro cellular experiments confirmed that compared to free emodin, PE-NS exhibited significantly higher cellular uptake in RAW264.7 cells. In addition, in vivo imaging demonstrated enhanced fluorescence accumulation in tumors. This indicated that PE-NS possesses the ability to effectively target tumor-associated macrophages (TAMs). We conducted experiments using a mouse model of the B16F10 tumor, treating the mice with PD-1 antibody, PE-NS, and various doses of PE-NS + anti-PD-1 antibody, and compared them with untreated controls. In the PE-NS and anti-PD-1 antibody combination therapy group, there was a notable decrease in the proportion of M2-TAMs and CD4 + Fop3+ T cells, alongside a significant increase in the proportion of M1-TAMs and CD8+ T cells, resulting in an increased tumor inhibition rate. The combination of PE-NS and anti-PD-1 antibody exhibited synergistic antitumor activity, enhancing the effectiveness of PD-1 checkpoint blockers in the mouse melanoma models. In conclusion, the combination of PE-NS and anti-PD-1 antibody immunotherapy holds great promise in improving the therapeutic effects of melanoma treatment and may offer a novel strategy for clinical application.
研究领域:
纳米技术
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免疫学
·
肿瘤学
·
药学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Arthritis & Rheumatology
·
2025
·
IF 10.9
Jin-Fen Ma,Ting Xu,Hao-Xian Zhu,Xiao-Min Chen,Liang Li,Zhi-Bin Zhao,Liwei Lu,Yang Li,Zhe-Xiong Lian,Cai-Yue Gao
Objective Activated T cells play a pivotal pathogenic role in the progression of Sjögren disease (SjD); however, there are currently no targeted therapies specifically designed to address them. This study aims to identify pathogenic CD8 + T cells in SjD and develop targeted therapeutic strategies. Methods Il12b-/-Il2ra-/- mice, a murine model for overlapping primary biliary cholangitis and SjD, were employed in this study. Pathogenic CD8 + T cells were identified through single-cell RNA sequencing and flow cytometry analyses of samples from both patients with SjD and relevant murine models. Shared T cell receptor analysis was conducted to trace the potential precursors of pathogenic CD8 + T cells. The efficacy of PD-1-targeted chimeric antigen receptor (CAR)–T cell therapy was evaluated through the assessment of salivary gland secretory function, immunologic profiles, and histopathological changes in the murine model. Results We identified PD-1 as a comprehensive marker of clonally expanded and activated pathogenic CD8 + T cells in the salivary glands and peripheral tissues. Flow cytometry further confirmed the activation phenotype and cytotoxicity of PD-1 + CD8 + T cells in the salivary glands of patients with SjD. Notably, the number of PD-1 + CD8 + T cells in the labial glands positively correlated with disease activity in patients with SjD. These findings highlight the therapeutic potential of depleting PD-1 + CD8 + T cells in SjD. Furthermore, PD-1-targeted CAR-T cell therapy significantly alleviated SjD symptoms in a murine model. Conclusion We identified the pathogenic role of PD-1 + CD8 + T cells in both patients with SjD and a murine model and demonstrated the efficacy of PD-1-targeted CAR-T cell therapy in SjD model mice. Our findings suggest a promising avenue for developing clinical therapeutic strategies for patients with SjD.
研究领域:
免疫学
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医学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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