UNASSIGNED: Lactic acid is a metabolite of glycolysis produced in the body, and its production is thought to be a mechanism by which cancer cells evade immune surveillance. Immune evasion and metabolic changes are well established as basic hallmarks of cancer. Although lactate has long been considered a waste product, it is now generally recognized to be a versatile small-molecule chemical that plays an important part in the tumor microenvironment (TME), with increased lactate production linked to the development of human malignancies. Metabolism in liver cancer is redirected toward glycolysis, which enhances the production of metabolic compounds used by tumor cells to produce proteins, lipids, and nucleotides, enabling them to maintain high proliferation rates and to establish the TME. Dysregulation of metabolic activity in liver cancer may impair antitumor responses owing to the immunosuppressive activity of the lactate produced by anaerobic glycolytic rates in tumor cells. This review primarily explores the link connection between lactic acid and the TME; evaluates the role of lactic acid in the occurrence, metastasis, prognosis, and treatment of liver cancer. Additionally, it investigates the associated pathways as potential targets for liver cancer treatment.
UNASSIGNED: Literature searches were conducted in PubMed, Web of Science, and Google Scholar, with the publication date of the most recent article included being January 2024. After eliminating duplicate articles and less relevant articles through titles and abstracts, we selected 113 articles for this review. We categorized references into two categories. One is to classify the content into lactate-related, liver cancer-related and tumor metabolism-related. The other is to classify the article types, which are divided into reviews, research articles and clinical trials. Additionally, we consulted the reference lists of the relevant articles to ensure coverage was comprehensive and unbiased.
UNASSIGNED: The connection between lactic acid and the TME has recently become an area of intense research interest, and many related articles have been published in this field. The main finding of this review is to summarize the proven link between lactate and the TME and its possible impact on the TME of liver cancer. And analyzed the potential of lactate in liver cancer treatment and prognosis prediction.
UNASSIGNED: Lactate may be key to developing novel approaches in the future treatment of liver cancer. Related research on the combination of classic therapies and molecular targeted drugs may provide innovative medicines that more selectively regulate immune cell activity.

Cancer is amenable to low-cost treatments, given that it has a significant metabolic component, which can be affected through diet and lifestyle change at minimal cost. The Warburg hypothesis states that cancer cells have an altered cell metabolism towards anaerobic glycolysis. Given this metabolic reprogramming in cancer cells, it is possible to target cancers metabolically by depriving them of glucose. In addition to dietary and lifestyle modifications which work on tumors metabolically, there are a panoply of nutritional supplements and repurposed drugs associated with cancer prevention and better treatment outcomes. These interventions and their evidentiary basis are covered in the latter half of this review to guide future cancer treatment.

Reprogramming cancer metabolism has become the hallmark of cancer progression. As the key enzyme catalyzing the conversion of pyruvate to lactate in aerobic glycolysis of cancer cells, human lactate dehydrogenase (LDH) has been a promising target in the discovery of anticancer agents. Natural products are important sources of new drugs. Up to now, some natural compounds have been reported with the activity to target LDH. To give more information on the development of LDH inhibitors and application of natural products, herein, we reviewed the natural compounds with inhibition of LDH from diverse structures and discussed the future direction of the discovery of natural LDH inhibitors for cancer therapy.

One of the most unique characteristics of cancer metabolism is activated aerobic glycolysis, which is called the \"Warburg effect\", and is a hallmark of cancer. An acidic tumor microenvironment (TME) resulting from activated anaerobic glycolysis is associated with cancer progression, multi-drug resistance, and immune escape. Several in vitro and in vivo studies reported that neutralization of the acidic TME by alkalizing agents, such as bicarbonate, resulted in the suppression of cancer progression and a potential benefit for anti-cancer drug responses. In clinical settings, alkalizing effects were achieved not only by alkalizing agents, but also by a following a particular diet. An epidemiological study demonstrated that more fruits and vegetables and less meat and dairy products are associated with an increase in urine pH, which may reflect the alkalizing effect on the body. However, it remains unclear whether alkaline dietary intervention improves the effects of cancer treatment. Moreover, there are few clinical reports to date regarding cancer treatments being performed on patients together with alkalization therapy. In this review, we investigated whether alkalization therapy, which includes an alkaline diet and/or alkalizing agents, improves cancer treatment.

Increased insulin level (or \"hyperinsulinemia\") is a common phenomenon in pancreatic ductal adenocarcinoma (PDA) patients and signals poor clinical outcomes. Insulin is safe in low PDA risk population, while insulin significantly promotes PDA risk in high PDA risk population. The correlation between insulin and PDA is a reciprocal self-reinforcing relationship. On the one hand, pancreatic cancer cells synthesize multiple molecules to cause elevated peripheral insulin resistance, thus enhancing hyperinsulinemia. On the other hand, insulin promotes pancreatic cancer initiation and sustains PDA development by eliciting tumorigenic inflammation, regulating lipid and glucose metabolic reprogram, overcoming apoptosis through the crosstalk with IGF-1, stimulating cancer metastasis, and activating tumor microenvironment formation (inflammation, fibrosis, and angiogenesis). Currently, taking glucose sensitizing agents, including metformin, SGLT-2 inhibitor, and GLP-1 agonist, is an effective way of lowering insulin levels and controlling PDA development at the same time. In the future, new drugs targeting insulin-related signal pathways may pave a novel way for suppressing PDA initiation and progression.

Reinterpretation of the Wartburg effect leads to understanding aerobic glycolysis as a process that provides considerable amount of molecular precursors for the production of lipids, nucleotides and amino acids that are necessary for continuous growth and rapid proliferation characteristic for cancer cells. Human papilloma virus (HPV) is a number one cause of cervical carcinoma with 99% of the cervical cancer patients being HPV positive. This tight link between HPV and cancer raises the question if and how HPV impact cells to reprogram their metabolism? Focusing on early phase proteins E1, E2, E5, E6 and E7 we demonstrate that HPV activates plethora of metabolic pathways and directly influences enzymes of the glycolysis pathway to promote the Warburg effect by increasing glucose uptake, activating glycolysis and pentose phosphate pathway, increasing the level of lactate dehydrogenase A synthesis and inhibiting β-oxidation. Our considerations lead to conclusion that HPV is substantially involved in metabolic cell reprogramming toward neoplastic phenotype and its metabolic activity is the fundamental reason of its oncogenicity.

Depending on their tissue of origin, genetic and epigenetic marks and microenvironmental influences, cancer cells cover a broad range of metabolic activities that fluctuate over time and space. At the core of most metabolic pathways, mitochondria are essential organelles that participate in energy and biomass production, act as metabolic sensors, control cancer cell death, and initiate signaling pathways related to cancer cell migration, invasion, metastasis and resistance to treatments. While some mitochondrial modifications provide aggressive advantages to cancer cells, others are detrimental. This comprehensive review summarizes the current knowledge about mitochondrial transfers that can occur between cancer and nonmalignant cells. Among different mechanisms comprising gap junctions and cell-cell fusion, tunneling nanotubes are increasingly recognized as a main intercellular platform for unidirectional and bidirectional mitochondrial exchanges. Understanding their structure and functionality is an important task expected to generate new anticancer approaches aimed at interfering with gains of functions (e.g., cancer cell proliferation, migration, invasion, metastasis and chemoresistance) or damaged mitochondria elimination associated with mitochondrial transfer.

Introduction:The phosphoglycerate dehydrogenase (PHGDH), a metabolic enzyme involved in the serine synthetic pathway (SSP), appears to play a central role in supporting cancer growth and proliferation. PHGDH is a dehydrogenase whose expression in cancers was first demonstrated in 2010. Because its silencing allows a significant reduction in tumor proliferation, it appears to be a promising target in the development of new anti-cancer agents.Areas covered: In this review, we will detail PHGDH inhibitors that were reported since 2015. These compounds will be ranked according to their chemical class and their site of action. Representative examples of each series will be presented as well as their inhibitory potency in vitro and/or in vivo. Finally, their most significant biological effects will be detailed.Expert opinion: Currently, and despite significant efforts, the search for PHGDH inhibitors has not yet led to the development of compounds that can be used therapeutically. The available inhibitors have either too weak inhibitory potency or limited selectivity. Therefore, it seems crucial, given the importance of this enzyme in the progression of cancer but also in other pathologies, to pursue the development of new chemical series.

Dysregulation of metabolic pathways in cancer cells is regarded as a hallmark of cancer. Identification of these abnormalities in cancer cells dates back to more than six decades, far before discovery of oncogenes and tumor suppressor genes. Based on the importance of these pathways, several researchers have aimed at modulation of these functions to intervene with the pathogenic course of cancer. Numerous genes have been shown to participate in the regulation of metabolic pathways, thus aberrant expression of these genes can be involved in the pathogenesis of cancer. The recent decade has experienced a significant attention toward the role of long non-coding RNAs (lncRNAs) in the biological functions. These transcripts regulate expression of genes at several levels, therefore influencing the activity of cancer-related pathways. Among the most affected pathways are those modulating glucose homeostasis, as well as amino acid and lipid metabolism. Moreover, critical roles of lncRNAs in regulation of mitochondrial function potentiate these transcripts as novel targets for cancer treatment. In the current review, we summarize the most recent literature regarding the role of lncRNAs in the cancer metabolism and their significance in the design of therapeutic modalities.

Several immunotherapy agents are the standard of care of many solid malignancies. Nevertheless, the majority of patients do not benefit from the currently available immunotherapies. It is therefore of paramount importance to identify the prognostic and predictive factors of tumor response/resistance and to design effective therapeutic strategies to overcome primary resistance and improve the efficacy of immunotherapy. The aim of this review is to underline the influence of the tumor and host metabolism on the antitumor immune response and to discuss possible strategies to improve the efficacy of available treatments by targeting the specific metabolic pathways in tumors or immune cells and by modifying patients\' nutritional statuses. A systematic search of the Medline and EMBASE databases was carried out to identify scientific papers published until February 2020, which reported original research articles on the influence of tumor or host metabolism on antitumor immune response. The literature data showed the key role of glycolysis and mitochondrial oxidative phosphorylation, arginine, tryptophan, glutamine, lipid metabolism and microbiome on immune cell function. Moreover, specific nutritional behaviors, such as a low dietary intake of vitamin C, low glycemic index and alpha-linolenic acid, eicosapentenoic acid, docosahexaenoic acid, ornithine ketoglutarate, tryptophan and probiotic supplementation were associated with the potential clinical benefits from the currently available immunotherapies.