Inhibition of ACLY overcomes cancer immunotherapy resistance via polyunsaturated fatty acids peroxidation and cGAS-STING activation

Xiang, Wei; Lv, Hongwei; Xing, Fuxue; Sun, Xiaoyan; Ma, Yue; Wu, Lu; Lv, Guishuai; Zong, Qianni; Wang, Liang; Wu, Zixin; Feng, Qiyu; Yang, Wen; Wang, Hongyang

doi:10.1126/sciadv.adi2465

Cited by 26 publications

(1 citation statement)

References 60 publications

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“…As an intricate malignancy, HCC is characterized by metabolic reprogramming, in which glycolytic and lipid metabolism aberrations can contribute to an immunosuppressive TME. The implicated metabolic regulators include XOR ( 88 ), SCD1 ( 89 ), and ACLY ( 90 ). Finally, transcription factors involved in regulating cancer stemness in HCC, such as SALL4 ( 80 ) and FOXM1 ( 91 ), are known to exert immunosuppressive effects on the TME of HCC.…”

Section: General Concept Of Cancer Stem Cellsmentioning

confidence: 99%

The roles of cancer stem cell-derived secretory factors in shaping the immunosuppressive tumor microenvironment in hepatocellular carcinoma

Muliawan,

Lee

2024

Front. Immunol.

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Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide and has a poor prognosis. Although immune checkpoint inhibitors have entered a new era of HCC treatment, their response rates are modest, which can be attributed to the immunosuppressive tumor microenvironment within HCC tumors. Accumulating evidence has shown that tumor growth is fueled by cancer stem cells (CSCs), which contribute to therapeutic resistance to the above treatments. Given that CSCs can regulate cellular and physical factors within the tumor niche by secreting various soluble factors in a paracrine manner, there have been increasing efforts toward understanding the roles of CSC-derived secretory factors in creating an immunosuppressive tumor microenvironment. In this review, we provide an update on how these secretory factors, including growth factors, cytokines, chemokines, and exosomes, contribute to the immunosuppressive TME, which leads to immune resistance. In addition, we present current therapeutic strategies targeting CSC-derived secretory factors and describe future perspectives. In summary, a better understanding of CSC biology in the TME provides a rational therapeutic basis for combination therapy with ICIs for effective HCC treatment.

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Section: General Concept Of Cancer Stem Cellsmentioning

confidence: 99%

The roles of cancer stem cell-derived secretory factors in shaping the immunosuppressive tumor microenvironment in hepatocellular carcinoma

Muliawan,

Lee

2024

Front. Immunol.

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A prognostic model for hepatocellular carcinoma patients based on polyunsaturated fatty acid‐related genes

Lin,

Li,

et al. 2024

Environmental Toxicology

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ObjectivePolyunsaturated fatty acids (PUFAs) have attracted increasing attention for their role in liver cancer development. The objective of this study is to develop a prognosis prediction model for patients with liver cancer based on PUFA‐related metabolic gene characteristics.MethodTranscriptome data and clinical data were obtained from public databases, while gene sets related to PUFAs were acquired from the gene set enrichment analysis (GSEA) database. Univariate Cox analysis was conducted on the training set, followed by LASSO logistic regression and multivariate Cox analysis on genes with p < .05. Subsequently, the stepwise Akaike information criterion method was employed to construct the model. The high‐ and low‐risk groups were divided based on the median score, and the model's survival prediction ability, diagnostic efficiency, and risk score distribution of clinical features were validated. The above procedures were also validated in the validation set. Immune infiltration levels were evaluated using four algorithms, and the immunotherapeutic potential of different groups was explored. Significant enrichment pathways among different groups were selected based on the GSEA algorithm, and mutation analyses were conducted. Nomogram prognostic models were constructed by incorporating clinical factors and risk scores using univariate and multivariate Cox regression analysis, validated through calibration curves and clinical decision curves. Additionally, sensitivity analysis of drugs was performed to screen potential targeted drugs.ResultsWe constructed a prognostic model comprising eight genes (PLA2G12A, CYP2C8, ABCCI, CD74, CCR7, P2RY4, P2RY6, and YY1). Validation across multiple datasets indicated the model's favorable prognostic prediction ability and diagnostic efficiency, with poorer grading and staging observed in the high‐risk group. Variations in mutation status and pathway enrichment were noted among different groups. Incorporating Stage, Grade, T.Stage, and RiskScore into the nomogram prognostic model demonstrated good accuracy and clinical decision benefits. Multiple immune analyses suggested greater benefits from immunotherapy in the low‐risk group. We predicted multiple targeted drugs, providing a basis for drug development.ConclusionOur study's multifactorial prognostic model across multiple datasets demonstrates good applicability, offering a reliable tool for personalized therapy. Immunological and mutation‐related analyses provide theoretical foundations for further research. Drug predictions offer important insights for future drug development and treatment strategies. Overall, this study provides comprehensive insights into tumor prognosis assessment and personalized treatment planning.

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The Mutual Regulatory Role of Ferroptosis and Immunotherapy in Anti-tumor Therapy

Mao,

Hu,

Zhao

et al. 2024

Apoptosis

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Ferroptosis is a form of cell death that is triggered by the presence of ferrous ions and is characterized by lipid peroxidation induced by these ions. The mechanism exhibits distinct morphological characteristics compared to apoptosis, autophagy, and necrosis. A notable aspect of ferroptosis is its ability to inhibit uncontrolled tumor replication and immortalization, especially in malignant, drug-resistant, and metastatic tumors. Additionally, immunotherapy, a novel therapeutic approach for tumors, has been found to have a reciprocal regulatory relationship with ferroptosis in the context of anti-tumor therapy. A comprehensive analysis of ferroptosis and immunotherapy in tumor therapy is presented in this paper, highlighting the potential for mutual adjuvant effects. Specifically, we discuss the mechanisms underlying ferroptosis and immunotherapy, emphasizing their ability to improve the tumor immune microenvironment and enhance immunotherapeutic effects. Furthermore, we investigate how immunotherapeutic factors may increase the sensitivity of tumor cells to ferroptosis. We aim to provide a prospective view of the promising value of combined ferroptosis and immunotherapy in anticancer therapy by elucidating the mutual regulatory network between each. Graphical Abstract Ferroptosis in the tumor microenvironment involves intricate crosstalk between tumor cells and immune cells. Through MHC recognition, CD8+T cells activate the JAK1/STAT1 pathway in tumor cells, impairing the function of System Xc and reducing GSH and GPX4 expression to promote tumor cell ferroptosis. Additionally, activation of the STAT1-IRF1-ACSL4 pathway could also promote ferroptosis. The blockade of the antioxidant pathway in tumor cells induces ferroptosis, and the released DAMPs could promote DCs maturation through the cGAMP-STING-TBK1 pathway, leading to antigen presentation that activates CD8+T cells. The release of DAMPs also induces the M1-type polarization of macrophages, which exerts an anti-tumor effect. The anti-tumor effects of CD8+T cells could also be enhanced by blocking inhibitory immune checkpoints such as PD-1, PD-L1, CTLA4, and LAG3. Abbreviations: ACSL4, acyl-CoA synthetase long-chain family member 4; BH4, tetrahydrobiopterin; cGAMP, cyclic GMP-AMP; CTLA4, cytotoxic T lymphocyte-associated antigen-4; DCs, dendritic cells; DHFR, dihydrofolate reductase; DHODH, dihydroorotate dehydrogenase; GPX4, glutathione peroxidase 4; GSH, glutathione; HIF-1α, Hypoxia-Inducible Factor-1α;IFN-γ, interferon-γ; IRF1, interferon regulatory factor 1;IRP1, iron regulatory protein 1; JAK 1, janus kinase; LAG3, lymphocyte activation gene 3; MHC, major histocompatibility complex; NRF2, nuclear factor erythroid-2-related factor 2; PD-1, programmed death protein -1; PD-L1, programmed death ligand 1; PUFA, polyunsaturated fatty acid; ROS, reative oxygen species; STAT1, signal transducer and activator of transcription 1; STING, stimulator of interferon genes; TBK1, TANK-binding kinase 1 TLR2, toll-like receptor 2. This diagram was drawn by Figdraw (www.figdraw.com).

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Inhibition of ACLY overcomes cancer immunotherapy resistance via polyunsaturated fatty acids peroxidation and cGAS-STING activation

Cited by 26 publications

References 60 publications

The roles of cancer stem cell-derived secretory factors in shaping the immunosuppressive tumor microenvironment in hepatocellular carcinoma

The roles of cancer stem cell-derived secretory factors in shaping the immunosuppressive tumor microenvironment in hepatocellular carcinoma

A prognostic model for hepatocellular carcinoma patients based on polyunsaturated fatty acid‐related genes

The Mutual Regulatory Role of Ferroptosis and Immunotherapy in Anti-tumor Therapy

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