MOLECULAR CELL
·
2024
·
IF 14.5
Zhenxi Zhang,Yanting Yang,Yang Chen,Jingyu Su,Wenjing Du
The functional integrity of CD8 + T cells is closely linked to metabolic reprogramming; therefore, understanding the metabolic basis of CD8 + T cell activation and antitumor immunity could provide insights into tumor immunotherapy. Here, we report that ME2 is critical for mouse CD8 + T cell activation and immune response against malignancy. ME2 deficiency suppresses CD8 + T cell activation and anti-tumor immune response in vitro and in vivo . Mechanistically, ME2 depletion blocks the TCA cycle flux, leading to the accumulation of fumarate. Fumarate directly binds to DAPK1 and inhibits its activity by competing with ATP for binding. Notably, pharmacological inhibition of DAPK1 abolishes the anti-tumor function conferred by ME2 to CD8 + T cells. Collectively, these findings demonstrate a role for ME2 in the regulation of CD8 + T cell metabolism and effector functions as well as an unexpected function for fumarate as a metabolic signal in the inhibition of DAPK1.
研究领域:
免疫学
·
肿瘤学
·
代谢生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2023
·
IF 11.2
Shufen Zhang,Yingping Zeng,Kai Wang,Guangtao Song,Yiru Yu,Tingting Meng,Hong Yuan,Fuqiang Hu
Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) signaling pathway is an essential DNA-sensing pathway to regulate the innate and adaptive immune response, which plays an important role in tumor immunotherapy. Although the STING agonists can be used, they are limited by their inability to target immune cells and systemic immunotoxicity, calling for novel strategies to accurately and effectively activate the cGAS-STING signaling pathway. Herein, mannose-modified stearic acid-grafted chitosan (M-CS-SA) micelles with the ability to activate the cGAS-STING signaling pathway and absorb tumor antigens were constructed. The chitosan-based nano-micelles showed valid dendritic cell (DCs) targeting and could escape from lysosomes leading to the activation of the cGAS-STING signaling pathway and the maturation of DCs. In addition, a combinatorial therapy was presented based on the programmed administration of oxaliplatin and M-CS-SA. M-CS-SA adsorbed tumor antigens released by chemotherapy to construct an autologous tumor vaccine and built a comprehensive antitumor immune response. In vivo , the combinatorial therapy achieved a tumor inhibition rate of 76.31 % at the oxaliplatin dose of 5 mg/kg and M-CS-SA dose of 15 mg/kg, and increased the CD3 + CD8 + T cell infiltration. This work demonstrated that M-CS-SA and its co-treatment with oxaliplatin showed great potential in tumor immunotherapy.
研究领域:
药学
·
免疫学
·
纳米技术
·
肿瘤学
✓ 已验证
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
·
肿瘤学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Jian Xiao,Nana Feng,Qiushi Li,Xianghui Cao,Qingqing Huang,Biyu Zhou,Zhenrui Fan,Liping Wei,Yang Liu
Ferroptosis is gaining attention as a potential cancer immunotherapy strategy, as it can stimulate antitumor responses by enhancing dendritic cell (DC) activation and the infiltration of cytotoxic T cells (CTLs). However, cancer cells often develop resistance to ferroptosis, reducing the effectiveness of existing treatments. This study demonstrates a novel mitochondria-targeted ferroptosis inducer, designated mitoFePDA@R, which is engineered to achieve a “closed-loop” cancer immunotherapy strategy of ferroptosis induction, antitumor immune activation, and ferroptosis enhancement. In this strategy, mitoFePDA@R is designed to release Fe 2+ and the mitoGPX4 inhibitor RSL3 within tumor mitochondria, thereby effectively inducing ferroptosis and activating strong antitumor immune responses. Additionally, interferon γ ( IFN-γ) released from CTLs inhibits GSH synthesis, which further enhances the ferroptosis sensitivity of tumor cells to form a “closed-loop” strategy. In vitro studies indicated that mitoFePDA@R induced strong ferroptosis in tumor cells by accumulating lipid peroxides (LPO) in mitochondria (which lacks mitochondria targeting). Animal studies confirmed that mitoFePDA@R effectively triggered ferroptosis and activated subsequent antitumor immune responses, leading to significant tumor growth inhibition. This provides a viable and effective strategy for ferroptosis-associated cancer immunotherapy.
研究领域:
肿瘤学
·
免疫学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Haihong Yang,Zhan Gao,Yizi Zhou,Xueer Ge,Xiaorong Pan,Jiakun Li,Zhihui Zhang,Xuanli Jin,Guotao Liu,Zepeng He,Hong Liu,Zhijia Liu,Lixin Liu,Yongming Chen
Lipid nanoparticles (LNPs) have emerged as a groundbreaking platform for delivering messenger RNA (mRNA)-based vaccines and therapeutics. However, clinically approved LNPs administered intramuscularly often lead to unintended liver antigen expression, raising safety concerns related to excessive immune activation and potential tissue damage. Extensive research has focused on optimizing LNPs to adjust their tissue specificity and immunogenicity, while the role of helper lipids as structural components has received little attention. Here, we developed a new LNP system by replacing traditional phospholipids with innovative tertiary amine N -oxide zwitterionic lipids (AOLs) synthesized using the Ugi four-component reaction (Ugi-4CR) followed by tertiary amine oxidation. After two rounds of structural screening and optimization, three top-performing AOL-based LNPs demonstrated muscle-selective mRNA delivery with minimal off-target effects. Using ovalbumin (OVA)-encoded mRNA as a model antigen, the optimized LNP-mRNA vaccine effectively activated more migratory and resident cDC1 cells in muscle and lymph nodes (LNs), increasing tumor CD8 + T cell infiltration and thus inhibiting tumor growth in a murine melanoma model, compared to the benchmark SM-102 LNP. Furthermore, co-formulating CpG adjuvants with the LNP-mRNA vaccine amplified cDC1-mediated antitumor efficacy. In addition, AOL-based LNP-mRNA vaccines reduced the infiltration of CD3 + CD45 + T cells in the liver, decreasing the risk of liver inflammatory responses. As a result, we provide a safe and efficient LNP system for muscle-selective mRNA vaccine delivery, enhancing cDC1-mediated antitumor treatment and offering a promising strategy for tumor immunotherapy.
研究领域:
生物医学工程
·
免疫学
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Jiaxiang Hu,Qingmiao Shi,Chen Xue,Qingqing Wang
Accumulating evidence suggests that berberine (BBR) exhibits anti-cancer effects in hepatocellular carcinoma (HCC). However, the mechanisms by which BBR regulates the immunological microenvironment in HCC has not been fully elucidated. In this study, a mouse model of orthotopic HCC is established and treated with varying doses of BBR. BBR showed effectiveness in reducing tumor burden in mice with HCC. Cytometry by time-of-flight depicted the alterations in the tumor immune landscape following BBR treatment, revealing the enhancement in the T lymphocytes effector function. In particular, BBR decreased the proportion of TCRb hi PD-1 hi CD69 + CD27 + effector CD8 + T lymphocytes and increased the proportion of Ly6C hi TCRb + CD69 + CD27 + CD62L + central memory CD8 + T lymphocytes. Single-cell RNA sequencing further elucidates the effects of BBR on transcriptional profiles of liver immune cells and confirms the phenotypical heterogeneity of T lymphocytes in HCC immune microenvironment. Additionally, it is found that BBR potentially regulated the antitumor immunity in HCC by modulating the receptor-ligand interaction among immune cells mediated by cytokines. In summary, the findings improve the understanding of BBR's impact on protecting against HCC, emphasizing BBR's role in regulating intrahepatic T cell heterogeneity. BBR has the potential to be a promising therapeutic strategy to hinder the advancement of HCC.
研究领域:
肿瘤学
·
免疫学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Guozhi Zhao,Fan Guo,Wenhui Yan,Ying Qu,Chongzheng Yan,Huaiyou Lv,Genju Li,Jianxiong Zhao,Hanmiao Xie,Yizhe Li,Tingting Tian,Zhongxi Zhao
Pancreatic cancer is intrinsically characterized by an immunosuppressive microenvironment, in which the malignant extracellular matrix (ECM) creates a barrier that significantly impedes drug delivery, thereby undermining the overall anti-tumor immune responses. In this study, we present a novel thermosensitive hydrogel (SCC15+PLHCu@Gel) that co-deliver two types of nanoparticles loaded with the disulfiram derivative CPD12C15 (SCC15) and tumor-targeting Cu 2+ (PLHCu) to overcome the degradation of CPD12C15 induced by Cu 2+ within the same nano formulation. SCC15 effectively reduced α-SMA and Collagen I and increased lipid droplets in the cancer-associated fibroblasts (CAFs) by inhibiting the Smad3 pathway, which was consistent with the ECM depletion achieved by using the in-vivo dosing of SCC15+PLHCu@Gel. In addition, the in-vivo treatment of SCC15+PLHCu@Gel significantly elevated pro-inflammatory cytokines IFN-γ, TNF-α and IL-12, indicating the remodeling of the suppressive tumor microenvironment. Finally, the immunity modulation effects of SCC15+PLHCu@Gel were evaluated on the enhancement of tumor-infiltrating cytotoxic CD8 + T cells, maturation of dendritic cells as well as inhibition of immunosuppressive Tregs and MDSCs. These enhanced antitumor immunity responses might be related to the immunogenic cell death (ICD) effects. Thereby, this study presents a promising therapeutic strategy for targeting the ECM and enhancing the immune responses against pancreatic cancer.
研究领域:
肿瘤学
·
生物材料学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2025
·
IF 9.6
Duo Wang,Tianqi Nie,Yifei Fang,Linzhu Zhang,Chao Yu,Ming Yang,Ruijie Du,Junjie Liu,Lei Zhang,Liangzhu Feng,Haidong Zhu
Radiofrequency ablation (RFA), a thermoablative treatment for small hepatocellular carcinoma (HCC), has limited therapeutic benefit for advanced HCC patients with large, multiple, and/or irregular tumors owing to incomplete RFA (iRFA) of the tumor mass. It is first identified that iRFA-treated tumors exhibited increased pyruvate kinase M2 (PKM2) expression, exacerbated tumor immunosuppression featured with increased tumor infiltration of suppressive immune cells and increased proliferation, and programmed cell death ligand 1 expression of cancer cell and ultimately a poor prognosis. Herein, a multifunctional nanomedicine is fabricated by encapsulating nanoassemblies of anti-PD-L1 and spermidine-grafted oxidized dextran with shikonin-containing lipid bilayers to reverse iRFA-induced treatment failure. Shikonin, a PKM2 inhibitor, is used to suppress glycolysis in cancer cells, while anti-PD-L1 and spermidine are introduced to collectively reprogram the proliferation and functions of infiltrated CD8+ T lymphocytes. Combined with iRFA, which promoted the exposure of tumor antigens, the intravenous injection of liposomal SPS-NPs effectively stimulated dendritic cell maturation and reversed tumor immunosuppression, thus eliciting potent antitumor immunity to synergistically suppress the growth of residual tumor masses and lung metastasis. The as-prepared liposomal nanomedicine is promising for potentiating the therapeutic benefits of RFA toward advanced HCC patients through reprogramming iRFA-induced tumor immunosuppression.
研究领域:
肿瘤学
·
免疫学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NATURE CELL BIOLOGY
·
2025
·Vol. 27
·期 8
·1357-1366
·
IF 19.1
Du Xian,Li Wenyan,Li Guiying,Guo Chenyue,Tang Xuyi,Bao Rujuan,Li Runchang,Huang Haiyan,Xu Shuiyu,Yu Xiaoyan,Han Qiaoqiao,Wan Jie,Li Song,Sun Jiayuan,Zhao Ren,Ye Youqiong,Gao Qiang,Ni Zhi-Yu,Cui Xingang,Zou Qiang
Dietary nutrients are inextricably linked to antitumour immune responses. However, the effect of diet-derived galactose on antitumour immunity remains unclear. Here we show that dietary galactose augments CD8 + T cell immunity to suppress tumour progression. High-galactose feeding drives hepatocyte-derived insulin-like growth factor binding protein 1 (IGFBP-1) production, thus restraining IGF-1 signalling-dependent T cell exhaustion. IGF-1 receptor (IGF-1R) deficiency in T cells potentiates antitumour CD8 + T cell responses and phenocopies high-galactose feeding by preventing T cell exhaustion. Circulating galactose reprograms hepatocyte metabolism to inactivate mTORC1, thereby inducing the production of IGFBP-1 to boost CD8 + T cell function. Furthermore, patients with cancer who have high plasma IGFBP-1 levels exhibit blocked T cell exhaustion and enhanced T cell responses in tumour tissues. These findings reveal that dietary galactose specifically elicits potent antitumour CD8 + T cell responses by facilitating hepatocyte-derived IGFBP-1 production, providing insights into the development of more effective immunotherapies against cancers.
研究领域:
免疫学
·
肿瘤学
·
分子生物学
·
转化医学
·
代谢调控
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cells
·
2023
·Vol. 12
·期 19
·2351
·
IF 6
Ziqi Zhou,Yan Zhang,Simin Xia,Xi Chen
Immunosuppressants are emerging as promising candidates for cancer therapy with lower cytotoxicity compared to traditional chemotherapy drugs; yet, the intrinsic side effects such as immunosuppression remain a critical concern. Herein, we introduce a photoactivatable antitumor immunosuppressant called dmBODIPY-FTY720 (BF) that shows no cytotoxicity but can be temporally and locally activated by deep-red light illumination to induce tumor cell apoptosis. To further reduce potential side effects, we integrate BF with another classic photosensitizer called methylene blue (MB) that is activated under the same wavelength of deep-red light (>650 nm) and successfully establish a red-light-activatable AND Boolean logic gate through a mechanism that we found to be synergetic apoptotic induction. At further decreased dosages, deep-red light illumination does not induce cell death in the presence of either BF or MB, but significant cancer cell death is triggered in the presence of both drugs. Therefore, the dosage of BF is further reduced, which will be highly beneficial to minimize any potential side effects of BF. This AND-gated strategy has been successfully applied in vivo for effective suppression of hepatocarcinoma tumors in living mice.Keywords:antitumor immunosuppressant;FTY720;logic gate;BODIPY photocage;red light;photodynamic therapy
研究领域:
癌症治疗
·
药理学
·
光化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Mengna Dong,Chan Xue,Xinhui Yang,Hongfang Liu,Hong Wang,Yonggui Liao,Yajiang Yang,Xiangliang Yang,Qin Wang
cGAS-STING pathway, an important innate immune signaling pathway, has attracted extensive attention in anti-tumor immunotherapy research. However, the limited delivery ratio of STING agonists and lactate-induced lactylation present significant challenges in advancing cGAS-STING antitumor immune response. Herein, natural anaerobic sulfate-reducing bacteria (SRB) are utilized as a biofactory to in situ biosynthesize MnS nanoparticles (MnS@SRB) for amplifying MnS-activated cGAS-STING anti-tumor immune responses through continuous lactate depletion by SRB. After intravenous injection, MnS@SRB can actively migrate to tumor tissues via SRB-mediated hypoxia targeting, further continually release H 2 S and Mn 2+ in the acidic tumor microenvironment. H 2 S stimulates mitochondrial dysfunction and induces mitochondrial DNA leakage, which is then recognized by cGAS to activate STING signaling pathway. Mn 2+ further augments STING-mediated secretion of type I interferons and inflammatory factors. Importantly, MnS@SRB can effectively metabolize lactate in tumors, thereby alleviating cGAS lactylation for amplifying cGAS-STING immune response and regulating macrophage phenotype to M1-type, reducing the tumor-infiltrating regulatory T cells and increasing CD8 + T cells level, further enhancing both adaptive and innate immunosurveillance. As a result, MnS@SRB effectively inhibite the tumors growth and metastasis. Therefore, MnS@SRB-based delivery system enables efficient cGAS activator delivery and tumor immunosuppressive microenvironment remodeling, thereby opening a new avenue for synergistically enhanced STING activation.
研究领域:
生物医学工程
·
免疫学
·
肿瘤学
✓ 已验证
产品关联
DOI
高影响因子
ACS Biomaterials Science & Engineering
·
2022
·
IF 5.395
Yuxi Gao,Jiayu Zhao,Zichao Huang,Hanqin Zhao,Zhaopei Guo,Sheng Ma,Xing Tang,Wantong Song,Xuesi Chen
OX40 (CD134, TNFRSF4) is a member of the tumor necrosis factor receptor superfamily that can be activated by its cognate ligand OX40L (CD252, TNFSF4) and functions as a pair of T cell costimulatory molecules. The interaction between OX40 and OX40L (OX40/OX40L) plays a critical role in regulating antitumor immunity, including promoting effector T cells expansion and survival, blocking natural regulatory T cells (Treg) activity, and antagonizing inducible Treg generation. However, current OX40 agonists including anti-OX40 monoclonal antibodies (aOX40) have serious side effects after systemic administration, which limits their clinical success and application. Herein, we propose a strategy to reprogram tumor cells into OX40L-expressing “artificial” antigen-presenting cells (APCs) by OX40L plasmid-loaded nanoparticles for boosting antitumor immunity in situ. A novel gene transfection carrier was prepared by a modular hierarchical assembly method, which could efficiently transfect various tumor cells and express OX40L proteins on their surface. These surface-decorated OX40L proteins were proved to stimulate T cell proliferation in vitro while stimulating strong antitumor immune responses in vivo. Importantly, this in situ reprogramming strategy did not induce any toxicity as observed in aOX40 treatment, thus providing a novel method for immune checkpoint stimulator application.
研究领域:
免疫学
·
肿瘤学
·
纳米技术
·
基因治疗
✓ 已验证
DOI
PubMed
高影响因子
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