Cell Death Discovery
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2025
·Vol. 11
·期 1
·1-13
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IF 7
Jiang Xiaoxiao,Fan Zhijin,Zhang Zhenzhen,Zeng Fanchu,Sun Tong,Li Yuchen,Huang Guojia,Nie Liming
Tumor cells balance ATP production and carbon skeleton synthesis by flexibly altering catabolic pathways to sustain their significant growth advantage. Uncouplers have shown potential for tumor suppression by converting chemical energy from catabolism into heat. However, their use may be limited due to indiscriminate metabolic interference in both tumor and normal cells, as well as the uncertainty surrounding their effects on the immune microenvironment. Herein, we found that low-dose uncoupler BAM15 promoted AMPK, AKT signaling, and the TCA cycle without increasing cell proliferation or inducing cell death in vitro, suggesting an increase in futile cycling. Intratumoral injection of 50 ng/mL BAM15 accelerated catabolic processes while inhibiting anabolic pathways, resulting in a metabolomic reshaping with increased levels of linoleic acid, C5DC, and others. These changes were shown to enhance tumor-killing effects by T cells. To reduce side effects on normal tissues and improve tumor retention, BAM15 was targeted for delivery by loading it into TCVs. This TCV-BAM15 treatment significantly increased CD8+ T cell counts and granzyme B levels. Our findings highlight a previously unrecognized therapeutic effect and signaling mechanism of low-dose BAM15 treatment in tumors. We propose that this novel strategy holds promise as a tumor immunity therapy with fewer adverse effects compared to free uncoupling drugs at high concentrations.
研究领域:
肿瘤学
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免疫学
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生物化学
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药理学
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DOI
PubMed
高影响因子
International Journal of Nanomedicine
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2022
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IF 7.033
An-Ran Shen,Xiao-Xiao Jin,Tao-Tao Tang,Yan Ding,Xiao-Tao Liu,Xin Zhong,Yan-Dan Wu,Xue-Lian Han,Guang-Yu Zhao,Chuan-Lai Shen,Lin-Li Lv,Bi-Cheng Liu
Purpose Current vaccines for the SARS-CoV-2 virus mainly induce neutralizing antibodies but overlook the T cell responses. This study aims to generate an exosomal vaccine carrying T cell epitope peptides of SARS-CoV-2 for the induction of CD8 + T cell response. Methods Thirty-one peptides presented by HLA-A0201 molecule were conjugated to the DMPE-PEG-NHS molecules, and mixed with DSPE-PEG to form the peptide-PEG-lipid micelles, then fused with exosomes to generate the exosomal vaccine, followed by purification using size-exclusion chromatography and validation by Western blotting, liquid nuclear magnetic resonance (NMR) test and transmission electron microscopy. Furthermore, the exosomal vaccine was mixed with Poly (I:C) adjuvant and subcutaneously administered for three times into the hybrid mice of HLA-A0201/DR1 transgenic mice with wild-type mice. Then, the epitope-specific T cell responses were detected by ex vivo ELISPOT assay and intracellular cytokine staining. Results The exosomal vaccine was purified from the Peak 2 fraction of FPLC and injected into the hybrid mice for three times. The IFN-γ spot forming units and the frequencies of IFN-γ + /CD8 + T cells were 10–82-fold and 13–65-fold, respectively, higher in the exosomal vaccine group compared to the Poly (I:C) control group, without visible organ toxicity. In comparison with the peptides cocktail vaccine generated in our recent work, the exosomal vaccine induced significantly stronger T cell response. Conclusion Exosomal vaccine loading T cell epitope peptides of SARS-CoV-2 virus was initially generated without pre-modification for both peptides and exosomes, and elicited robust CD8 + T cell response in HLA-A transgenic mice.
研究领域:
免疫学
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病毒学
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分子生物学
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疫苗研究
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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Tao Bo,Chenfei Wang,Dingjin Yao,Qiuyu Jiang,Yitong Zhao,Feifei Wang,Wei He,Weiyi Xu,Hao Zhou,Ming Li,Si Zhang,Ruyi Xue
Gene delivery to macrophages holds great promise for cancer immunotherapy. However, traditional gene delivery methods exhibit low transfection efficiency in macrophages. The star -shaped topological structure of polymers is known to encapsulate genes inside their cores, thereby facilitating sustained release of the genetic material. Herein, combining the structural advantages of star polymers and the transfection advantages of poly (β-amino ester)s (PAEs), we developed a novel linear oligomer grafting-onto strategy to synthesize a library of multi-terminal star structured PAEs (SPAEs), and evaluated their gene delivery efficiency in various tissue cells. The transfection with human hepatocellular carcinoma cells (HepG2, HCC-LM3 cells and MHCC-97H cells), rat normal liver cells (BRL-3 A cells), human ovarian cancer cells (A2780 cells), African green monkey kidney cells (Vero cells), human cervical cancer cells (HeLa cells), human chondrosarcoma cells (SW1353 cells), and difficult-to-transfect human epidermal keratinocytes (HaCaT cells) and normal human fibroblast cells (NHF cells) showed that SPAEs exhibited superior transfection profile. The GFP transfection efficiency of top-performing SPAEs in HeLa cells (96.1%) was 2.1-fold, and 3.2-fold higher compared to jetPEI and Lipo3000, respectively, indicating that the star-shaped topological structure can significantly enhance the transfection efficiency of PAEs. More importantly, the top-performing SPAEs could efficiently deliver Nod2 DNA to difficult-to-transfect RAW264.7 macrophages, with a high transfection efficiency of 33.9%, which could promote macrophage M1 polarization and enhanced CD8+ T cell response in co-incubation experiments. This work advances gene therapy by targeting difficult-to-transfect macrophages and remodeling the tumor immune microenvironment.
研究领域:
生物技术
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药学
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免疫学
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癌症研究
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DOI
高影响因子
Nano Today
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2024
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IF 13.2
Yanjie Han,Haifeng Lu,Zikuan Gu,Peixin Guan,Zhen Liu
In situ reprogramming of tumor associated macrophages (TAMs) to resurge their phagocytic ability holds great potential in cancer treatment. However, most of currently existing TAMs-reshaping approaches fail to effectively reprogram TAMs due to low efficiency, poor specificity, and potential immune side effects. Herein, we report a strategy called molecularly imprinted lysosomal nanodegrader (MILND) for resurging the phagocytosis of macrophages and reversing the "don't eat me" CD47-SIRPα signal via degrading SIRPα in lysosomes. The MILND, which was rationally engineered by controllable molecular imprinting using the N-terminal epitope of SIRPα as template, could specifically bind SIPRα on TAMs. Upon being engulfed by TAMs via endocytosis, the MILND-SIRPα complex was transferred to lysosomes for degradation. The degradation of SIRPα induced a cascade reaction of the downstream PI3K signaling pathway to resurging the phagocytic and recognition capability of TAMs towards cancer cells. Ultimately, MILND resulted in a subsequent series of anti-tumor effects. Benefiting from this, MILND effectively sensitized the immune microenvironment and amplified CD8+ T cell responses, leading to substantial tumor growth inhibition in tumor-bearing mouse model. Thus, this work provides an efficient and versatile immunomodulatory strategy for enhanced antitumor immunotherapy.
研究领域:
癌症生物学
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免疫治疗
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纳米技术
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细胞信号传导
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DOI
高影响因子
Biomaterials Science
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2020
·Vol. 9
·期 3
·973-984
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IF 6.183
Ya Wen,Yiqiong Liu,Fangfang Guo,Yi Han,Qiansai Qiu,Yan Li,Haiqing Dong,Tianbin Ren,Yongyong Li
It has been suggested that immunogenic cell death (ICD) has therapeutic potential; however, its anticancer immunity is considerably hampered by the in situ immunosuppressive microenvironment within the tumor area, such as the dysfunction of antigen-presenting cells. Herein, we present an in vitro ICD-inducing modality to circumvent such impairment of immune activation. To this end, a “hot”, i.e., immunogenic, whole tumor cell vaccine is generated in vitro and subcutaneously vaccinated in the normal tissue, departing from the site of the in situ immunosuppressive tumor area, to fully leverage the ICD-inducing antitumor immunity. In particular, the immunogenic dying tumor cells, caged by cellular disulfide–thiol exchange, are mediated by photoactivation. After subcutaneous vaccination, the photoactivated caged live cell vaccine (CLCV) exerts multi-durable immunostimulatory property, which, when adjuvanted by CpG, efficiently promotes dendritic cell (DC) activation and elicits robust CD8+ T-cell responses in vivo. Importantly, the generated T-cell responses are shown to protect 75% mice preimmunized with CLCV against tumor initiation and significantly retards tumor growth in the therapeutic setting. The strategy presented here may help to enrich the current vaccine design for cancer immunotherapy.
研究领域:
癌症免疫治疗
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免疫学
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肿瘤学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
ACS Nano
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2024
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IF 15.8
Pei Xu,Yuan Gu,Chenze Li,Jiahao Shen,Xiaju Cheng,Leshuai W. Zhang,Yangyun Wang,Yong Wang
Tumor in situ vaccination (ISV) strategies have emerged in clinical trials as promising approaches, involving the release of tumor antigens through local radiotherapy and intratumorally adjuvant injections. However, the current fabrication strategy for achieving a sustainable immune response to ISV remains a pressing challenge. In this study, we present an empowered sustainable ISV method for antitumor therapy using 177Lu-labeled manganese-doped mesoporous hydroxyapatite (177Lu/Mn-HAP) microspheres. The ISV enables the sustained utilization of tumor antigens, leading to the activation of dendritic cells and polarization of macrophages toward the M1 subtype. Consequently, it facilitates the generation of potent CD8+ T-cell responses, enhancing the antitumor effects of internal radiation in both primary and distant tumors. Importantly, this approach achieves complete remission in all tumor-bearing mice and stimulates immune memory to prevent tumor recurrence. Our study highlights a universal and safe ISV strategy capable of inducing potent tumor-specific and sustainable immune response.
研究领域:
肿瘤学
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免疫疗法
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放射治疗
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癌症研究
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产品关联
DOI
PubMed
高影响因子
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