Small
·
2021
·Vol. 18
·期 9
·2105118
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IF 13.281
Yu Hei,Yang Chen,Qian Li,Zi Mei,Jijia Pan,Siqi Zhang,Chunyang Xiong,Xiaodong Su,Shicheng Wei
The immunosuppressive tumor microenvironment (TME) can significantly limit the immunotherapeutic effects of the PD-L1 antibody (aPDL1) by inhibiting the infiltration of CD8 + cytotoxic T cells (CTLs) into the tumor tissues. However, how to reprogram the immunosuppressive TME and promote the infiltration of CTLs remains a huge challenge for aPDL1 to achieve the maximum benefits. Herein, the authors design a multifunctional immunoliposome that encapsulates the adrenergic receptor blocker carvedilol (CAR) and connects the “don't eat me” signal antibody (aCD47) and aPDL1 in series via a reactive oxygen species (ROS)-sensitive linker on the surface. In ROS-enriched immunosuppressive TME, the multifunctional immunoliposome (CAR@aCD47/aPDL1-SSL) can first release the outer aCD47 to block the “do not eat me” pathway, promote the phagocytosis of tumor cells by phagocytic cells, and activate CTLs. Then, the aPDL1 on the liposome surface is exposed to block the PD-1/PD-L1 signaling pathway, thereby inducing CTLs to kill tumor cells. CAR encapsulated in CAR@aCD47/aPDL1-SSL can block the adrenergic nerves in the tumor tissues and reduce their densities, thereby inhibiting angiogenesis in the tumor tissues and reprogramming the immunosuppressive TME. According to the results, CAR@aCD47/aPDL1-SSL holds an effective way to reprogram the immunosuppressive TME and significantly enhance immunotherapeutic efficiency of aPDL1 against the primary cancer and metastasis.
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BIOCHEMICAL PHARMACOLOGY
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2020
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IF 4.96
Xuqian Deng,Jiaqi Zhao,Linlin Qu,Zhiguang Duan,Rongzhan Fu,Chenhui Zhu,Daidi Fan
Ginsenoside Rh4, as a bioactive component obtained from Panax notoginseng , has excellent pharmacological efficacy especially antitumor effects. However, its anticancer effects and target mechanisms in regulating human esophageal cancer are still poorly understood. Here, the results suggested that Rh4 exhibited potent anti-esophageal cancer effects in vivo and in vitro . Flow cytometric analysis and Western Blot showed that Rh4 significantly inhibited the growth by inducing G1 phase arrest. In parallel, Rh4 inhibited aerobic glycolysis in esophageal cancer cells by hindering lactate production, glucose uptake and ATP production; reducing the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR); suppressing aerobic glycolysis-related protein expression. Mechanistic studies demonstrated that AKT is a possible target of Rh4, which suppresses aerobic glycolysis. Rh4 administration resulted in AKT deregulation, whereas treatment with insulin abolished the inhibitory effect of Rh4 on aerobic glycolysis. In contrast, treatment with AKT inhibitors or siRNA that silenced AKT enhanced the inhibitory effect of Rh4 on aerobic glycolysis. Moreover, molecular docking results indicated that Rh4 was able to bind to the interdomain region of AKT. Interestingly, the results revealed that Rh4 also inhibited the expression of PD-L1 via the AKT/mTOR pathway. Taken together, our findings provide important insights into the anti-esophageal cancer effects of Rh4 via suppressing aerobic glycolysis and PD-L1 expression, which indicated Rh4 could be as promising drug for clinical treatment.
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Materials Today Bio
·
2025
·
IF 10.2
Wenzhe Yuan,Xiaoli Jiang,Jiayang Qin,Shenglan Wang,Mengxue Liu,Jiayi Jin,Feng Geng,Xiaohong Pan,Jing Zhang
Combining immunotherapy with photodynamic therapy (PDT) can optimize their synergistic therapeutic efficacy against triple-negative breast cancer (TNBC), but the limited accumulation of photosensitizers at the tumor site and the off-target binding of PD-L1 antibody with hematopoietic cells and normal tissues severely reduce the therapeutic efficacy and increase the systemic toxicity, leading to failure in the clinical treatment. Therefore, engineered Escherichia coli Rosetta(DE3) expressing PD-L1 nanobody (Rosetta(pPD-L1nb)) are constructed and covalently conjugated with a photosensitizer, chlorin e6 (Ce6), to develop hybrid bacteria (CeRosetta(pPD-L1nb)). As a facultative anaerobe, CeRosetta(pPD-L1nb) can targetedly accumulate and colonize at the hypoxic and hypernutrient microenvironment of tumor, consistently synthesize PD-L1nb and compete for nutrition consumption with tumor cells to inhibit tumor growth. Under light irradiation, CeRosetta(pPD-L1nb) can not only generate reactive oxygen species (ROS) to directly eliminate tumor cells and induce the infiltration of immune cells into tumors and the immunogenic cell death (ICD) to activate adaptive immune responses, but also spatiotemporally release PD-L1nb due to the PDT-induced lysis in the tumor site to reverse the immunosuppressive tumor microenvironment and activate the systemic antitumor immune response, therefore exert synergistic antitumor effects of anti-PD-L1 therapy and PDT. Altogether, the hybrid bacteria CeRosetta(pPD-L1nb) can serve as an all-in-one strategy for optimizing the synergistic therapeutic efficacy in the combination therapy of TNBC.
研究领域:
肿瘤学
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生物医学工程
·
药理学
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CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Fei Kong,Zhiqiang Zeng,Xiaorong Zhu,Qingqing Wu,Lu Zhou,Changwei Dou,Zhongbo Xie,Lidong Cao
The combination of photodynamic therapy and immunotherapy has emerged as a safe and effective cancer treatment strategy. However, traditional photodynamic therapy and precision anti-tumor immunotherapy still face challenges, such as weak light source penetration, poor targeting specificity, low response rates and immune-related adverse effects. Herein, a smart polymer nano-immunomodulator (SPNI) that can respond to the tumor microenvironment for precise photodynamic immunotherapy of cancer is reported. This SPNI is self-assembled from pH and glutathione (GSH) bi-responsive amphiphilic polymers, simultaneously loaded with photosensitive materials and oxygen-carrying molecules, subsequently is wrapped by hepatocellular carcinoma (HCC) cell membrane using a simple coextrusion method to generate biomimetic nanoparticles. Upon reaching the tumor site, the SPNI degrades in the tumor microenvironment, effectively releasing photosensitive substances with chemophotodynamic effects to directly eliminate tumors without an external light source. Additionally, the immunosuppressant blocks PD-1/PD-L1 signaling pathways to enhance the body’s endogenous anti-tumor immune response, inhibiting tumor growth and metastasis. Furthermore, the incorporated immunosuppressant effectively blocks PD-1/PD-L1 signaling pathways, thereby potentiating endogenous anti-tumor immune responses to suppress both primary tumor growth and metastatic progression. This innovative combination of tumor microenvironment-responsive photodynamic therapy and checkpoint blockade immunotherapy demonstrates remarkable efficacy in anti-HCC treatment and shows substantial potential for clinical translation. The SPNI platform represents a significant advancement in precision cancer therapy by simultaneously addressing multiple limitations of current treatment modalities.
研究领域:
医学
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生物材料学
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肿瘤学
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BIOMATERIALS
·
2026
·
IF 13.6
Yingtao Zhong,Keyan Zhang,Xinyu Li,Zhuofeng Li,Xinjia Huang,Ziwen Qiu,Junmei Nie,Jiaqi Wang,Shiying Li,Hong Cheng
Despite its critical role in treating localized breast cancer, radiotherapy (RT) rarely provokes systemic immune responses or abscopal effects. In this work, immunological profiling reveals that RT upregulates CD47 and PD-L1 expressions in tumor cells and promotes the accumulation of M2-type tumor-associated macrophages (TAMs), suggesting a potential immunosuppressive mechanism that restricts abscopal responses. To overcome this limitation, a legumain-activated radio-immunological synergist (LARIS) is rationally designed to amplify RT-induced abscopal effects through dual CD47/PD-L1 blockade and TAM repolarization. LARIS is constructed from a bispecific immune checkpoint blockade chimeric peptide (BiCCP) linking CD47-and PD-L1-blocking peptides via a legumain-cleavable linker, and co-formulated with the Toll-like receptor 7/8 agonist R848. Within the tumor microenvironment, abundant legumain can cleave LARIS to release R848 together with the checkpoint blockade peptides, thereby reprogramming TAMs toward an M1 phenotype and mitigating CD47/PD-L1-mediated immune evasion. Both in vitro and in vivo studies demonstrated that LARIS significantly enhances systemic antitumor immunity and effectively induces abscopal responses of RT, thus suppressing the growth of distant and rechallenged tumors. Overall, this work offers a promising strategy to counteract RT-induced immunosuppression and potentiate abscopal effects for improved breast cancer therapy.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
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IF 5.6
Songping Wang,Shuai Zhou,Jiankang Huang,Qing Pang,Hao Jin,Huichun Liu
This study elucidates how H3K4 methylation-driven upregulation of Calbindin 2 (CALB2) promotes immune evasion and chemoradioresistance in cholangiocarcinoma (CCA). Integrated bioinformatics analyses identified CALB2 as a hub gene linked to an immunosuppressive microenvironment. In vitro, CALB2 knockdown suppressed tumor cell proliferation, migration, invasion, and calcium signaling—evidenced by reduced phosphorylation of CaMKII, PKC, and NF-κB—while increasing apoptosis. Mechanistically, CALB2-activated NF-κB transcriptionally upregulated Keratin 7 (KRT7), which subsequently induced PD-L1 expression. This CALB2/KRT7/PD-L1 axis impaired T cell activation, reducing CD69 and IFN-γ expression. In vivo, CALB2 silencing inhibited tumor growth, downregulated PD-L1 and Ki-67, and enhanced apoptosis. Notably, CALB2 knockdown significantly sensitized CCA tumors to gemcitabine plus radiotherapy, an effect attenuated by KRT7 overexpression. These findings define a novel H3K4 methylation/CALB2/calcium/NF-κB/KRT7/PD-L1 signaling axis that drives immune suppression and therapy resistance in CCA, highlighting its potential as a multi-target strategy for combined immunotherapy and chemoradiotherapy.
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Cell Death & Disease
·
2023
·Vol. 14
·期 2
·1-13
·
IF 9
Liu Nian,Zhang Jianglin,Yan Mingjie,Chen Lihui,Wu Jie,Tao Qian,Yan Bei,Chen Xiang,Peng Cong
Patients with advanced melanoma have shown an improved outlook after anti-PD1 therapy, but the low response rate restricts clinical benefit; therefore, enhancing anti-PD1 therapeutic efficacy remains a major challenge. Here, our findings showed a significantly increased abundance of α-KG in healthy controls, anti-PD1-sensitive melanoma-bearing mice, and anti-PD1-sensitive melanoma patients; moreover, supplementation with α-KG enhanced the efficacy of anti-PD1 immunotherapy and increased PD-L1 expression in melanoma tumors via STAT1/3. We also found that supplementation with α-KG significantly increased the activity of the methylcytosine dioxygenases TET2/3, which led to an increased 5-hydroxymethylcytosine (5-hmC) level in the PD-L1 promoter. As a consequence, STAT1/3 binding to the PD-L1 promoter was stabilized to upregulate PD-L1 expression. Importantly, single-cell sequencing of preclinical samples and analysis of clinical data revealed that TET2/3-STAT1/3-CD274 signaling was associated with sensitivity to anti-PD1 treatment in melanoma. Taken together, our results provide novel insight into α-KG’s function in anti-PD1 treatment of melanoma and suggest supplementation with α-KG as a novel promising strategy to improve the efficacy of anti-PD1 therapy.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2022
·
IF 8.025
Mengya Ma,Xiaobin Liu,Chaoqun Ma,Ruyue Guo,Xueling Zhang,Zhenzhong Zhang,Xueling Ren
Improved curative effects with reduced toxicity has always been the ultimate goal of gene delivery vectors for tumor immunotherapy. Panax notoginseng polysaccharide (PNP), a natural plant-derived macromolecule, not only has antitumor immune activity but also has the typical structural characteristics useful for gene delivery. In this work, positively charged polyethyleneimine (PEI) was directly grafted to the backbone of PNP to induced its charge reversal and generate a functional gene vector (PNP-PEI). Moreover, a short hairpin RNA targeting the programmed death-ligand 1 (PD-L1) was loaded into PNP-PEI to generate a potentially therapeutic nanoparticle (PNP-PEI/shPD-L1). In vitro and in vivo experiments demonstrated that PNP-PEI could efficiently carry the therapeutic shPD-L1 into tumor cells and that PNP-PEI/shPD-L1 could significantly inhibit the expression of PD-L1 and growth of B16-F10 cells. Noteworthily, treatment with PNP-PEI reversed the phenotype of macrophages from M2 to M1 subtype and promoted dendritic cell maturation, which encouraged the host immunity and enhanced the therapeutic antitumor effects. In summary, this study describes a PNP-based gene delivery vector and highlights the beneficial immunopotentiating therapeutic outcomes of PNP-PEI for tumor immunotherapy.
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BIOMATERIALS
·
2022
·
IF 15.304
Yan Gao,Zilin Song,Li Jia,Yi Tang,Chengcheng Wang,Xiuli Zhao,Haiyang Hu,Dawei Chen,Mingxi Qiao
Despite the important role of reactive oxygen species (ROS) in battling cancer, ROS production with current approaches has been severely limited by the deficiency of oxy-substrates in tumor microenvironment . Herein, an atorvastatin (Ato)-catalytic self-amplified approach was utilized for sustainable ROS production and enhancing anti-tumor efficacy of PD-L1 silencing. A C 18 -pArg 8 -ss-pHis 10 lipopeptide based self-assembled nanoplexes was developed to co-encapsulate AMP-activated protein kinase (AMPK) activator of Ato and PD-L1 siRNA. Efficient delivery of payloads was achieved because of the acidic pH triggered the protonation of pHis 10 , disulfide-bond exposure for cleavage and subsequent cytosolic translocation. Ato was found to activate AMPK, boosting the highly restrained mitochondrial fatty acid oxidation (FAO) in cancer cells for ROS production. The ROS derived from FAO further activated AMPK, creating a positive-feedback mechanism of sustainable ROS production. The self-amplified ROS production from cellular mitochondrial FAO was maintained by the sufficient intracellular fatty acid substrates arising from the dysregulated lipid metabolism and Ato inhibited triglyceride synthesis in cancer cells. The excessive ROS level was found to successfully induce immunogenic cell death effect, boosting the anti-tumor efficacy of PD-L1 silencing. Overall, the Ato catalyzed self-amplified ROS production has been demonstrated as a promising alternative for cancer therapy.
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NEOPLASIA
·
2021
·
IF 5.715
Yihui Ma,Peiyi Xia,Zhengyang Wang,Jingjing Xu,Lan Zhang,Yanan Jiang
Protein Disulfide Isomerase Family A Member 6 (PDIA6) is an endoplasmic reticulum protein that is capable of catalyzing protein folding and disulfide bond formation. Abnormally elevated expression of PDIA6 has been reported to predict poor outcomes in various cancers. Herein, gain-of- and loss-of-function experiments were performed to investigate how PDIA6 participated in the carcinogenesis of pancreatic cancer (PC). By analyzing the protein expression of PDIA6 in 28 paired PC and para carcinoma specimens, we first found that PDIA6 expression was higher in PC samples. Both the overall survival and disease-free survival rates of PC patients with higher PDIA6 expression were poorer than those with lower PDIA6 ( n = 178). Furthermore, knockdown of PDIA6 impaired the malignancies of PC cells — suppressed cell proliferation, invasion, migration, cisplatin resistance, and xenografted tumor growth. PDIA6-silenced PC cells were more sensitive to cytotoxic natural killer (NK) cells. Overexpression of PDIA6 had opposite effects on PC cells. Interestingly, COP9 signalosome subunit 5 (CSN5), a regulator of E3 ubiquitin ligases known to promote deubiquitination of its downstream targets, was demonstrated to interact with PDIA6, and its expression was increased in PC cells overexpressing PDIA6. Additionally, PDIA6 overexpression promoted deubiquitination of β-catenin and PD-L1 and subsequently upregulated their expression in PC cells. These alterations were partly reversed by CSN5 shRNA. Collectively, the above results demonstrate that PDIA6 contributes to PC progression, which may be associated with CSN5-regulated deubiquitination of β-catenin and PD-L1. Our findings suggest PDIA6 as a potential target for the treatment of PC.
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Biomolecules
·
2020
·Vol. 10
·期 2
·285
·
IF 4.082
Ehexige Ehexige,Mingming Bao,Purevbat Bazarjav,Xiang Yu,Hai Xiao,Shuqin Han,Huricha Baigude
Cutaneous melanoma is the most aggressive skin cancer with notorious drug resistance. Inhibition of immune checkpoint molecules is one of the most promising approaches for cancer therapy. Herein, we show that RNAi mediated silencing of STAT3 expression in the tumor tissue robustly inhibit tumor growth in B16F10 mouse model of melanoma. We designed a peptidomimetic-based lipid nanoparticles (LNPs) for the delivery of siRNA in mouse model of melanoma. When systemically administered, the novel formulation (denote DoCh) preferentially delivered siRNA to the tumor tissue. Remarkably, sequential intravenous injections of siRNA against STAT3 induced profound silencing of STAT3 expression in tumor tissue, which resulted in significant downregulation of PD-L1, leading to significant inhibition of tumor growth through inhibition of tumor immune checkpoint. Moreover, DoCh-mediated siRNA delivery did not show noticeable damage to the major organs. Collectively, our data demonstrated that DoCh LNP is a promising tumor-targeted siRNA delivery system.Keywords:peptidomimetic lipid nanoparticle;RNAi;STAT3;PD-L1;cancer immune checkpoints
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Shengsheng Mei,Shanshan Peng,Eu Gene Vong,Jinbiao Zhan
Background Clinical data indicate that a substantial portion of cancer patients, though eligible for immune checkpoint inhibitor (ICI) therapy, cannot fully benefit from ICI monotherapy due to the poor immunogenicity of tumors and lack of tumor-infiltrating lymphocytes within the ‘cold’ tumor microenvironment (TME). In addition to poor antibody penetrance into the TME, systemic delivery of ICIs is associated with immune-related adverse events (irAEs) among recipients, some of which are life-threatening. Oncolytic virotherapy is a potentially viable approach to improving the efficacy of ICI therapy because of their ability to selectively replicate and lyse tumor cells, release tumor-associated antigens (TAAs), induce inflammatory response and promote lymphocyte infiltration in tumors. Methods A recombinant oncolytic adenoviruses (OAd), denoted ZD55-aPD-L1 scFv, which carried the expression cassette for anti-PD-L1 scFv was constructed by molecular cloning. Western blot and ELISA assay were performed to detect aPD-L1 scFv expression. Flow cytometry were used to analyse PD-L1 expression and count tumor cells. Co-culture assay of human peripheral blood mononuclear cells (PBMCs) with tumor cells in vitro and triple-negative breast cancer (TNBC) MDA-MB-231 tumor-bearing model in vivo were evaluated the antitumor effects of recombinant oncolytic adenoviruses ZD55-aPD-L1 scFv. Results We found that cells infected with recombinant oncolytic adenovirus ZD55-aPD-L1 scFv can effectively express aPD-L1 scFv, which function similarly to its full-length anti-PD-L1 antibody. PBMCs have inherently very limited killing effect on tumor cells even with administration of anti-PD-L1 antibody as observed from our in vitro co-cultures. Treatment consisting of ZD55 alone or ZD55 combined with anti-PD-L1 antibody yielded mediocre antitumor efficacy in subsequent in vitro and in vivo investigations, but were all substantially surpassed by the synergistic antitumor effects observed with ZD55-aPD-L1 scFv treatment. We show that the concomitant direct oncolysis by the recombinant OAd and localized autocrine/paracrine interception of PD-1:PD-L1 checkpoint interaction mediated by ZD55-aPD-L1 scFv-infected cells is exceedingly superior to co-administration of ZD55 and anti-PD-L1 antibody in the human TNBC mice model. Conclusions Our results provided evidence for the development of novel strategies, in this case an anti-PD-L1 scFv-armed OAd, to bolster immune responses to ‘cold’ tumors and to improve therapeutic responsiveness to ICIs.
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