Tumor Metabolic Reprogramming Research Articles

Bioinformatics and Experimental Study revealed LINC00982/ miR-183-5p/ABCA8 Axis Suppresses LUAD Progression.

Lung adenocarcinoma (LUAD) is a major health challenge worldwide with an undesirable prognosis. LINC00982 has been implicated as a tumor suppressor in diverse human cancers; however, its role in LUAD has not been fully characterized. Expression level and prognostic value of LINC00982 were investigated in pan-cancer and lung cancer from The Cancer Genome Atlas (TCGA) project. Differential expression analysis based on the LINC00982 expression level was performed in LUAD followed by gene set enrichment analysis (GSEA) and functional enrichment analyses. The association between LINC00982 expression and tumor immune microenvironment characteristics was evaluated. A potential ceRNA regulatory axis was identified and experimentally validated. We found that LINC00982 expression was downregulated and correlated with poor prognosis in LUAD. Enrichment analyses revealed that LINC00982 could inhibit DNA damage repair and cell proliferation, but enhance tumor metabolic reprogramming. We identified a competing endogenous RNA network involving LINC00982, miR-183-5p, and ATP-binding cassette subfamily A member 8 (ABCA8). Luciferase assays confirmed that miR-183-5p can interact with LINC00982 and ABCA8. Forced miR-183-5p expression reduced LINC00982 transcript levels and suppressed ABCA8 expression. Our findings revealed the LINC00982/miR-183-5p/ABCA8 axis as a potential therapeutic target in LUAD.

Choline metabolism reprogramming mediates an immunosuppressive microenvironment in non-small cell lung cancer (NSCLC) by promoting tumor-associated macrophage functional polarization and endothelial cell proliferation

IntroductionLung cancer is a prevalent malignancy globally, and immunotherapy has revolutionized its treatment. However, resistance to immunotherapy remains a challenge. Abnormal cholinesterase (ChE) activity and choline metabolism are associated with tumor oncogenesis, progression, and poor prognosis in multiple cancers. Yet, the precise mechanism underlying the relationship between ChE, choline metabolism and tumor immune microenvironment in lung cancer, and the response and resistance of immunotherapy still unclear.MethodsFirstly, 277 advanced non-small cell lung cancer (NSCLC) patients receiving first-line immunotherapy in Sun Yat-sen University Cancer Center were enrolled in the study. Pretreatment and the alteration of ChE after 2 courses of immunotherapy and survival outcomes were collected. Kaplan–Meier survival and cox regression analysis were performed, and nomogram was conducted to identify the prognostic and predicted values. Secondly, choline metabolism-related genes were screened using Cox regression, and a prognostic model was constructed. Functional enrichment analysis and immune microenvironment analysis were also conducted. Lastly, to gain further insights into potential mechanisms, single-cell analysis was performed.ResultsFirstly, baseline high level ChE and the elevation of ChE after immunotherapy were significantly associated with better survival outcomes for advanced NSCLC. Constructed nomogram based on the significant variables from the multivariate Cox analysis performed well in discrimination and calibration. Secondly, 4 choline metabolism-related genes (MTHFD1, PDGFB, PIK3R3, CHKB) were screened and developed a risk signature that was found to be related to a poorer prognosis. Further analysis revealed that the choline metabolism-related genes signature was associated with immunosuppressive tumor microenvironment, immune escape and metabolic reprogramming. scRNA-seq showed that MTHFD1 was specifically distributed in tumor-associated macrophages (TAMs), mediating the differentiation and immunosuppressive functions of macrophages, which may potentially impact endothelial cell proliferation and tumor angiogenesis.ConclusionOur study highlights the discovery of ChE as a prognostic marker in advanced NSCLC, suggesting its potential for identifying patients who may benefit from immunotherapy. Additionally, we developed a prognostic signature based on choline metabolism-related genes, revealing the correlation with the immunosuppressive microenvironment and uncovering the role of MTHFD1 in macrophage differentiation and endothelial cell proliferation, providing insights into the intricate workings of choline metabolism in NSCLC pathogenesis.

Multi-omics study on the molecular mechanism of anlotinib in regulating tumor metabolism

Anlotinib, an orally administered small molecule inhibitor of receptor tyrosine kinases (RTKs), exerts significant anti-angiogenic and vascular normalization effects. However, the mechanisms underlying its involvement in tumor metabolic reprogramming are still unclear. This study aims to investigate the distribution and expression levels of metabolites within tumors after anlotinib treatment using spatial metabolomics analysis. Subsequently, by integrating the transcriptomics and proteomics analyses, we identified that anlotinib treatment primarily modulated four metabolic pathways, including taurine and hypotaurine metabolism, steroid synthesis, pentose phosphate pathway, and lipid biosynthesis. This regulation significantly influenced the metabolic levels of compounds such as sulfonic acids, cholesterol, inositol phosphate pyrophosphate, and palmitoyl-CoA in the tumor, thereby impacting tumor initiation and progression. This study provides potential metabolic biomarkers for anlotinib treatment in tumors.

Single-cell analysis revealing the metabolic landscape of prostate cancer.

Tumor metabolic reprogramming is a hallmark of cancer development, and targeting metabolic vulnerabilities has been proven to be an effective approach for castration-resistant prostate cancer (CRPC) treatment. Nevertheless, treatment failure inevitably occurs, largely due to cellular heterogeneity, which cannot be deciphered by traditional bulk sequencing techniques. By employing computational pipelines for single-cell RNA sequencing, we demonstrated that epithelial cells within the prostate are more metabolically active and plastic than stromal cells. Moreover, we identified that neuroendocrine (NE) cells tend to have high metabolic rates, which might explain the high demand for nutrients and energy exhibited by neuroendocrine prostate cancer (NEPC), one of the most lethal variants of prostate cancer (PCa). Additionally, we demonstrated through computational and experimental approaches that variation in mitochondrial activity is the greatest contributor to metabolic heterogeneity among both tumor cells and nontumor cells. These results establish a detailed metabolic landscape of PCa, highlight a potential mechanism of disease progression, and emphasize the importance of future studies on tumor heterogeneity and the tumor microenvironment from a metabolic perspective.

High expression of NXPH4 correlates with poor prognosis, metabolic reprogramming, and immune infiltration in colon adenocarcinoma.

Colon adenocarcinoma (COAD) is a prevalent gastrointestinal malignant disease with high mortality rate, and identification of novel prognostic biomarkers and therapeutic targets is urgently needed. Although neurexophilin 4 (NXPH4) has been investigated in several tumors, its role in COAD remains unclear. The aim of this study was to explore the prognostic value and potential functions of NXPH4 in COAD. The expression of NXPH4 in COAD were analyzed using The Cancer Genome Atlas (TCGA) and datasets from the Gene Expression Omnibus (GEO) database. The prognostic value of NXPH4 was determined using Kaplan-Meier analysis and Cox regression analysis. To investigate the possible mechanism underlying the role of NXPH4 in COAD, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) were employed. The correlation between NXPH4 expression and immune cell infiltration levels was examined thorough single-sample gene set enrichment analysis (ssGSEA). Furthermore, the competing endogenous RNA (ceRNA) regulatory network that may be involved in NXPH4 in COAD was predicted and constructed through a variety of databases. NXPH4 expression was significantly higher in COAD tissue compared with normal colon tissues. Meanwhile, high expression of NXPH4 was associated with poor prognosis in COAD patients. GO-KEGG and GSEA analyses indicated that NXPH4 was associated with glycolysis and hypoxia pathway, and may promote COAD progression and metastasis by modulating metabolic reprogramming. ssGSEA analysis demonstrated that NXPH4 expression also associated with immune infiltration. Furthermore, we identified various microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) as upstream regulators of NXPH4 in COAD. The present study revealed that high expression of NXPH4 is associated with tumor progression, metabolic reprogramming, and immune infiltration. These findings suggest that NXPH4 could serve as a reliable prognostic biomarker and a promising therapeutic target in COAD.

Pan-cancer analyses reveal genomics and clinical outcome association of the fatty acid oxidation regulators in cancer

BackgroundFatty acid oxidation (FAO) is considered to play a vital part in tumor metabolic reprogramming. But the comprehensive description of FAO dysregulation in tumors has not been unknown. MethodsWe obtained FAO genes, RNA-seq data and clinical information from the Msigdb, TCGA and GTEx databases. We assessed their prognosis value using univariate cox analysis, survival analysis and Kaplan-Meier curve. We determined the function of FAO genes using gene set variation analysis. The correlation analysis was calculated by corrplot R package. Immunotherapy response was assessed through TIDE scores. The protein expression levels of FAO genes were validated using immunohistochemistry (IHC). ResultsThe FAO scores were highest in COAD but lowest in PCPG. FAO scores were significantly associated with the prognosis of some cancers in OS, DSS, DFI and PFI. Besides, gene set variation analysis identified that FAO scores were related to immune-related pathways, and immune infiltration analysis showed FAO scores were positively related to cancer-associated fibroblasts and various immune-related genes. TIDE scores were significantly decreased in ACC, CHOL, ESCA, GBM, LAML, SARC, SKCM and THCA compared with normal samples, while it was significantly increased in BLCA, LUAD, LUSC, PCPG, PRAD and STAD. Besides, most FAO genes were downregulated in pan-cancer compared with normal samples. Moreover, we found copy number variation (CNV) of FAO genes played a positive role in their mRNA expression, while methylation was negative. We determined FAO genes were closely related to some drugs in pan-cancer. ConclusionsFAO score is a novel and promising factor for predicting outcomes.

Abstract 7235: Exosome-mediated delivery of siRNA against NRF2 for treatment of lung cancer

Abstract Nuclear factor erythroid 2-related factor 2 (NRF2) activation is the third most common genetic event in lung adenocarcinomas (25%), primarily induced by loss of function mutations in its master regulator, KEAP1. NRF2 is a key modulator of tumor growth and metabolic reprogramming, resulting in resistance to traditional chemotherapeutics. Due to its role in modulating oxidative stress, sustained NRF2 overexpression promotes disease progression, particularly in lung cancer. This study demonstrates the effective knockdown of NRF2 expression by small interfering RNA (siRNA) delivered via a nanoplatform based on bovine colostrum exosomes to lung cancer cells, both in vitro and in vivo, resulting in inhibition of proliferation and disease progression. Bovine colostrum is an abundant source of exosomes. Here we present a novel exosome-polyethyleneimine matrix (EPM) to deliver therapeutic siRNA targeting NRF2 expression (siNRF2). Specific delivery of the EPM to tumors was further enhanced via folic acid (FA) functionalization, targeting folate receptors highly expressed on lung tumor cells. Exosomes were isolated from standardized colostrum powder through rehydration and differential centrifugation, and characterized by size, polydispersity index (pdi) and surface charge by Zetasizer, and the presence of surface protein markers by Western blot. siNRF2 was loaded onto the EPM, and the resultant EPM-siNRF2 complex was harvested by PEG precipitation. Entrapment efficiency was determined using 5’-32P-labeled siRNA as a tracer. The gene knockdown efficiency of EPM-siNRF2 was assessed in lung cancer (A549) cells by Western blot and the therapeutic effect of target knockdown in vitro was confirmed by analyzing the corresponding modulation in downstream targets of NRF2. The anti-tumor effect was then evaluated using both subcutaneous and orthotropic lung tumor models in immunocompromised mice. The EPM exhibited high entrapment efficiency (>90%) of siNRF2 (up to 20 μg) and protected entrapped siRNA from enzymatic degradation upon exposure to RNases. EPM-siNRF2 dose dependently decreased NRF2 expression in A549 lung cancer cells. When formulated with FA-functionalized exosomes, EPM-siNRF2 inhibited subcutaneous and orthotropic lung tumors in mice by over 57% (p<0.01) and 84% (p<0.001), respectively. Mice treated with FA-EPM-siNRF2 showed decreased levels of NRF2 in tumor tissue, but not in the adjacent lung, indicating FA-mediated targeted delivery. This bovine colostrum exosome based EPM technology showcases high efficiency in gene knockdown and lung tumor inhibition, providing a promising nanoplatform for delivering nucleic acid therapeutics to the tumor site. Funding: Supported from the NIH grant R44 CA-221487, 3P Biotechnology Contract and, in part, Agnes Brown Duggan Endowment. Keywords: Bovine colostrum, Exosomes, NRF2, siRNA, Lung cancer. Citation Format: Raghuram Kandimalla, Margaret Wallen, Jeyaprakash Jeyabalan, Disha N. Moholkar, Wendy Spencer, Ramesh C. Gupta, Farrukh Aqil. Exosome-mediated delivery of siRNA against NRF2 for treatment of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7235.

Abstract 250: Sex differences in cancer stemness among individuals with early onset colorectal cancer

Abstract Since 1990, the overall incidence and mortality rates of late onset colorectal cancer (LOCRC ≥50 years) have been decreasing due to improvements in access to screening and available treatment options. However, the rates for early onset CRC (EOCRC ≤ 49 years) have steadily increased in men and women. Less than 30% of LOCRC patients present with late-stage tumors (clinical stages III or IV) at the time of diagnosis compared to 70% of EOCRC patients. Despite this, the cellular and molecular mechanisms underlying the incidence and stage are unclear, as are appropriate strategies for prevention of recurrence in men and women with EOCRC. Effective prognostic markers are therefore urgently needed. To address this issue, we performed a detailed bioinformatics analysis based on Gene Expression Omnibus database (GSE39582; n=585 patients), wherein we identified 7 prognostic biomarkers for EOCRC: KRAS, LGR5, CTNNB1, MYC, BMI1, CD44 and ASNS. Importantly, Kaplan Meier analysis revealed tumor onset at a younger age was significantly (p = 0.0082) associated with poorer 5-year survival in men with EOCRC only, after adjusting for KRAS status. CTNBB1 and CD44 transcript levels were higher in men with EOCRC versus men with LOCRC. Conversely, female EOCRC had a higher frequency of KRAS mutations (52.6%) compared to their LOCRC counterpart (38.8%), and an increased expression of markers of tumor stem cell and metabolic reprogramming including LGR5, MYC, BMI, and ASNS. A single CRISPR-Cas9 deletion of ASNS in HCT116 cell lines, a pre-clinical model of EOCRC, caused an inhibition of 3D spheroid formation compared to HCT116 ASNS wild type cells. In vivo study using a cell line derived R2G2 mouse xenograft model showed that ASNS disruption caused a reduction in tumor burden that was accompanied by low Lgr5 and Myc transcripts compared to the ASNS wild type group, indicating that ASNS may regulate cancer stemness. Together, this data suggests a unique molecular fingerprint for EOCRC and highlights sex-specific influences on cellular metabolism during EOCRC progression. Citation Format: Oladimeji Aladelokun, Kaelyn Sumigray, Sajid A. Khan, Caroline Johnson. Sex differences in cancer stemness among individuals with early onset colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 250.

Abstract 5850: Multiomics analysis unravels tumor metabolic reprogramming and potential resistance mechanism(s) to curative therapy in TNBC

Abstract Drug resistance is the leading cause of treatment failure to completely eliminate viable tumor cells in ~40% of patients with triple negative breast cancer (TNBC). Making a major impact on the treatment and prognosis for TNBC patients requires a better understanding of drug resistance mechanism(s). Combining clinical data with high-throughput metabolomic and proteomic analyses, we probed the molecular basis for chemotherapy resistance in treatment-naive TNBC primary tumors, reflected by pathological complete response (pCR) and non-pCR after neoadjuvant chemotherapy (NAC). Metabolic profiling uncovered that glycolysis and oxidative phosphorylation (OXPHOS) co-exist in TNBC primary tumors compared to benign lesions regardless of pCR status, indicating metabolic reprogramming. However, non-pCR tumors were more enriched in OXPHOS and less in glycolysis relative to pCR tumors, pointing to the potential importance of OXPHOS in drug resistance. Moreover, parallel proteomic profiling of these same TNBC tumors supported the results from metabolic profiling, showing that OXPHOS was indeed highly enriched at the protein level, and may be regulated by SIRT5-mediated sirtuin signaling. In alignment with these findings, non-pCR tumors were abundantly enriched in immune-inhibitory metabolites that may be due to the products of SIRT5-mediated mitochondrial metabolism. Thus, these findings led me to hypothesize that SIRT5 may play an important role in chemoresistance through regulation of mitochondrial metabolism and ROS detoxification. Together, the metabolite resulted from SIRT5-mediated mitochondrial metabolism led to the suppression of immune cell infiltration in non-pCR tumors. Understanding SIRT5-mediated chemoresistance mechanism may uncover a metabolic and therapeutic vulnerability to resistant TNBCs. Citation Format: Zuen Ren, Kiran Kurmi, Robert Morris, Shakchhi Joshi, Eric Zaniewski, Johannes Kreuzer, Gabrielle Elena Gioia, Veerle I. Bossuyt, Brian N. Dontchos, Gary X. Wang, Shinn-Huey S. Chou, Laura M. Spring, Wilhelm Haas, Marcia C. Haigis, Leif W. Ellisen. Multiomics analysis unravels tumor metabolic reprogramming and potential resistance mechanism(s) to curative therapy in TNBC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5850.

Gastric Cancer in the Era of Epigenetics.

Gastric cancer (GC) remains a significant contributor to cancer-related mortality. Novel high-throughput techniques have enlightened the epigenetic mechanisms governing gene-expression regulation. Epigenetic characteristics contribute to molecular taxonomy and give rise to cancer-specific epigenetic patterns. Helicobacter pylori (Hp) infection has an impact on aberrant DNA methylation either through its pathogenic CagA protein or by inducing chronic inflammation. The hypomethylation of specific repetitive elements generates an epigenetic field effect early in tumorigenesis. Epstein-Barr virus (EBV) infection triggers DNA methylation by dysregulating DNA methyltransferases (DNMT) enzyme activity, while persistent Hp-EBV co-infection leads to aggressive tumor behavior. Distinct histone modifications are also responsible for oncogene upregulation and tumor-suppressor gene silencing in gastric carcinomas. While histone methylation and acetylation processes have been extensively studied, other less prevalent alterations contribute to the development and migration of gastric cancer via a complex network of interactions. Enzymes, such as Nicotinamide N-methyltransferase (NNMT), which is involved in tumor's metabolic reprogramming, interact with methyltransferases and modify gene expression. Non-coding RNA molecules, including long non-coding RNAs, circular RNAs, and miRNAs serve as epigenetic regulators contributing to GC development, metastasis, poor outcomes and therapy resistance. Serum RNA molecules hold the potential to serve as non-invasive biomarkers for diagnostic, prognostic or therapeutic applications. Gastric fluids represent a valuable source to identify potential biomarkers with diagnostic use in terms of liquid biopsy. Ongoing clinical trials are currently evaluating the efficacy of next-generation epigenetic drugs, displaying promising outcomes. Various approaches including multiple miRNA inhibitors or targeted nanoparticles carrying epigenetic drugs are being designed to enhance existing treatment efficacy and overcome treatment resistance.

Cytotoxic response of tumor-infiltrating lymphocytes of head and neck cancer slice cultures under mitochondrial dysfunction.

Head and neck squamous cell carcinomas (HNSCC) are highly heterogeneous tumors. In the harsh tumor microenvironment (TME), metabolic reprogramming and mitochondrial dysfunction may lead to immunosuppressive phenotypes. Aerobic glycolysis is needed for the activation of cytotoxic T-cells and the absence of glucose may hamper the full effector functions of cytotoxic T-cells. To test the effect of mitochondrial dysfunction on cytotoxic T cell function, slice cultures (SC) of HNSCC cancer were cultivated under different metabolic conditions. Tumor samples from 21 patients with HNSCC were collected, from which, SC were established and cultivated under six different conditions. These conditions included high glucose, T cell stimulation, and temporarily induced mitochondrial dysfunction (MitoDys) using FCCP and oligomycin A with or without additional T cell stimulation, high glucose and finally, a control medium. Over three days of cultivation, sequential T cell stimulation and MitoDys treatments were performed. Supernatant was collected, and SC were fixed and embedded. Granzyme B was measured in the supernatant and in the SC via immunohistochemistry (IHC). Staining of PD1, CD8/Ki67, and cleaved-caspase-3 (CC3) were performed in SC. Hematoxylin eosin stains showed that overall SC quality remained stable over 3 days of cultivation. T cell stimulation, both alone and combined with MitoDys, led to significantly increased granzyme levels in SC and in supernatant. Apoptosis following T cell stimulation was observed in tumor and stroma. Mitochondrial dysfunction alone increased apoptosis in tumor cell aggregates. High glucose concentration alone had no impact on T cell activity and apoptosis. Apoptosis rates were significantly lower under conditions with high glucose and MitoDys (p=0.03). Stimulation of tumor-infiltrating lymphocytes in SC was feasible, which led to increased apoptosis in tumor cells. Induced mitochondrial dysfunction did not play a significant role in the activation and function of TILs in SC of HNSCC. Moreover, high glucose concentration did not promote cytotoxic T cell activity in HNSCC SC.

Progesterone receptor potentiates macropinocytosis through CDC42 in pancreatic ductal adenocarcinoma

Endocrine receptors play an essential role in tumor metabolic reprogramming and represent a promising therapeutic avenue in pancreatic ductal adenocarcinoma (PDAC). PDAC is characterized by a nutrient-deprived microenvironment. To meet their ascendant energy demands, cancer cells can internalize extracellular proteins via macropinocytosis. However, the roles of endocrine receptors in macropinocytosis are not clear. In this study, we found that progesterone receptor (PGR), a steroid-responsive nuclear receptor, is highly expressed in PDAC tissues obtained from both patients and transgenic LSL-KrasG12D/+; LSL-Trp53R172H/+; PDX1-cre (KPC) mice. Moreover, PGR knockdown restrained PDAC cell survival and tumor growth both in vitro and in vivo. Genetic and pharmacological PGR inhibition resulted in a marked attenuation of macropinocytosis in PDAC cells and subcutaneous tumor models, indicating the involvement of this receptor in macropinocytosis regulation. Mechanistically, PGR upregulated CDC42, a critical regulator in macropinocytosis, through PGR-mediated transcriptional activation. These data deepen the understanding of how the endocrine system influences tumor progression via a non-classical pathway and provide a novel therapeutic option for patients with PDAC.

The potential of aryl hydrocarbon receptor as receptors for metabolic changes in tumors.

Cancer cells can alter their metabolism to meet energy and molecular requirements due to unfavorable environments with oxygen and nutritional deficiencies. Therefore, metabolic reprogramming is common in a tumor microenvironment (TME). Aryl hydrocarbon receptor (AhR) is a ligand-activated nuclear transcription factor, which can be activated by many exogenous and endogenous ligands. Multiple AhR ligands can be produced by both TME and tumor cells. By attaching to various ligands, AhR regulates cancer metabolic reprogramming by dysregulating various metabolic pathways, including glycolysis, lipid metabolism, and nucleotide metabolism. These regulated pathways greatly contribute to cancer cell growth, metastasis, and evading cancer therapies; however, the underlying mechanisms remain unclear. Herein, we review the relationship between TME and metabolism and describe the important role of AhR in cancer regulation. We also focus on recent findings to discuss the idea that AhR acts as a receptor for metabolic changes in tumors, which may provide new perspectives on the direction of AhR research in tumor metabolic reprogramming and future therapeutic interventions.

Breast Cancer Stem Cells Secrete MIF to Mediate Tumor Metabolic Reprogramming That Drives Immune Evasion.

MIF secreted by breast cancer stem cells induces metabolic reprogramming in bulk tumor cells and engenders an immunosuppressive microenvironment, identifying MIF targeting as a strategy to improve immunotherapy efficacy in breast cancer.

The roles of epigallocatechin gallate in the tumor microenvironment, metabolic reprogramming, and immunotherapy.

Cancer, a disease that modern medicine has not fully understood and conquered, with its high incidence and mortality, deprives countless patients of health and even life. According to global cancer statistics, there were an estimated 19.3 million new cancer cases and nearly 10 million cancer deaths in 2020, with the age-standardized incidence and mortality rates of 201.0 and 100.7 per 100,000, respectively. Although remarkable advancements have been made in therapeutic strategies recently, the overall prognosis of cancer patients remains not optimistic. Consequently, there are still many severe challenges to be faced and difficult problems to be solved in cancer therapy today. Epigallocatechin gallate (EGCG), a natural polyphenol extracted from tea leaves, has received much attention for its antitumor effects. Accumulating investigations have confirmed that EGCG can inhibit tumorigenesis and progression by triggering apoptosis, suppressing proliferation, invasion, and migration, altering tumor epigenetic modification, and overcoming chemotherapy resistance. Nevertheless, its regulatory roles and biomolecular mechanisms in the immune microenvironment, metabolic microenvironment, and immunotherapy remain obscure. In this article, we summarized the most recent updates about the effects of EGCG on tumor microenvironment (TME), metabolic reprogramming, and anti-cancer immunotherapy. The results demonstrated EGCG can promote the anti-cancer immune response of cytotoxic lymphocytes and dendritic cells (DCs), attenuate the immunosuppression of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), and inhibit the tumor-promoting functions of tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), and various stromal cells including cancer-associated fibroblasts (CAFs), endothelial cells (ECs), stellate cells, and mesenchymal stem/stromal cells (MSCs). Additionally, EGCG can suppress multiple metabolic reprogramming pathways, including glucose uptake, aerobic glycolysis, glutamine metabolism, fatty acid anabolism, and nucleotide synthesis. Finally, EGCG, as an immunomodulator and immune checkpoint blockade, can enhance immunotherapeutic efficacy and may be a promising candidate for antitumor immunotherapy. In conclusion, EGCG plays versatile regulatory roles in TME and metabolic reprogramming, which provides novel insights and combined therapeutic strategies for cancer immunotherapy.

Prognostic and immune predictive roles of a novel tricarboxylic acid cycle-based model in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer. Since the tricarboxylic acid cycle is widely involved in tumor metabolic reprogramming and cuproptosis, investigating related genes may help to identify prognostic signature of patients with HCC. Data on patients with HCC were sourced from public datasets, and were divided into train, test, and single-cell cohorts. A variety of machine learning algorithms were used to identify different molecular subtypes and determine the prognostic risk model. Our findings revealed that the risk score (TRscore), based on the genes OGDHL, CFHR4, and SPP1, showed excellent predictive performance in different datasets. Pathways related to cell cycle and immune inflammation were enriched in the high-risk group, whereas metabolism-related pathways were significantly enriched in the low-risk group. The high-risk group was associated with a greater number of mutations of detrimental biological behavior and higher levels of immune infiltration, immune checkpoint expression, and anti-cancer immunotherapy response. Low-risk patients demonstrated greater sensitivity to erlotinib and phenformin. SPP1 was mainly involved in the interaction among tumor-associated macrophages, T cells, and malignant cells via SPP1–CD44 and SPP1–(ITGA5 + ITGB1) ligand-receptor pairs. In summary, our study established a prognostic model, which may contribute to individualized treatment and clinical management of patients with HCC.

A Lactate-Depleting metal organic framework-based nanocatalyst reinforces intratumoral T cell response to boost anti-PD1 immunotherapy

Infiltration and activation of intratumoral T lymphocytes are critical for immune checkpoint blockade (ICB) therapy. Unfortunately, the low tumor immunogenicity and immunosuppressive tumor microenvironment (TME) induced by tumor metabolic reprogramming cooperatively hinder the ICB efficacy. Herein, we engineered a lactate-depleting MOF-based catalytic nanoplatform (LOX@ZIF-8@MPN), encapsulating lactate oxidase (LOX) within zeolitic imidazolate framework-8 (ZIF-8) coupled with a coating of metal polyphenol network (MPN) to reinforce T cell response based on a “two birds with one stone” strategy. LOX could catalyze the degradation of the immunosuppressive lactate to promote vascular normalization, facilitating T cell infiltration. On the other hand, hydrogen peroxide (H2O2) produced during lactate depletion can be transformed into anti-tumor hydroxyl radical (•OH) by the autocatalytic MPN-based Fenton nanosystem to trigger immunogenic cell death (ICD), which largely improved the tumor immunogenicity. The combination of ICD and vascular normalization presents a better synergistic immunopotentiation with anti-PD1, inducing robust anti-tumor immunity in primary tumors and recurrent malignancies. Collectively, our results demonstrate that the concurrent depletion of lactate to reverse the immunosuppressive TME and utilization of the by-product from lactate degradation via cascade catalysis promotes T cell response and thus improves the effectiveness of ICB therapy.

Immunosurveillance encounters cancer metabolism.

Tumor cells reprogram nutrient acquisition and metabolic pathways to meet their energetic, biosynthetic, and redox demands. Similarly, metabolic processes in immune cells support host immunity against cancer and determine differentiation and fate of leukocytes. Thus, metabolic deregulation and imbalance in immune cells within the tumor microenvironment have been reported to drive immune evasion and to compromise therapeutic outcomes. Interestingly, emerging evidence indicates that anti-tumor immunity could modulate tumor heterogeneity, aggressiveness, and metabolic reprogramming, suggesting that immunosurveillance can instruct cancer progression in multiple dimensions. This review summarizes our current understanding of how metabolic crosstalk within tumors affects immunogenicity of tumor cells and promotes cancer progression. Furthermore, we explain how defects in the metabolic cascade can contribute to developing dysfunctional immune responses against cancers and discuss the contribution of immunosurveillance to these defects as a feedback mechanism. Finally, we highlight ongoing clinical trials and new therapeutic strategies targeting cellular metabolism in cancer.

UCP2 promotes NSCLC proliferation and glycolysis via the mTOR/HIF-1α signaling.

Metabolic disturbance is a hallmark of cancers. Targeting key metabolic pathways and metabolism-related molecular could be a potential therapeutic approach. Uncoupling protein 2 (UCP2) plays a pivotal part in the malignancy of cancer and its capacity to develop resistance to pharmaceutical interventions. However, it is unclear about the mechanism of how UCP2 acts in the tumor growth and metabolic reprogramming process in non-small cell lung cancer (NSCLC). Here, we conducted qRT-PCR to investigate the expression of UCP2 in both NSCLC tissues and cell lines. Subsequent functional studies including colony formation assay, CCK-8 assay, and glycolysis assay were conducted to investigate the functions of UCP2 in NSCLC. The regulatory mechanism of UCP2 toward the mammalian target of rapamycin (mTOR) and hypoxia-inducible factor-1 alpha (HIF-1α) signaling in NSCLC was confirmed through western blotting. We observed a significant upregulation of UCP2 in both NSCLC tissues and cell lines. The increased expression of UCP2 has a strong association with a worse outlook. Silencing UCP2 remarkably dampened NSCLC cell proliferation and glycolysis capacities. Mechanically, UCP2 promoted NSCLC tumorigenesis partially via regulating the mTOR/HIF-1α axis. Taken together, we explored the functions as well as the mechanisms of the UCP2/mTOR/HIF-1α axis in NSCLC progression, uncovering potential biological signatures and targets for NSCLC treatment.

The Role of Tumor Metabolic Reprogramming in Tumor Immunity.

The occurrence and development of tumors require the metabolic reprogramming of cancer cells, namely the alteration of flux in an autonomous manner via various metabolic pathways to meet increased bioenergetic and biosynthetic demands. Tumor cells consume large quantities of nutrients and produce related metabolites via their metabolism; this leads to the remodeling of the tumor microenvironment (TME) to better support tumor growth. During TME remodeling, the immune cell metabolism and antitumor immune activity are affected. This further leads to the escape of tumor cells from immune surveillance and therefore to abnormal proliferation. This review summarizes the regulatory functions associated with the abnormal biosynthesis and activity of metabolic signaling molecules during the process of tumor metabolic reprogramming. In addition, we provide a comprehensive description of the competition between immune cells and tumor cells for nutrients in the TME, as well as the metabolites required for tumor metabolism, the metabolic signaling pathways involved, and the functionality of the immune cells. Finally, we summarize current research targeted at the development of tumor immunotherapy. We aim to provide new concepts for future investigations of the mechanisms underlying the metabolic reprogramming of tumors and explore the association of these mechanisms with tumor immunity.