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
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DOI
PubMed
高影响因子
International Journal of Biological Sciences
·
2025
·Vol. 21
·期 8
·3555
·
IF 10
Pengyi Liu,Minmin Shi,Yang Liu,Yihao Liu,Jiayu Lin,Shuyu Zhai,Yizhi Cao,Dongjie Chen,Yongsheng Jiang,Chenghong Peng,Lei Zhang,Chunyong Ding,Lingxi Jiang,Baiyong Shen
Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with limited treatment options and poor response to immunotherapy. The immunosuppressive tumor microenvironment, characterized by a dense extracellular matrix, and immunosuppressive cells, plays a crucial role in this resistance. The cGAS-STING pathway, traditionally recognized for antiviral defense, has emerged as a potential target for cancer immunotherapy due to its ability to activate both innate and adaptive immune responses. Methods: A novel small-molecule STING agonist, D166, was synthesized by incorporating deuterium into the structure, leading to improved stability and activation of the STING pathway. The effects of D166 were evaluated using human pancreatic tumor organoids, mouse pancreatic tumor models, and various in vitro and in vivo assays, including flow cytometry, RNA sequencing, ELISA and western blotting. And an organoid-immune cells co-culture system was established for further investigate the effects on immune cells. Results: D166 demonstrated significant anti-tumor activity, effectively activating the cGAS-STING pathway in a time- and dose-dependent manner. D166 inhibited the progression of pancreatic tumor organoids and mouse pancreatic tumors, reshaping the tumor immune microenvironment. The drug enhanced T cell activation, promoted macrophage polarization toward the M1 phenotype, and increased the infiltration of immune cells. Additionally, D166 acted as a sensitizer for anti-PD-1 therapy, significantly improving therapeutic efficacy in combination treatments. Conclusion: D166 is a novel and stable STING agonist that inhibits pancreatic tumor progression by activating the cGAS-STING pathway and remodeling the tumor immune microenvironment. Its combination with anti-PD-1 antibodies offers a promising strategy for overcoming the immunosuppressive barriers in pancreatic cancer, providing new therapeutic insights and directions.
研究领域:
肿瘤学
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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
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Jian Wu,Zhiqiang Chen,Haojie Shang,Yonghua Tong,Wen Deng,Yu He,Xiaozhuo Ba,Zichen Zhong,Yongke Bai,Tao Ye,Xiaoqi Yang,Kehua Jiang,Yijing Liu,Kun Tang
Limited lymphocyte infiltration and insufficient tumor immunogenicity remain major challenges for effective immunotherapy in bladder cancer, particularly in immunologically “cold” tumors with a highly suppressive immune microenvironment. Effective activation of the innate immune system is critical for initiating a robust adaptive anti-tumor immune response, primarily mediated by dendritic cells (DCs). Here, we designed genetically engineered hybrid membrane-coated nanoparticles (HM-MPS NPs) with excellent photothermal stability, tumor-targeting capability, and biocompatibility. HM-MPS NPs demonstrated significant tumor-suppressive effects in multiple preclinical models, including murine subcutaneous, orthotopic, and distant bladder tumor models. By combining photothermal therapy (PTT), a STING agonist (SR717), and antigen presentation, HM-MPS NPs achieve triple activation of DCs, leading to enhanced T-cell activation and a remodeled immune microenvironment. Furthermore, HM-MPS NPs synergize effectively with anti-PD-1 therapy, amplifying immunogenic cell death (ICD) and overcoming immune suppression within the tumor microenvironment. This strategy significantly boosts tumor immunogenicity and enhances anti-tumor immune responses, offering a promising approach for bladder cancer treatment.
研究领域:
肿瘤学
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免疫学
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纳米医学
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产品关联
DOI
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 7.3
Zhiyuan Cheng,Yijie Wang,Yao Zhang,Chan Zhang,Mengru Wang,Wei Wang,Jiacheng He,Yang Wang,Hankun Zhang,Qiansen Zhang,Chunyong Ding,Deyan Wu,Linlin Yang,Mingyao Liu,Weiqiang Lu
Nowadays, small-molecule drugs have become an indispensable part of tumor immunotherapy. Accumulating evidence has indicated that specifically blocking PGE2/EP4 signaling to induce robust antitumor immune response represents an attractive immunotherapy strategy. Herein, a 2H-indazole-3-carboxamide containing compound 1 was identified as a EP4 antagonist hit by screening our in-house small-molecule library. Systematic structure–activity relationship exploration leads to the discovery of compound 14, which displayed single-nanomolar EP4 antagonistic activity in a panel of cell functional assays, high subtype selectivity, and favorable drug-like profiles. Moreover, compound 14 profoundly inhibited the up-regulation of multiple immunosuppression-related genes in macrophages. Oral administration of compound 14, either as monotherapy or in combination with an anti-PD-1 antibody, significantly impaired tumor growth via enhancing cytotoxic CD8+ T cell-mediated antitumor immunity in a syngeneic colon cancer model. Thus, these results demonstrate the potential of compound 14 as a candidate for developing novel EP4 antagonists for tumor immunotherapy.
研究领域:
肿瘤学
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免疫学
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Lipeng Zhu,Dongliang Leng,Ziang Guo,Yuetao Zhao,Kam-Tong Leung,Yeneng Dai,Junnan Li,Qi Zhao
Ferroptosis, triggered by membrane lipid peroxidation (LPO) and diminished antioxidants, can be induced by intracellular iron (II, Fe 2+ ). However, the role of nitric oxide (NO) in causing Fe 2+ overload for ferroptosis remains uncertain. This study reveals that NO can stimulate endogenous Fe 2+ release by upregulating heme oxygenase 1 (HMOX1) expression. Here, ferritin heavy chain (FHC) siRNA and hyaluronic acid (HA)-modified Arg-stabilized zinc peroxide (AZOSH), a non-ferrous-based nanoagent, is synthesized to trigger ferroptosis by inducing intracellular Fe 2+ overload. AZOSH, a self-catalyzed NO nanocomplex, effectively generates NO through a reaction of self-supplied Arginine (Arg) and hydrogen peroxide (H 2 O 2 ), which promotes glutathione (GSH) consumption to downregulate glutathione peroxidase 4 (GPX4) expression and produces peroxynitrite (ONOO − ) to enhance LPO. Meanwhile, NO promotes endo/lysosomal escape of siRNA by damaging membrane structures. Moreover, AZOSH significantly triggers Fe 2+ overload through the synergistic effects of NO-activated HMOX1 expression and FHC siRNA-mediated ferritin sequestration. Additionally, the released Zn 2+ from AZOSH induces oxidative stress by inhibiting mitochondrial function, further promoting ferroptosis. Consequently, AZOSH-mediated ferroptosis exhibits a strong cellular immunogenic response for T-cell activation and infiltration. Importantly, the integration of AZOSH with an anti-PD-1 antibody results in notable antitumor efficacy in vivo . Therefore, this study provides a novel concept of NO-induced ferroptosis, highlighting its role in enhancing PD-1-based immunotherapeutic efficacy.
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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治疗学
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产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Weiting Jiang,Wei Deng,Qi Chen,Huahua Zhang,Min Zhu,Rongze Wang,Yong Wang
Pancreatic cancers are marked by a highly fibrotic extracellular matrix (ECM) that fosters an immunosuppressive tumor microenvironment (TME), severely limiting the effectiveness of traditional therapies. Emerging evidence suggests that ECM modulation represents a promising strategy to enhance treatment outcomes in pancreatic cancer. Herein, we developed a polymeric nanovesicle for the co-encapsulation and delivery of gemcitabine and prolyl isomerase Pin1 inhibitor sulfopin (Gem/Sul-NP). The engineered Gem/Sul-NP features a compact size of approximately 50 nm, facilitating improved accumulation and penetration within pancreatic tumor tissues. Additionally, the Gem/Sul-NP demonstrates pH-responsive characteristics, undergoing structural disintegration at the acidic pH of 6.5 to achieve controlled drug release in the TME, thereby facilitating synergistic antitumor effects. Sulfopin functions to inhibit pancreatic stellate cells (PSCs) activation, reducing ECM component secretion and disrupting stromal barriers. Besides, it upregulates the expression of the gemcitabine transporter equilibrative nucleoside transporter 1 (ENT1) on tumor cell membranes, thereby enhancing the cellular uptake of gemcitabine and its chemotherapeutic impact. Our in vivo studies confirmed that Gem/Sul-NP treatment effectively remodeled the immunosuppressive TME. When combined with anti-PD-1 therapy, this approach significantly increased CD8 + IFNγ + T cell infiltration, indicating its potential to create favorable conditions for synergistic chemoimmunotherapy against pancreatic cancers.
研究领域:
肿瘤学
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纳米技术
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药剂学
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免疫学
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生物化学
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产品关联
DOI
PubMed
高影响因子
iScience
·
2024
·
IF 4.6
Quguang Li,Yifan Yan,Chunjie Wang,Ziliang Dong,Yu Hao,Minming Chen,Zhuang Liu,Liangzhu Feng
Autologous cancer vaccines represent a promising therapeutic approach against tumor relapse. Herein, a concise biomineralization strategy was developed to prepare an immunostimulatory autologous cancer vaccine through protein antigen-mediated growth of flower-like manganese phosphate (MnP) nanoparticles. In addition to inheriting the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING)-activating capacity of Mn 2+ , the resulting ovalbumin (OVA)-loaded MnP (OVA@MnP) nanoparticles with superior stability and pH-responsiveness enabled efficient priming of antigen-specific CD8 + T cell expansion through promoting the endo/lysosome escape and subsequent antigen cross-presentation of OVA. Resultantly, OVA@MnP vaccines upon subcutaneous vaccination elicited both prophylactic and therapeutic effects against OVA-expressing B16-F10 melanoma. Furthermore, the biomineralized autologous cancer vaccines prepared from the whole tumor cell lysates of the dissected tumors suppressed the growth of residual tumors, particularly in combination with anti-PD-1 immunotherapy. This study highlights a simple biomineralization approach for the controllable synthesis of cGAS-STING-activating autologous cancer vaccines to suppress postsurgical tumor relapse.
研究领域:
癌症免疫疗法
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纳米技术
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
STAR Protocols
·
2021
·
IF 0
Zhengxin Peng,Man Yu,Jiaming Lin,Tianqi Dong,Xiao Zhang,Mingjun Shi,Min Qin,Shasha Li,Wencong Guo,Huixia Zhang,Shuguo Sun
Summary Anti-PD-1/PD-L1 therapy shows long-term effects in many cancer types, but resistance and relapse remain the main limitations of this therapy. Here, we describe a protocol to evaluate the tumor response to immunotherapy in a mouse lung cancer model. The protocol includes the establishment of the lung cancer mouse model, anti-PD-1 treatment, tumor-infiltrating lymphocyte isolation, immunofluorescence, and flow cytometry analysis. This protocol can also be applied to other cancer types and immunotherapies. For complete details on the use and execution of this protocol, please refer to Yu et al. (2021)
研究领域:
肿瘤学
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免疫学
·
分子生物学
✓ 已验证
DOI
PubMed
Acta Biomaterialia
·
2025
·
IF 9.6
Yue Hu,Xi He,Ping Chen,Xiao-Li Tian,Rong Wang,Xiangrong Song,Xiao-Qi Yu,Ji Zhang
mRNA-based protein replacement therapy has become one of the most widely applied forms of mRNA therapy, with lipid nanoparticles (LNPs) being extensively studied as efficient delivery platforms for mRNA. However, existing LNPs tend to accumulate in the liver or kidneys after intravenous injection, highlighting the need to develop vectors capable of targeting specific organs. In this study, we synthesized a small library of ionizable lipids and identified PPz-2R 1 as a promising candidate, exhibiting lung-targeting capabilities, high mRNA transfection efficiency, and good stability through structure-activity relationship studies. In an in situ lung cancer model with PTEN deletion, precise delivery of PTEN mRNA to the lungs restored the cancer-suppressing function of the PTEN protein and successfully alleviated the immunosuppressive tumor microenvironment in the lungs by modulating immune cell activity and cytokine levels. Additionally, the upregulation of PD-L1 expression at the tumor site was triggered. Building on this, in vivo treatment with PTEN mRNA combined with anti-PD-1 therapy was tested in tumor-bearing mice. The results demonstrated that the combined treatment strategy effectively overcame immune escape, promoted T cell infiltration, improved survival rates over 60 days, and significantly inhibited tumor growth. Furthermore, the combination treatment was more effective than either therapy alone. This study presents an effective and practical strategy for the targeted treatment of lung diseases and relevant combination therapies. Statement of significance Lipid nanoparticles (LNPs) have been extensively studied as efficient delivery vectors for mRNA. However, it remains essential to develop vectors that can specifically target distinct organs. In this study, we designed and synthesized a series of piperazine-containing ionizable lipids and their analogues, which were initially explored as lung-targeting vectors for PTEN mRNA delivery. Through screening in both in vitro and in vivo experiments, we found that the leading LNPs-assisted PTEN mRNA-mediated protein supplementation therapy effectively downregulated Treg expression and activated immune cells, thereby reversing the immunosuppressive tumor microenvironment in a mouse model of lung cancer. Furthermore, when combined with anti-PD-1-mediated immunotherapy, the combination therapy exhibited the strongest tumor growth inhibition. This approach offers a novel strategy for the targeted treatment of lung diseases and associated combination therapies.
研究领域:
肿瘤学
·
分子生物学
·
药学
·
免疫疗法
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2024
·Vol. 43
·期 1
·1-22
·
IF 11.4
Tu Xiaoxuan,Chen Longxian,Zheng Yi,Mu Chenglin,Zhang Zhiwei,Wang Feiyu,Ren Yiqing,Duan Yingxin,Zhang Hangyu,Tong Zhou,Liu Lulu,Sun Xunqi,Zhao Peng,Wang Lie,Feng Xinhua,Fang Weijia,Liu Xia
Background The paucity of reliable biomarkers for predicting immunotherapy efficacy in patients with advanced hepatocellular carcinoma (HCC) has emerged as a burgeoning concern with the expanding use of immunotherapy. This study endeavors to delve into the potential peripheral biomarkers capable of prognosticating efficacy in HCC patients who are poised to receive anti-PD-1 monotherapy within the phase III clinical trial, KEYNOTE394. Additionally, we sought to elucidate the underlying molecular mechanisms for resistance to immune checkpoint blockade (ICB) and propose innovative combination immunotherapy strategies for future clinical application.Methods Patient blood samples were collected for single-cell RNA sequencing to evaluate the immune cell signature before receiving ICB therapy. Subsequently, in vitro assays and in vivo murine model experiments were conducted to validate the mechanism that S100A9+CD14+ monocytes play a role in ICB resistance.Results Our study demonstrates a notable enrichment of S100A9+CD14+ monocytes in the peripheral blood of patients exhibiting suboptimal responses to anti-PD-1 therapy. Moreover, we identified the Mono_S100A9 signature as a predictive biomarker, indicative of reduced efficacy in immunotherapy and decreased survival benefits across various tumor types. Mechanistically, S100A9 activates PD-L1 transcription by directly binding to the CD274 (PD-L1) gene promoter, thereby suppressing T-cell proliferation and cytotoxicity via the PD-1/PD-L1 axis, consequently diminishing the therapeutic effectiveness of subsequent anti-PD-1 treatments. Furthermore, our in vivo studies revealed that inhibiting S100A9 can synergistically enhance the efficacy of anti-PD-1 drugs in the eradication of hepatocellular carcinoma.Conclusion sOur study underscores the significance of S100A9+CD14+ monocytes in predicting inadequate response to ICB treatment and provides insights into the monocyte cell-intrinsic mechanisms of resistance to ICB therapy. We also propose a combined therapeutic approach to enhance ICB efficacy by targeting S100A9.
研究领域:
肿瘤学
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免疫学
·
分子生物学
·
临床试验
✓ 已验证
产品关联
DOI
PubMed
高影响因子
npj Precision Oncology
·
2025
·Vol. 9
·期 1
·1-15
·
IF 8
Huo Ran,Xu Quan-guo,You Yi-qing,Chen Yan-lin,Su Guang-jian,Yang Kun-rong,Xiao Yan-ping,Xue Zhong,Li Yang-jin,Sun Pei,Cui Zhao-lei,Lin Ying-ying,Guo Jun-ying,Xu Hai-yan,Chen Zhao-shuo,Xie Wen-ting,Xu Shao-hua,Chen Min-yong,Wu Jing,He Shi-jie,Xiao Zhen-zhou,Chen Yan
Hepatocellular carcinoma (HCC) is a prevalent and deadly cancer. Gut microbiota affect tumor immunity and immunotherapy efficacy, but the exact mechanisms are unclear. A study compared gut microbiota in HCC patients and healthy controls (HC) using 16S rDNA analysis and metabolomics. It found higher levels of Bifidobacterium and a positive correlation between Bifidobacterium and isobutyric acid in HC group. Animal models showed that the combination of HC fecal matter and αPD-1 treatment reduced tumor volume more effectively than the combination of HCC fecal matter and αPD-1. The combination of Bifidobacterium or isobutyrate with αPD-1 also decreased tumor size. In vitro, isobutyrate-stimulated CD8 + T cells increased IFN-γ secretion, suppressed liver cancer cells, and downregulated the JAK/STAT3 pathway. Combined treatments increased CD8 + T cells and IFN-γ levels and reduced JAK/STAT3 signaling in the tumor microenvironment. This suggests that Bifidobacterium and isobutyrate can inhibit tumor growth, offering insights into gut microbiota-host interactions and potential strategies to overcome HCC immunotherapy resistance.
研究领域:
癌症研究
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免疫学
·
微生物学
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分子生物学
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胃肠病学
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生物信息学
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药理学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2025
·
IF 9.6
Jiaxuan Li,Kuirong Mao,Xiandi Meng,Jialiang Wang,Mengfei Zhao,Yue Lv,Yanbao Xin,Huating Sun,Yuning Zhang,Yong-Guang Yang,Tianmeng Sun
Tumor-associated macrophages (TAMs) significantly influence the clinical outcomes of immune checkpoint blockade (ICB) therapy. Strategies aimed at reprogramming TAMs from the immunosuppressive M2 phenotype to the pro-inflammatory M1 phenotype hold promise for enhancing ICB efficacy. Lipopolysaccharide (LPS), a potent Toll-like receptor 4 (TLR4) ligand, can reprogram TAMs toward an M1 phenotype. However, the systemic application of LPS is restricted due to its pronounced pro-inflammatory properties, which limit safe dosing in cancer treatment. To address this, thermosensitive hydrogels offer a viable solution by optimizing drug bioavailability and reducing systemic dissemination. In our study, carboxymethyl chitosan (CS) was incorporated into Pluronic F127 to extend the hydrogel's degradation period, facilitating the localized delivery and accumulation of LPS within tumor sites. Peritumoral injection of this hydrogel enhanced the tumor-inhibitory effects of anti-PD-1 antibodies, significantly improving the survival of 4T1 tumor-bearing mice. The GelF127CS-LPS hydrogel also increased the expression of the activation marker on tumor-infiltrating dendritic cells, promoted a higher M1/M2 TAM ratio, and enhanced CD8 + T cell infiltration into tumors—key indicators of T-cell-mediated anti-tumor immunity. Notably, no significant liver or hematological toxicity was observed with GelF127CS-LPS treatment, underscoring its favorable safety profile. These findings demonstrate the potential of GelF127CS-LPS as a TAMs-modulating agent and a promising combinatorial strategy to boost ICB therapy effectiveness. Statement of significance LPS, a potent TLR4 ligand, can reprogram tumor-associated macrophages (TAMs) toward an M1 phenotype, thereby contributing to tumor inhibition. However, its anti-tumor application is constrained by the contradiction between high-dose toxicity and insufficient efficacy at low doses. To address this issue, we developed a thermosensitive hydrogel encapsulating LPS, GelF127CS-LPS, which allows localized LPS release within the tumor area. This hydrogel reprograms TAMs at a picogram level of LPS to achieve a favorable M1/M2 ratio and promotes the activation of T cell-mediated antitumor immunity without observable toxicity. Consequently, when combined with immune checkpoint blockade (ICB), the hydrogel can inhibit tumor growth and improve overall survival. This study provides an effective method for tumor-targeted therapeutic LPS delivery to enhance the efficacy of ICB.
研究领域:
肿瘤学
·
免疫疗法
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药学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）