Cell Metabolism
·
2025
·
IF 30.9
Yizeng Fan,Weichao Dan,Yuzhao Wang,Zhiqiang Ma,Yanlin Jian,Tianjie Liu,Mengxing Li,Zixi Wang,Yi Wei,Bo Liu,Peng Ding,Yuzeshi Lei,Chendong Guo,Jin Zeng,Xiaolong Yan,Wenyi Wei,Lei Li
Itaconate is a metabolite catalyzed by cis- aconitate decarboxylase (ACOD1), which is mainly produced by activated macrophages and secreted into the extracellular environment to exert complex bioactivity. In the tumor microenvironment, itaconate is concentrated and induces an immunosuppressive response. However, whether itaconate can be taken up by tumor cells and its mechanism of action remain largely unclear. Here, we identified solute carrier family 13 member 3 (SLC13A3) as a key protein transporting extracellular itaconate into cells, where it elevates programmed cell death ligand 1 (PD-L1) protein levels and decreases the expression of immunostimulatory molecules, thereby promoting tumor immune evasion. Mechanistically, itaconate alkylates the cysteine 272 residue on PD-L1, antagonizing PD-L1 ubiquitination and degradation. Consequently, SLC13A3 inhibition enhances the efficacy of anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) immunotherapy and improves the overall survival rate in syngeneic mouse tumor models. Collectively, our findings identified SLC13A3 as a key transporter of itaconate and revealed its immunomodulatory role, providing combinatorial strategies to overcome immunotherapy resistance in tumors.
研究领域:
肿瘤学
·
免疫学
·
分子生物学
·
癌症免疫治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Junhong Li,Wenxing Lv,Ziwei Han,Yike Li,Jinqi Deng,Yanjuan Huang,Shuo Wan,Jiashu Sun,Bo Dai
Chemo-immunotherapy, combining systemic chemotherapeutic drugs and immune checkpoint blockers, is a promising paradigm in cancer treatment. However, challenges such as limited induction of immune responses and systemic immune toxicity have hindered its clinical applications. Here, a zeolite imidazolate framework-8 (ZIF-8) that encapsulates mitoxantrone (MIT), an immune cell death (ICD)-inducing chemotherapeutic agent (MIT@ZIF-8), is synthesized using a one-pot aqueous-phase process. ZIF-8 serves as a dual-functional nanomaterial for chemo-immunotherapy: a carrier to enhance tumor uptake of MIT for improved chemotherapy efficacy, and a pyroptosis inducer to amplify MIT-induced ICD for augmented anti-tumor immune responses. As a result, in vivo administration of MIT@ZIF-8 markedly inhibits tumor growth in both immunologically “hot” colon cancer and immunologically “cold” prostate cancer. Moreover, MIT@ZIF-8 treatment increases the abundance of cytotoxic CD8 + T cells and reduces the amount of immunosuppressive regulatory T cells in tumors, thereby enhancing anti-tumor immunity and sensitizing prostate cancer to anti-CTLA-4 immunotherapy. In summary, MIT@ZIF-8 offers a highly translational approach for chemo-immunotherapy.
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
产品关联
DOI
PubMed
高影响因子
NANOTECHNOLOGY
·
2021
·Vol. 32
·期 42
·425101
·
IF 3.874
Qing Zhang,Lian Wu,Shaozheng Liu,Qingjie Chen,Lingpeng Zeng,Xuezhong Chen,Qing Zhang
Photodynamic therapy (PDT) and immunotherapy have been often adopted for ovarian cancer therapy, yet their application is limited by the high recurrence rate and toxic side effects. Intriguingly, nanoparticles contribute to enhancing the performance of PDT. Here, we investigated the synthesis of HER-2-Nanobody (Nb)-conjugated human serum albumin (HSA) incorporated with chlorin (Ce6) and catalase (CAT) (Nb@HCC), and analyzed the synergic effect of Nb@HCC-mediated PDT and immunotherapy for SK-OV-3 tumors. The Ce6 and CAT were incorporated into HSA to construct the HCC nanoparticles. HER-2-Nanobody was the purified bacterial crude extract, and conjugated with HCC to prepare Nb@HCC via heterodisulfide. The effects of Nb@HCC with near infrared ray (NIR) irradiation on moderating hypoxia and hypoxia inducible factor-1α (HIF-1α) expression were evaluated in the SK-OV-3 cells and tumor tissues. A SK-OV-3 tumor-bearing model was developed, where the synergistic effect of Nb@HCC-mediated PDT and anti-CTLA-4 therapy was investigated. Nb@HCC with a 660 nm laser irradiation could induce massive reactive oxygen species and trigger apoptosis in SK-OV-3 cells. Nb@HCC and PDT promoted danger-associated molecular patterns (DAMPs), which indicated immunogenic cell death and maturation of dendritic cells in the SK-OV-3 cells. Irradiated by NIR, Nb@HCC alleviated the hypoxia and decreased the expression of HIF-1α. The Nb@HCC-mediated PDT and anti-CTLA-4 therapy synergically inhibited the progression of distant tumor, and induced T cell infiltration. Biosafety tests suggested that Nb@HCC would not cause damage to the major organs with less toxicity and side effects. To conclude, a combination of Nb@HCC-mediated PDT and anti-CTLA-4 therapy could inhibit the progression of distant tumor to attain remarkable therapeutic outcomes.
研究领域:
肿瘤学
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纳米技术
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免疫治疗
·
药学
✓ 已验证
DOI
PubMed
高影响因子
Materials Today
·
2022
·
IF 26.943
Cheng Gao,Cheryl H.T. Kwong,Qingfu Wang,Hiotong Kam,Jianwen Wei,Qian Chen,Jian Zhang,Simon M.Y. Lee,Dayong Gu,Ruibing Wang
A large number of chemotherapeutic and immunotherapeutic agents have been shown to be less effective when exposed to a hypoxic solid tumor. The tumor hypoxia microenvironment contributes to multidrug resistance and immunosuppression, and current delivery of oxygen or enzyme to alleviate hypoxic microenvironment is often limited by the oxygen supplying capacity of material-based carriers and short window of oxygen production. Herein, macrophage membrane coated chlorella (M-Chl) is constructed for targeted delivery to the solid tumor and sustainable oxygen production via photosynthesis, which provides a new general strategy to overcome tumor hypoxia and improve chemotherapy and immunotherapy. The camouflaged strategy via macrophage membrane coating enhances tumor accumulation and retention of Chl due to the inflammatory homing effects of macrophage membrane, which contributes to long term oxygen production for at least 6 days with one dose of Chl, resulting in efficient downregulation of tumor HIF-1α. In vivo antitumor therapy in mice shows that M-Chl enhances the chemotherapeutic efficacy of doxorubicin via inhibiting hypoxia-mediated overexpression of drug efflux proteins, and also improves the poor immunotherapeutic performance of T cell activation agent, anti-CTLA-4 antibody, via downregulating hypoxia-mediated immunosuppressive proteins. Thus, M-Chl may serve as an important adjuvant for enhancing the therapeutic efficacy of clinical antitumor drugs against solid tumors.
研究领域:
癌症研究
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药学
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生物技术
·
免疫学
✓ 已验证
DOI
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-14
·
IF 10.6
Shen Wenqi,Li Yecheng,Yang Ziyi,Li Wenjing,Cao Yi,Liu Yilin,Wang Zheng,Pei Renjun,Xing Chungen
The combination of immune checkpoint inhibitors and immunogenic cell death (ICD) inducers has become a promising strategy for the treatment of various cancers. However, its efficacy remains unmet because of the dense stroma and defective vasculatures in the tumor microenvironment (TME) that restricts the intratumoral infiltration of cytotoxic T lymphocytes (CTLs). Herein, cancer-associated fibroblasts (CAFs)-targeted nanoemulsions are tailored to combine the ICD induction and the TME reprogramming to sensitize checkpoint blockade immunotherapy. Melittin, as an ICD inducer and an antifibrotic agent, is efficiently encapsulated into the nanoemulsion accompanied by a nitric oxide donor to improve its bioavailability and tumor targeting. The nanoemulsions exhibited dual functionality by directly inducing direct cancer cell death and enhancing the tumoral immunogenicity, while also synergistically reprogramming the TME through reversing the activated CAFs, decreasing collagen deposition and restoring tumor vessels. Consequently, these nanemulsions successfully facilitated the CTLs infiltration and suppressing the recruitment of immunosuppressive cells. A combination of AE-MGNPs and anti-CTLA-4 antibody greatly elicited a striking level of antitumor T-cell response to suppress tumor growth in CAFs-rich colorectal tumor models. Our work emphasized the integration of the ICD induction with simultaneous modulation of the TME to enhance the sensitivity of patients to checkpoint blockade immunotherapy.
研究领域:
癌症免疫治疗
·
纳米技术
·
肿瘤微环境
·
免疫学
✓ 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）