bims-glucam 2023-01-08 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2023–01–08
fourteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Characterization of metabolic reprogramming by metabolomics in the oncocytic thyroid cancer cell line XTC.UC1.
Glutamine Metabolism Targeting Liposomes for Synergistic Chemosensitization and Starvation Therapy in Ovarian Cancer.
STAT proteins in cancer: orchestration of metabolism.
Carrier-Free Immunotherapeutic Nano-Booster with Dual Synergistic Effects Based on Glutaminase Inhibition Combined with Photodynamic Therapy.
Enhanced glutaminolysis drives hypoxia-induced chemoresistance in pancreatic cancer.
Glutamine mitigates murine burn sepsis by supporting macrophage M2 polarization through repressing the SIRT5-mediated desuccinylation of pyruvate dehydrogenase.
Single-cell and spatial analyses reveal the association between gene expression of glutamine synthetase with the immunosuppressive phenotype of APOE+CTSZ+TAM in cancers.
Lipid droplets and ferroptosis as new players in brain cancer glioblastoma progression and therapeutic resistance.
Understanding gut-liver axis nitrogen metabolism in Fatty Liver Disease.
Small extracellular vesicles in metabolic remodeling of tumor cells: Cargos and translational application.
Early immune pressure makes tumors metabolically stronger.
Mitochondrial uncoupler DNP induces coexistence of dual-state hyper-energy metabolism leading to tumor growth advantage in human glioma xenografts.
Recent progress in the development of nanomaterials targeting multiple cancer metabolic pathways: a review of mechanistic approaches for cancer treatment.
Immunoediting instructs tumor metabolic reprogramming to support immune evasion.

Sci Rep. 2023 Jan 04. 13(1): 149

Characterization of metabolic reprogramming by metabolomics in the oncocytic thyroid cancer cell line XTC.UC1.

Tomomi Kurashige, Mika Shimamura, Koichiro Hamada, Michiko Matsuse, Norisato Mitsutake, Yuji Nagayama.

Oncocytic thyroid cancer is characterized by the aberrant accumulation of abnormal mitochondria in the cytoplasm and a defect in oxidative phosphorylation. We performed metabolomics analysis to compare metabolic reprogramming among the oncocytic and non-oncocytic thyroid cancer cell lines XTC.UC1 and TPC1, respectively, and a normal thyroid cell line Nthy-ori 3-1. We found that although XTC.UC1 cells exhibit higher glucose uptake than TPC1 cells, the glycolytic intermediates are not only utilized to generate end-products of glycolysis, but also diverted to branching pathways such as lipid metabolism and the serine synthesis pathway. Glutamine is preferentially used to produce glutathione to reduce oxidative stress in XTC.UC1 cells, rather than to generate α-ketoglutarate for anaplerotic flux into the TCA cycle. Thus, growth, survival and redox homeostasis of XTC.UC1 cells rely more on both glucose and glutamine than do TPC1 cells. Furthermore, XTC.UC1 cells contained higher amounts of intracellular amino acids which is due to higher expression of the amino acid transporter ASCT2 and enhanced autophagy, thus providing the building blocks for macromolecules and energy production. These metabolic alterations are required for oncocytic cancer cells to compensate their defective mitochondrial function and to alleviate excess oxidative stress.

DOI: https://doi.org/10.1038/s41598-023-27461-2
Acta Biomater. 2022 Dec 31. pii: S1742-7061(22)00865-0. [Epub ahead of print]

Glutamine Metabolism Targeting Liposomes for Synergistic Chemosensitization and Starvation Therapy in Ovarian Cancer.

Xuzi Cai, Si Shi, Gui Chen, Min Zhong, Yuanyuan Yang, Ziyi Mai, Yang Tian, Jinxiu Tan, Lijuan He, Chunhui Cui, Zhiqiang Yu, Xuefeng Wang.

  Platinum-based chemotherapy is a first-line therapeutic regimen against ovarian cancer (OC); however, the therapeutic potential is always reduced by glutamine metabolism. Herein, a valid strategy of inhibiting glutamine metabolism was proposed to cause tumor starvation and chemosensitization. Specifically, reactive oxygen species-responsive liposomes were developed to co-deliver cisplatin (CDDP) and bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) [C@B LPs]. The C@B LPs induced effective tumor cell starvation and significantly sensitized OC cells to CDDP by reducing glutathione generation to prevent CDDP detoxification, suppressing ATP production to avoid CDDP efflux, hindering nucleotide synthesis to aggravate DNA damage induced by CDDP, and blocking mammalian target of rapamycin (mTOR) signaling to promote cell apoptosis. More importantly, C@B LPs remarkably inhibited tumor growth in vivo and reduced the side effects. Taken together, this study provided a successful strategy of synergistic chemosensitization and starvation therapy escalating the rate of therapeutic success in OCs. STATEMENT OF SIGNIFICANCE: : This work proposed a valid strategy of inhibiting glutamine metabolism to cause tumor starvation and chemosensitization. Specifically, ROS-responsive liposomes were developed to co-deliver cisplatin CDDP and BPTES [C@B LPs]. The C@B LPs induced effective tumor cell starvation and significantly sensitized OC cells to cisplatin by reducing glutathione generation to prevent cisplatin detoxification, suppressing ATP production to avoid cisplatin efflux, hindering nucleotide synthesis to aggravate DNA damage induced by cisplatin, and blocking mTOR signaling to promote cell apoptosis. More importantly, C@B LPs remarkably inhibited tumor growth in vivo and reduced the side effects. Taken together, this study provided a successful strategy of synergistic chemosensitization and starvation therapy escalating the rate of therapeutic success in OCs.

Keywords:  chemotherapy; cisplatin sensitization; glutamine metabolism; ovarian cancer; starvation therapy

DOI:  https://doi.org/10.1016/j.actbio.2022.12.052
Nat Rev Cancer. 2023 Jan 03.

STAT proteins in cancer: orchestration of metabolism.

Yi-Jia Li, Chunyan Zhang, Antons Martincuks, Andreas Herrmann, Hua Yu.

Reprogrammed metabolism is a hallmark of cancer. However, the metabolic dependency of cancer, from tumour initiation through disease progression and therapy resistance, requires a spectrum of distinct reprogrammed cellular metabolic pathways. These pathways include aerobic glycolysis, oxidative phosphorylation, reactive oxygen species generation, de novo lipid synthesis, fatty acid β-oxidation, amino acid (notably glutamine) metabolism and mitochondrial metabolism. This Review highlights the central roles of signal transducer and activator of transcription (STAT) proteins, notably STAT3, STAT5, STAT6 and STAT1, in orchestrating the highly dynamic metabolism not only of cancer cells but also of immune cells and adipocytes in the tumour microenvironment. STAT proteins are able to shape distinct metabolic processes that regulate tumour progression and therapy resistance by transducing signals from metabolites, cytokines, growth factors and their receptors; defining genetic programmes that regulate a wide range of molecules involved in orchestration of metabolism in cancer and immune cells; and regulating mitochondrial activity at multiple levels, including energy metabolism and lipid-mediated mitochondrial integrity. Given the central role of STAT proteins in regulation of metabolic states, they are potential therapeutic targets for altering metabolic reprogramming in cancer.

DOI: https://doi.org/10.1038/s41568-022-00537-3
ACS Nano. 2023 Jan 03.

Carrier-Free Immunotherapeutic Nano-Booster with Dual Synergistic Effects Based on Glutaminase Inhibition Combined with Photodynamic Therapy.

Ziyi Mai, Jing Zhong, Jiasi Zhang, Guimei Chen, Yan Tang, Wen Ma, Guang Li, Zhenzhen Feng, Fangzhou Li, Xing-Jie Liang, Yuanyuan Yang, Zhiqiang Yu.

  The immunotherapeutic effect elicited by photodynamic therapy (PDT) is attenuated by tumor defense mechanisms associated with glutamine metabolism, including the metabolic regulation of redox homeostasis and the limitation of the immunosuppressive tumor microenvironment (ITM). Herein, a carrier-free immunotherapeutic nanobooster C9SN with dual synergistic effects was constructed by the self-assembly of glutaminase (GLS) inhibitor compound 968 (C968) and photosensitizer Chlorin e6. C968-mediated GSH deprivation through inhibiting glutamine metabolism prevented PDT-generated reactive oxygen species from being annihilated by GSH, amplifying intracellular oxidative stress, which caused severe cell death and also enhanced the immunogenic cell death (ICD) effect. In addition, genome-wide analysis was carried out using RNA-sequencing to evaluate the changes in cell transcriptome induced by amplifying oxidative stress. Thereafter, neoantigens generated by the enhanced ICD effect promoted the maturation of dendritic cells, thereby recruiting and activating cytotoxic T lymphocytes (CTLs). Meanwhile, C9SN remodeled the ITM by blocking glutamine metabolism to polarize M2-type tumor-associated macrophages (TAMs) into M1-type TAMs, which further recruited and activated the CTLs. Ultimately, this immunotherapeutic nanobooster suppressed primary and distant tumors. This "kill two birds with one stone" strategy would shed light on enhancing tumor immunogenicity and alleviating tumor immunosuppression to improve the immunotherapeutic effect of PDT.

Keywords:  carrier-free nanomedicine; glutamine metabolism; immunogenicity; macrophage polarization; tumor immunotherapy

DOI:  https://doi.org/10.1021/acsnano.2c11037
Cancer Res. 2023 Jan 03. pii: CAN-22-2045. [Epub ahead of print]

Enhanced glutaminolysis drives hypoxia-induced chemoresistance in pancreatic cancer.

Seung Joon Park, Hee Chan Yoo, Eunyong Ahn, Enzhi Luo, Yeabeen Kim, Yulseung Sung, Ya Chun Yu, Kibum Kim, Do Sik Min, Hee Seung Lee, Geum-Sook Hwang, TaeJin Ahn, Junjeong Choi, Seungmin Bang, Jung Min Han.

Pancreatic ductal adenocarcinoma (PDAC) exhibits severe hypoxia, which is associated with chemoresistance and worse patient outcome. It has been reported that hypoxia induces metabolic reprogramming in cancer cells. However, it is not well known whether metabolic reprogramming contributes to hypoxia. Here, we established that increased glutamine catabolism is a fundamental mechanism inducing hypoxia, and thus chemoresistance, in PDAC cells. An extracellular matrix (ECM) component-based in vitro 3D cell printing model with patient-derived PDAC cells that recapitulates the hypoxic status in PDAC tumors showed that chemoresistant PDAC cells exhibit markedly enhanced glutamine catabolism compared to chemoresponsive PDAC cells. The augmented glutamine metabolic flux increased the oxygen consumption rate via mitochondrial oxidative phosphorylation (OXPHOS), promoting hypoxia and hypoxia-induced chemoresistance. Targeting glutaminolysis relieved hypoxia and improved chemotherapy efficacy in vitro and in vivo. This work suggests that targeting the glutaminolysis-OXPHOS-hypoxia axis is a novel therapeutic target for treating patients with chemoresistant PDAC.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-2045
Burns Trauma. 2022 ;10 tkac041

Glutamine mitigates murine burn sepsis by supporting macrophage M2 polarization through repressing the SIRT5-mediated desuccinylation of pyruvate dehydrogenase.

Yuanfeng Zhu, Xiaoli Chen, Yongling Lu, Lin Xia, Shijun Fan, Qianying Huang, Xin Liu, Xi Peng.

   Background: Alternative (M2)-activated macrophages drive the anti-inflammatory response against sepsis, a leading cause of death in patients suffering from burn injury. Macrophage M2 polarization is intrinsically linked with dominant oxidative phosphorylation (OXPHOS). Glutamine serves as a major anaplerotic source to fuel OXPHOS, but it remains unknown whether glutamine can modulate metabolic checkpoints in OXPHOS that favour M2 polarization. The study aims to explore whether glutamine essentially supports M2 polarization in IL-4-stimulated murine macrophages by sustaining the activity of PDH and whether glutamine augments macrophage M2 polarization and thus alleviates inflammation and organ injury in a murine burn sepsis model.
Methods: To understand how glutamine promotes M2 activation in interleukin (IL-4)-treated murine macrophages, we detected glutamine-dependent M2 polarization and its relationship with the pyruvate dehydrogenase (PDH) complex by RT-PCR, flow cytometry and western blot. To explore how glutamine modulates PDH activity and thus supports M2 polarization, we compared the expression, phosphorylation and succinylation status of PDHA1 and then examined sirtuin SIRT5-dependent desuccinylation of PDHA1 and the effects of SIRT5 overexpression on M2 polarization by RT-PCR, flow cytometry and western blot. To determine whether glutamine or its metabolites affect M2 polarization, macrophages were cocultured with metabolic inhibitors, and then SIRT5 expression and M2 phenotype markers were examined by RT-PCR, flow cytometry and western blot. Finally, to confirm the in vivo effect of glutamine, we established a burn sepsis model by injecting Pseudomonas aeruginosa into burn wounds and observing whether glutamine alleviated proinflammatory injuries by RT-PCR, flow cytometry, western blot, immunofluorescent staining, hematoxylin-eosin staining and enzyme-linked immuno sorbent assay.
Results: We showed that consumption of glutamine supported M2 activation in IL-4-treated murine macrophages by upregulating the activity of PDH. Mechanistically, glutamine did not affect the expression or alter the phosphorylation status of PDHA1 but instead downregulated the expression of SIRT5 and repressed SIRT5-dependent desuccinylation on PDHA1, which in turn recovered PDH activity and supported M2 polarization. This effect was implemented by its secondary metabolite α-ketoglutarate (αKG) rather than glutamine itself. Finally, we demonstrated that glutamine promoted macrophage M2 polarization in a murine burn sepsis model, thereby repressing excessive inflammation and alleviating organ injury in model mice.
Conclusions: Glutamine mitigates murine burn sepsis by essentially supporting macrophage M2 polarization, with a mechanism involving the repression of the SIRT5-mediated desuccinylation of pyruvate dehydrogenase that replenishes OXPHOS and sustains M2 macrophages.

Keywords:  Burn, Sepsis; Desuccinylation; Glutamine; Macrophages polarization; PDH; SIRT5

DOI:  https://doi.org/10.1093/burnst/tkac041
Mol Oncol. 2023 Jan 01.

Single-cell and spatial analyses reveal the association between gene expression of glutamine synthetase with the immunosuppressive phenotype of APOE+CTSZ+TAM in cancers.

Jinfen Wei, Wenqi Yu, Juanzhi Chen, Guanda Huang, Lingjie Zhang, Zixi Chen, Meiling Hu, Xiaocheng Gong, Hongli Du.

  An immunosuppressive state is regulated by various factors in the tumor microenvironment (TME), including, but not limited to, metabolic plasticity of immunosuppressive cells and cytokines secreted by these cells. We used single-cell RNA sequencing (scRNA-seq) data and applied single-cell flux estimation analysis to characterize the link between metabolism and cellular function within the hypoxic TME of colorectal (CRC) and lung cancer (LC). In terms of metabolic heterogeneity, we found myeloid cells potentially inclined to accumulate glutamine, but tumor cells inclined to accumulate glutamate. In particular, we uncovered a tumor-associated macrophage (TAM) subpopulation, APOE+CTSZ+TAM, that was present in high proportions in tumor samples and exhibited immunosuppressive characteristics through upregulating the expression of anti-inflammatory genes. The proportion of APOE+CTSZ+TAM and regulatory T cells (Treg) were positively correlated across CRC scRNA-seq samples. APOE+CTSZ+TAM potentially interacted with Treg via CXCL16-CCR6 signals, as seen by ligand-receptor interactions analysis. Notably, glutamate-to-glutamine metabolic flux score and glutamine synthetase (GLUL) expression were uniquely higher in APOE+CTSZ+TAM, compared with other cell types within the TME. GLUL expression in macrophages was positively correlated with anti-inflammatory score and was higher in high-grade and invasive tumor samples. Moreover, spatial transcriptome (ST) and multiplex immunofluorescence (mIF) staining of samples showed that APOE+CTSZ+TAM and Treg potentially colocalized in the tissue sections from CRC clinical samples. These results highlight the specific role and metabolic characteristic of the APOE+CTSZ+TAM subpopulation and provide a new perspective for macrophage-subcluster-targeted therapeutic interventions or metabolic-checkpoint-based cancer therapies.

Keywords:  Colorectal cancer; GLUL; Immunosuppressive microenvironment; Metabolism; Single-cell and spatial RNA-seq; Tumor-associated macrophages

DOI:  https://doi.org/10.1002/1878-0261.13373
Front Oncol. 2022 ;12 1085034

Lipid droplets and ferroptosis as new players in brain cancer glioblastoma progression and therapeutic resistance.

Ayenachew Bezawork-Geleta, James Dimou, Matthew J Watt.

  A primary brain tumor glioblastoma is the most lethal of all cancers and remains an extremely challenging disease. Apparent oncogenic signaling in glioblastoma is genetically complex and raised at any stage of the disease's progression. Many clinical trials have shown that anticancer drugs for any specific oncogene aberrantly expressed in glioblastoma show very limited activity. Recent discoveries have highlighted that alterations in tumor metabolism also contribute to disease progression and resistance to current therapeutics for glioblastoma, implicating an alternative avenue to improve outcomes in glioblastoma patients. The roles of glucose, glutamine and tryptophan metabolism in glioblastoma pathogenesis have previously been described. This article provides an overview of the metabolic network and regulatory changes associated with lipid droplets that suppress ferroptosis. Ferroptosis is a newly discovered type of nonapoptotic programmed cell death induced by excessive lipid peroxidation. Although few studies have focused on potential correlations between tumor progression and lipid droplet abundance, there has recently been increasing interest in identifying key players in lipid droplet biology that suppress ferroptosis and whether these dependencies can be effectively exploited in cancer treatment. This article discusses how lipid droplet metabolism, including lipid synthesis, storage, and use modulates ferroptosis sensitivity or tolerance in different cancer models, focusing on glioblastoma.

Keywords:  brain cancer; cell death; glioma; lipid droplet (LD); lipids; metabolism; therapeutic vulnerabilities

DOI:  https://doi.org/10.3389/fonc.2022.1085034
Front Endocrinol (Lausanne). 2022 ;13 1058101

Understanding gut-liver axis nitrogen metabolism in Fatty Liver Disease.

Teresa C Delgado, Javier de Las Heras, María L Martínez-Chantar.

  The homeostasis of the most important nitrogen-containing intermediates, ammonia and glutamine, is a tightly regulated process in which the gut-liver axis plays a central role. Several studies revealed that nitrogen metabolism is altered in Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD), a consensus-driven novel nomenclature for Non-Alcoholic Fatty Liver Disease (NAFLD), the most common chronic liver disease worldwide. Both increased ammonia production by gut microbiota and decreased ammonia hepatic removal due to impaired hepatic urea cycle activity or disrupted glutamine synthetase activity may contribute to hepatic ammonia accumulation underlying steatosis, which can eventually progress to hyperammonemia in more advanced stages of steatohepatitis and overt liver fibrosis. Furthermore, our group recently showed that augmented hepatic ammoniagenesis via increased glutaminase activity and overexpression of the high activity glutaminase 1 isoenzyme occurs in Fatty Liver Disease. Overall, the improved knowledge of disrupted nitrogen metabolism and metabolic miscommunication between the gut and the liver suggests that the reestablishment of altered gut-liver axis nitrogenous balance is an appealing and attractive therapeutic approach to tackle Fatty Liver Disease, a growing and unmet health problem.

Keywords:  Fatty Liver Disease; Gut-liver axis; ammonia; glutaminase; glutamine; nitrogen metabolism; urea cycle

DOI:  https://doi.org/10.3389/fendo.2022.1058101
Front Pharmacol. 2022 ;13 1009952

Small extracellular vesicles in metabolic remodeling of tumor cells: Cargos and translational application.

Hao Yang, Jingyi Wang, Gang Huang.

  Warburg effect is characterized by excessive consumption of glucose by the tumor cells under both aerobic and hypoxic conditions. This metabolic reprogramming allows the tumor cells to adapt to the unique microenvironment and proliferate rapidly, and also promotes tumor metastasis and therapy resistance. Metabolic reprogramming of tumor cells is driven by the aberrant expression and activity of metabolic enzymes, which results in the accumulation of oncometabolites, and the hyperactivation of intracellular growth signals. Recent studies suggest that tumor-associated metabolic remodeling also depends on intercellular communication within the tumor microenvironment (TME). Small extracellular vesicles (sEVs), also known as exosomes, are smaller than 200 nm in diameter and are formed by the fusion of multivesicular bodies with the plasma membrane. The sEVs are instrumental in transporting cargoes such as proteins, nucleic acids or metabolites between the tumor, stromal and immune cells of the TME, and are thus involved in reprogramming the glucose metabolism of recipient cells. In this review, we have summarized the biogenesis and functions of sEVs and metabolic cargos, and the mechanisms through they drive the Warburg effect. Furthermore, the potential applications of targeting sEV-mediated metabolic pathways in tumor liquid biopsy, imaging diagnosis and drug development have also been discussed.

Keywords:  drug development; exosomes; glycolysis; liquid biopsy; small extracellular vesicles; tumor metabolism; warburg effect

DOI:  https://doi.org/10.3389/fphar.2022.1009952
Cell Metab. 2023 Jan 03. pii: S1550-4131(22)00546-0. [Epub ahead of print]35(1): 3-5

Early immune pressure makes tumors metabolically stronger.

Sujing Yuan, Hongbo Chi.

Metabolic communication in the tumor microenvironment underscores tumor-immune interactions and affects anti-tumor immunity, yet cell-extrinsic signals driving tumor metabolic remodeling are incompletely understood. In this issue, Tsai et al. show that during initial tumorigenesis, T cell-derived IFNγ triggers STAT3 activation and c-Myc-dependent alterations of tumor cell metabolism, which potentiates immune evasion.

DOI: https://doi.org/10.1016/j.cmet.2022.12.009
Front Oncol. 2022 ;12 1063531

Mitochondrial uncoupler DNP induces coexistence of dual-state hyper-energy metabolism leading to tumor growth advantage in human glioma xenografts.

Yogesh Rai, Saurabh Singh, Sanjay Pandey, Dhananjay Sah, Raj Kumar Sah, B G Roy, Bilikere S Dwarakanath, Anant Narayan Bhatt.

   Introduction: Cancer bioenergetics is an essential hallmark of neoplastic transformation. Warburg postulated that mitochondrial OXPHOS is impaired in cancer cells, leading to aerobic glycolysis as the primary metabolic pathway. However, mitochondrial function is altered but not entirely compromised in most malignancies, and that mitochondrial uncoupling is known to increase the carcinogenic potential and modifies treatment response by altering metabolic reprogramming. Our earlier study showed that transient DNP exposure increases glycolysis in human glioma cells (BMG-1). The current study investigated the persistent effect of DNP on the energy metabolism of BMG-1 cells and its influence on tumor progression in glioma xenografts.
Methods: BMG-1 cells were treated with 2,4-dinitrophenol (DNP) in-vitro, to establish the OXPHOS-modified (OPM-BMG) cells. Further cellular metabolic characterization was carried out in both in-vitro cellular model and in-vivo tumor xenografts to dissect the role of metabolic adaptation in these cells and compared them with their parental phenotype.
Results and Discussion: Chronic exposure to DNP in BMG-1 cells resulted in dual-state hyper-energy metabolism with elevated glycolysis++ and OXPHOS++ compared to parental BMG-1 cells with low glycolysis+ and OXPHOS+. Tumor xenograft of OPM-BMG cells showed relatively increased tumor-forming potential and accelerated tumor growth in nude mice. Moreover, compared to BMG-1, OPM-BMG tumor-derived cells also showed enhanced migration and invasion potential. Although mitochondrial uncouplers are proposed as a valuable anti-cancer strategy; however, our findings reveal that prolonged exposure to uncouplers provides tumor growth advantage over the existing glioma phenotype that may lead to poor clinical outcomes.

Keywords:  Warburg effect; cancer cell metabolism; glioma tumor; oxidative phosphorylation; tumor bioenergetics

DOI:  https://doi.org/10.3389/fonc.2022.1063531
Drug Deliv. 2023 Dec;30(1): 1-18

Recent progress in the development of nanomaterials targeting multiple cancer metabolic pathways: a review of mechanistic approaches for cancer treatment.

Ling Zhang, Bing-Zhong Zhai, Yue-Jin Wu, Yin Wang.

  Cancer is a very heterogeneous disease, and uncontrolled cell division is the main characteristic of cancer. Cancerous cells need a high nutrition intake to enable aberrant growth and survival. To do so, cancer cells modify metabolic pathways to produce energy and anabolic precursors and preserve redox balance. Due to the importance of metabolic pathways in tumor growth and malignant transformation, metabolic pathways have also been given promising perspectives for cancer treatment, providing more effective treatment strategies, and target-specific with minimum side effects. Metabolism-based therapeutic nanomaterials for targeted cancer treatment are a promising option. Numerous types of nanoparticles (NPs) are employed in the research and analysis of various cancer therapies. The current review focuses on cutting-edge strategies and current cancer therapy methods based on nanomaterials that target various cancer metabolisms. Additionally, it highlighted the primacy of NPs-based cancer therapies over traditional ones, the challenges, and the future potential.

Keywords:  Cancer metabolisms; anticancer drugs; drug delivery; nanomedicine; nanoparticles

DOI:  https://doi.org/10.1080/10717544.2022.2144541
Cell Metab. 2023 Jan 03. pii: S1550-4131(22)00540-X. [Epub ahead of print]35(1): 118-133.e7

Immunoediting instructs tumor metabolic reprogramming to support immune evasion.

Chin-Hsien Tsai, Yu-Ming Chuang, Xiaoyun Li, Yi-Ru Yu, Sheue-Fen Tzeng, Shao Thing Teoh, Katherine E Lindblad, Mario Di Matteo, Wan-Chen Cheng, Pei-Chun Hsueh, Kung-Chi Kao, Hana Imrichova, Likun Duan, Hector Gallart-Ayala, Pei-Wen Hsiao, Massimiliano Mazzone, Julijana Ivanesevic, Xiaojing Liu, Karin E de Visser, Amaia Lujambio, Sophia Y Lunt, Susan M Kaech, Ping-Chih Ho.

  Immunoediting sculpts immunogenicity and thwarts host anti-tumor responses in tumor cells during tumorigenesis; however, it remains unknown whether metabolic programming of tumor cells can be guided by immunosurveillance. Here, we report that T cell-mediated immunosurveillance in early-stage tumorigenesis instructs c-Myc upregulation and metabolic reprogramming in tumor cells. This previously unexplored tumor-immune interaction is controlled by non-canonical interferon gamma (IFNγ)-STAT3 signaling and supports tumor immune evasion. Our findings uncover that immunoediting instructs deregulated bioenergetic programs in tumor cells to empower them to disarm the T cell-mediated immunosurveillance by imposing metabolic tug-of-war between tumor and infiltrating T cells and forming the suppressive tumor microenvironment.

Keywords:  IFNγ; Myc; STAT3; immunoediting; immunosurveillance; tumor immunology

DOI:  https://doi.org/10.1016/j.cmet.2022.12.003