A theranostic metallodrug modulates immunovascular crosstalk to combat immunosuppressive liver cancer

Luo, Ying; Wang, Junrui; Liu, Xu; Du, Qianying; Ni, Fang; Wu, Hong‐Yun; Liu, Fan; Hu, Liu; Xu, Jie; Hou, Jingxin; Zhong, Yixin; Liu, Yun; Wang, Zhigang; Ran, Haitao; Guo, Dajing

doi:10.1016/j.actbio.2022.10.032

Cited by 18 publications

(4 citation statements)

References 38 publications

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“…Given the above findings, we conducted a series of analyses to investigate the downstream mechanisms for its carcinogenetic and risk role. It has been reported that the characteristics of TIME play a crucial role in LIHC initiation and progression [34,35], therefore, the relationship between ZBTB9 and TIME was analyzed, subsequently showing that ZBTB9 had negative relationships with the infiltration of lymphocytes, (Th1, CD8+ T cells), immune checkpoint stimulators (IL6, IL2R) and immune checkpoint inhibitors (CD274, CTLA-4). The correlations between ZBTB9, CD8A, and FOXP3 were preliminarily verified with IHC analysis based on LIHC samples, which showed that high ZBTB9 levels in LIHC patients might be associated with the lower infiltration of CD8+ T cells and Tregs (although the IHC result of CD8A in sample #2 was positive too, the proportion of high positive intensity was still lower than sample #1).…”

Section: Discussionmentioning

confidence: 99%

Identification of ZBTB9 as a potential therapeutic target against dysregulation of tumor cells proliferation and a novel biomarker in Liver Hepatocellular Carcinoma

Zhang

et al. 2022

J Transl Med

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Background Zinc finger and bric-a-brac/tramtrack/broad (ZBTB) domain-containing proteins have been reported to be associated with many tumors’ development. However, in tumor initiation and progression, the role of ZBTB9, one of the protein family, and its prognostic value were yet to be elucidated in Liver Hepatocellular Carcinoma (LIHC). Methods We used R software and online bioinformatics analysis tools such as GEPIA2, cBioPortal, TIMER2, Metascape, UALCAN, STRING, TISIDB, and COSMIC to investigate ZBTB9’s characteristics and function in LIHC, including abnormal expression, carcinogenic role, related signaling pathways and prognostic value. Furthermore, cell experiments (such as formation, wound healing, and transwell assays) and analyses based on clinical samples (such as immunohistochemistry (IHC) and promoter methylation analysis) were conducted to verify pivotal conclusions. Results ZBTB9 was overexpressed in LIHC samples compared to adjacent normal tissues. Through the analysis of genomic alteration and promoter hypomethylation, the clinical value and etiology of abnormal expression of ZBTB9 were preliminarily exlpored. Subsequent evidence showed that it could result in tumor progression and poor prognosis via activating cell cycle, DNA repair, MYC, and KRAS-associated signaling pathways as well as rendering immune dysregulation. After the knockdown of ZBTB9, evidently inhibited capacities of tumor cells proliferation and migration were observed. These results together indicated that ZBTB9 could be a promising prognostic biomarker and had the potential value to offer novel therapeutic targets for LIHC treatment. Conclusions ZBTB9 was identified as a novel biomarker to predict the prognosis and tumor progression in LIHC, and a promising therapeutic target to invert tumor development.

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Section: Discussionmentioning

confidence: 99%

Identification of ZBTB9 as a potential therapeutic target against dysregulation of tumor cells proliferation and a novel biomarker in Liver Hepatocellular Carcinoma

Zhang

et al. 2022

J Transl Med

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“…Nanosized iron oxide NPs with their intrinsic imaging capabilities are exquisitely suitable and even approved (e.g., ferumoxsil) for theranostic applications. pH-degradable bovine serum albumin-functionalized Fe 3 O 4 NPs and loaded with lenvatinib was able to induce vessel normalization and modulate immunosuppressive TME of HCC while Fe 3 O 4 provided in vivo visualization tracking by magnetic resonance imaging (MRI) and also magnetic particle imaging ( 108 ). Combined, nanotechnology has and will continue to maximize the clinical benefits of existing therapies targeting tumor angiogenesis.…”

Section: Nanomaterials Improve Antiangiogenic Cancer Immunotherapymentioning

confidence: 99%

Immunotherapies targeting tumor vasculature: challenges and opportunities

Dianat-Moghadam,

Nedaeinia,

Keshavarz

et al. 2023

Front. Immunol.

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Angiogenesis is a hallmark of cancer biology, and neoadjuvant therapies targeting either tumor vasculature or VEGF signaling have been developed to treat solid malignant tumors. However, these therapies induce complete vascular depletion leading to hypoxic niche, drug resistance, and tumor recurrence rate or leading to impaired delivery of chemo drugs and immune cell infiltration at the tumor site. Achieving a balance between oxygenation and tumor growth inhibition requires determining vascular normalization after treatment with a low dose of antiangiogenic agents. However, monotherapy within the approved antiangiogenic agents’ benefits only some tumors and their efficacy improvement could be achieved using immunotherapy and emerging nanocarriers as a clinical tool to optimize subsequent therapeutic regimens and reduce the need for a high dosage of chemo agents. More importantly, combined immunotherapies and nano-based delivery systems can prolong the normalization window while providing the advantages to address the current treatment challenges within antiangiogenic agents. This review summarizes the approved therapies targeting tumor angiogenesis, highlights the challenges and limitations of current therapies, and discusses how vascular normalization, immunotherapies, and nanomedicine could introduce the theranostic potentials to improve tumor management in future clinical settings.

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“…Multikinase inhibitors inhibit tumor proliferation, angiogenesis, metastasis, and invasion by targeting multiple intracellular and cell surface kinases, including sorafenib, lenvatinib, regorafenib, cabozantinib, and ramucirumab, which have been approved as targeted treatments for HCC [ 5 ]. To date, immunotherapy, particularly immune checkpoint inhibitors (ICIs), has shown efficacy in HCC, but the complex tumor immune microenvironment (TIME) of HCC has somewhat limited the clinical response rate to current mainstream drug therapy and T-cell-based immunotherapy [ 6 , 7 ]. Crosstalk between tumor cells and the surrounding TME has been implicated in tumorigenesis and immune evasion [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Integrating TCGA and Single-Cell Sequencing Data for Hepatocellular Carcinoma: A Novel Glycosylation (GLY)/Tumor Microenvironment (TME) Classifier to Predict Prognosis and Immunotherapy Response

Wu,

Chen,

Zhu

et al. 2024

Metabolites

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The major liver cancer subtype is hepatocellular carcinoma (HCC). Studies have indicated that a better prognosis is related to the presence of tumor-infiltrating lymphocytes (TILs) in HCC. However, the molecular pathways that drive immune cell variation in the tumor microenvironment (TME) remain poorly understood. Glycosylation (GLY)-related genes have a vital function in the pathogenesis of numerous tumors, including HCC. This study aimed to develop a GLY/TME classifier based on glycosylation-related gene scores and tumor microenvironment scores to provide a novel prognostic model to improve the prediction of clinical outcomes. The reliability of the signatures was assessed using receiver operating characteristic (ROC) and survival analyses and was verified with external datasets. Furthermore, the correlation between glycosylation-related genes and other cells in the immune environment, the immune signature of the GLY/TME classifier, and the efficacy of immunotherapy were also investigated. The GLY score low/TME score high subgroup showed a favorable prognosis and therapeutic response based on significant differences in immune-related molecules and cancer cell signaling mechanisms. We evaluated the prognostic role of the GLY/TME classifier that demonstrated overall prognostic significance for prognosis and therapeutic response before treatment, which may provide new options for creating the best possible therapeutic approaches for patients.

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A theranostic metallodrug modulates immunovascular crosstalk to combat immunosuppressive liver cancer

Cited by 18 publications

References 38 publications

Identification of ZBTB9 as a potential therapeutic target against dysregulation of tumor cells proliferation and a novel biomarker in Liver Hepatocellular Carcinoma

Identification of ZBTB9 as a potential therapeutic target against dysregulation of tumor cells proliferation and a novel biomarker in Liver Hepatocellular Carcinoma

Immunotherapies targeting tumor vasculature: challenges and opportunities

Integrating TCGA and Single-Cell Sequencing Data for Hepatocellular Carcinoma: A Novel Glycosylation (GLY)/Tumor Microenvironment (TME) Classifier to Predict Prognosis and Immunotherapy Response

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