bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2025–01–12
ten papers selected by
Oltea Sampetrean, Keio University
  1. Glucose Metabolism Reprogramming of Immune Cells in the Microenvironment of Pancreatic and Hepatobiliary Cancers.
  2. Tumor metabolic regulators: key drivers of metabolic reprogramming and the promising targets in cancer therapy.
  3. Bile acid synthesis impedes tumor-specific T cell responses during liver cancer.
  4. N6-methyladenosine RNA methylation, a new hallmark of metabolic reprogramming in the immune microenvironment.
  5. Induction of macrophage efferocytosis in pancreatic cancer via PI3Kγ inhibition and radiotherapy promotes tumour control.
  6. Systemic metabolic crosstalk as driver of cancer cachexia.
  7. CD36 as a Therapeutic Target in Tumor Microenvironment and Lipid Metabolism.
  8. Lactate and Lactylation: Dual Regulators of T-Cell-Mediated Tumor Immunity and Immunotherapy.
  9. Metabolic adaptation of myeloid cells in the glioblastoma microenvironment.
  10. Metabolic Fitness of NAC1-Deficient Regulatory T Cells in the Tumor Microenvironment Fuels Tumor Growth.
  1. J Gastroenterol Hepatol. 2025 Jan 08.
    Glucose Metabolism Reprogramming of Immune Cells in the Microenvironment of Pancreatic and Hepatobiliary Cancers.
    Yongqing Zhao, Weixiong Zhu, Shi Dong, Hui Zhang, Wence Zhou.
       BACKGROUND AND AIM: Pancreatic and hepatobiliary cancers are increasing in prevalence and contribute significantly to cancer-related mortality worldwide. Emerging therapeutic approaches, particularly immunotherapy, are gaining attention for their potential to harness the patient's immune system to combat these tumors. Understanding the role of immune cells in the tumor microenvironment (TME) and their metabolic reprogramming is key to developing more effective treatment strategies. This review aims to explore the relationship between immune cell function and glucose metabolism in the TME of pancreatic and hepatobiliary cancers.
    METHODS: This review synthesizes current research on the metabolic adaptations of immune cells, specifically focusing on glucose metabolism within the TME of pancreatic and hepatobiliary cancers. We examine the mechanisms by which immune cells influence tumor progression through metabolic reprogramming and how these interactions can be targeted for therapeutic purposes.
    RESULTS: Immune cells in the TME undergo significant metabolic changes, with glucose metabolism playing a central role in modulating immune responses. These metabolic shifts not only affect immune cell function but also influence tumor behavior and progression. The unique metabolic features of immune cells in pancreatic and hepatobiliary cancers provide new opportunities for targeting immune responses to combat these malignancies more effectively.
    CONCLUSION: Understanding the complex relationship between immune cell glucose metabolism and tumor progression in the TME of pancreatic and hepatobiliary cancers offers promising therapeutic strategies. By modulating immune responses through targeted metabolic interventions, it may be possible to improve the efficacy of immunotherapies and better combat these aggressive cancers.
    Keywords:  glucose metabolism; immune cell; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1111/jgh.16873
  2. Mol Cancer. 2025 Jan 09. 24(1): 7
    Tumor metabolic regulators: key drivers of metabolic reprogramming and the promising targets in cancer therapy.
    Kun Huang, Ying Han, Yihong Chen, Hong Shen, Shan Zeng, Changjing Cai.
      Metabolic reprogramming within the tumor microenvironment (TME) is a hallmark of cancer and a crucial determinant of tumor progression. Research indicates that various metabolic regulators form a metabolic network in the TME and interact with immune cells, coordinating the tumor immune response. Metabolic dysregulation creates an immunosuppressive TME, impairing the antitumor immune response. In this review, we discuss how metabolic regulators affect the tumor cell and the crosstalk of TME. We also summarize recent clinical trials involving metabolic regulators and the challenges of metabolism-based tumor therapies in clinical translation. In a word, our review distills key regulatory factors and their mechanisms of action from the complex reprogramming of tumor metabolism, identified as tumor metabolic regulators. These regulators provide a theoretical basis and research direction for the development of new strategies and targets in cancer therapy based on tumor metabolic reprogramming.
    Keywords:  Cancer therapy; Metabolic regulators; Metabolic reprogramming; TME
    DOI:  https://doi.org/10.1186/s12943-024-02205-6
  3. Science. 2025 Jan 10. 387(6730): 192-201
    Bile acid synthesis impedes tumor-specific T cell responses during liver cancer.
    Siva Karthik Varanasi, Dan Chen, Yingluo Liu, Melissa A Johnson, Cayla M Miller, Souradipta Ganguly, Kathryn Lande, Michael A LaPorta, Filipe Araujo Hoffmann, Thomas H Mann, Marcos G Teneche, Eduardo Casillas, Kailash C Mangalhara, Varsha Mathew, Ming Sun, Isaac J Jensen, Yagmur Farsakoglu, Timothy Chen, Bianca Parisi, Shaunak Deota, Aaron Havas, Jin Lee, H Kay Chung, Andrea Schietinger, Satchidananda Panda, April E Williams, Donna L Farber, Debanjan Dhar, Peter D Adams, Gen-Sheng Feng, Gerald S Shadel, Mark S Sundrud, Susan M Kaech.
      The metabolic landscape of cancer greatly influences antitumor immunity, yet it remains unclear how organ-specific metabolites in the tumor microenvironment influence immunosurveillance. We found that accumulation of primary conjugated and secondary bile acids (BAs) are metabolic features of human hepatocellular carcinoma and experimental liver cancer models. Inhibiting conjugated BA synthesis in hepatocytes through deletion of the BA-conjugating enzyme bile acid-CoA:amino acid N-acyltransferase (BAAT) enhanced tumor-specific T cell responses, reduced tumor growth, and sensitized tumors to anti-programmed cell death protein 1 (anti-PD-1) immunotherapy. Furthermore, different BAs regulated CD8+ T cells differently; primary BAs induced oxidative stress, whereas the secondary BA lithocholic acid inhibited T cell function through endoplasmic reticulum stress, which was countered by ursodeoxycholic acid. We demonstrate that modifying BA synthesis or dietary intake of ursodeoxycholic acid could improve tumor immunotherapy in liver cancer model systems.
    DOI:  https://doi.org/10.1126/science.adl4100
  4. Front Immunol. 2024 ;15 1464042
    N6-methyladenosine RNA methylation, a new hallmark of metabolic reprogramming in the immune microenvironment.
    Xiaoyue Li, Lin Peng, Xuelian Yang, Jing Luo, Jianmei Wang, Kelin Mou, Huan Zhou, Yuhao Luo, Li Xiang.
      N6-methyladenosine is one of the most common and reversible post-transcriptional modifications in eukaryotes, and it is involved in alternative splicing and RNA transcription, degradation, and translation. It is well known that cancer cells acquire energy through metabolic reprogramming to exhibit various biological behaviors. Moreover, numerous studies have demonstrated that m6A induces cancer metabolic reprogramming by regulating the expression of core metabolic genes or by activating metabolic signaling pathways. Meanwhile, m6A modifications and related regulators are key targets in the regulation of immune effects. We further summarize how m6A modifications contribute to tumor metabolism, and how these events affect the tumor immune microenvironment, with a specific focus on different cell types. Finally, we focus on the specific applications of this field to tumor immunotherapy. We review the potential role of m6A in metabolic reprogramming of tumor immune microenvironment and its regulatory mechanism, with the aim of providing new targets for tumor metabolic regulation and immunotherapy.
    Keywords:  N6-methyladenosine; immunotherapy; m6A modification; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1464042
  5. Gut. 2025 Jan 09. pii: gutjnl-2024-333492. [Epub ahead of print]
    Induction of macrophage efferocytosis in pancreatic cancer via PI3Kγ inhibition and radiotherapy promotes tumour control.
    Shannon Nicole Russell, Constantinos Demetriou, Giampiero Valenzano, Alice Evans, Simei Go, Tess Stanly, Ahmet Hazini, Frances Willenbrock, Alex Nicolas Gordon-Weeks, Somnath Mukherjee, Matthias Tesson, Jennifer P Morton, Eric O'Neill, Keaton Ian Jones.
       BACKGROUND: The immune suppression mechanisms in pancreatic ductal adenocarcinoma (PDAC) remain unknown, but preclinical studies have implicated macrophage-mediated immune tolerance. Hence, pathways that regulate macrophage phenotype are of strategic interest, with reprogramming strategies focusing on inhibitors of phosphoinositide 3-kinase-gamma (PI3Kγ) due to restricted immune cell expression. Inhibition of PI3Kγ alone is ineffective in PDAC, despite increased infiltration of CD8+ T cells.
    OBJECTIVE: We hypothesised that the immune stimulatory effects of radiation, and its ability to boost tumour antigen availability could synergise with PI3Kγ inhibition to augment antitumour immunity.
    DESIGN: We used orthoptic and genetically engineered mouse models of pancreatic cancer (LSL-KrasG12D/+;Trp53R172H/+;Pdx1-Cre). Stereotactic radiotherapy was delivered using contrast CT imaging, and PI3Kγ inhibitors by oral administration. Changes in the tumour microenvironment were quantified by flow cytometry, multiplex immunohistochemistry and RNA sequencing. Tumour-educated macrophages were used to investigate efferocytosis, antigen presentation and CD8+ T cell activation. Single-cell RNA sequencing data and fresh tumour samples with autologous macrophages to validate our findings.
    RESULTS: Tumour-associated macrophages that employ efferocytosis to eradicate apoptotic cells can be redirected to present tumour antigens, stimulate CD8+ T cell responses and increase local tumour control. Specifically, we demonstrate how PI3Kγ signalling restricts inflammatory macrophages and that inhibition supports MERTK-dependent efferocytosis. We further find that the combination of PI3Kγ inhibition with targeted radiotherapy stimulates inflammatory macrophages to invoke a pathogen-induced like efferocytosis that switches from immune tolerant to antigen presenting.
    CONCLUSIONS: Our data supports a new immunotherapeutic approach and a translational rationale to improve survival in PDAC.
    Keywords:  ANTIGEN PRESENTATION; CANCER; MACROPHAGES; PANCREATIC CANCER
    DOI:  https://doi.org/10.1136/gutjnl-2024-333492
  6. Trends Endocrinol Metab. 2025 Jan 04. pii: S1043-2760(24)00327-8. [Epub ahead of print]
    Systemic metabolic crosstalk as driver of cancer cachexia.
    Elisabeth Wyart, Giovanna Carrà, Elia Angelino, Fabio Penna, Paolo E Porporato.
      Cachexia is a complex metabolic disorder characterized by negative energy balance due to increased consumption and lowered intake, leading to progressive tissue wasting and inefficient energy distribution. Once considered as passive bystander, metabolism is now acknowledged as a regulator of biological functions and disease progression. This shift in perspective mirrors the evolving understanding of cachexia itself, no longer viewed merely as a secondary consequence of cancer but as an active process. However, metabolic dysregulations in cachexia are currently studied in an organ-specific manner, failing to be fully integrated into a comprehensive framework that explains their functional roles in disease progression. Thus, in this review, we aim to provide a general overview of the various metabolic alterations with a potential systemic impact.
    Keywords:  cachexia; cross-talk; metabolism; muscle wasting
    DOI:  https://doi.org/10.1016/j.tem.2024.12.005
  7. Anticancer Agents Med Chem. 2025 Jan 01.
    CD36 as a Therapeutic Target in Tumor Microenvironment and Lipid Metabolism.
    Jiaxuan Li, Jiaqi Chen, Guang Yang, Shulin Zhang, Peiyao Li, Lan Ye.
      Dysregulated lipid metabolism within the tumor microenvironment (TME) is a critical hallmark of cancer progression, with lipids serving as a major energy source for tumor cells. Beyond their role in cell membrane synthesis, lipids also provide essential substrates for biomolecule production and activate signaling pathways that regulate various cellular processes. Aberrant lipid metabolism impacts not only function but also alters the behavior of immune and stromal cells within the TME. CD36, a key lipid transporter, plays a crucial role in regulating fatty acid sensing and lipid metabolism, and its dysregulated expression has been associated with poor prognosis in several cancers. Studies have demonstrated that elevated CD 36 expression in the TME is closely linked to abnormal lipid metabolism, promoting tumor growth, migration, and metastasis. In recent years, significant progress has been made in developing CD36-targeted therapies, including small-molecule inhibitors, antibodies, and nanoparticle-based drugs, with many entering experimental or preclinical stages. This review comprehensively summarizes the latest advances in understanding the role of CD36 in the TME, focusing on its metabolic regulatory mechanisms in tumor cells, immune cells, and stromal cells. Additionally, it highlights the contribution of CD36 to immune evasion, drug resistance, and cancer stem cell maintenance while discussing several therapeutic strategies targeting CD36, including novel therapies currently in clinical trials. By exploring the therapeutic potential of CD36, this review provides critical insights for the future development of CD36-targeted cancer therapies.
    Keywords:  CD36; cancer stem cells.; lipid metabolism; targeted therapy; tumor microenvironment
    DOI:  https://doi.org/10.2174/0118715206353634241111113338
  8. Biomolecules. 2024 Dec 21. pii: 1646. [Epub ahead of print]14(12):
    Lactate and Lactylation: Dual Regulators of T-Cell-Mediated Tumor Immunity and Immunotherapy.
    Zhi-Nan Hao, Xiao-Ping Tan, Qing Zhang, Jie Li, Ruohan Xia, Zhaowu Ma.
      Lactate and its derivative, lactylation, play pivotal roles in modulating immune responses within the tumor microenvironment (TME), particularly in T-cell-mediated cancer immunotherapy. Elevated lactate levels, a hallmark of the Warburg effect, contribute to immune suppression through CD8+ T cell functionality and by promoting regulatory T cell (Treg) activity. Lactylation, a post-translational modification (PTM), alters histone and non-histone proteins, influencing gene expression and further reinforcing immune suppression. In the complex TME, lactate and its derivative, lactylation, are not only associated with immune suppression but can also, under certain conditions, exert immunostimulatory effects that enhance cytotoxic responses. This review describes the dual roles of lactate and lactylation in T-cell-mediated tumor immunity, analyzing how these factors contribute to immune evasion, therapeutic resistance, and immune activation. Furthermore, the article highlights emerging therapeutic strategies aimed at inhibiting lactate production or disrupting lactylation pathways to achieve a balanced regulation of these dual effects. These strategies offer new insights into overcoming tumor-induced immune suppression and hold the potential to improve the efficacy of cancer immunotherapies.
    Keywords:  T cell; glycolysis; immune modulation; lactate; lactylation; tumor microenvironment
    DOI:  https://doi.org/10.3390/biom14121646
  9. Front Immunol. 2024 ;15 1431112
    Metabolic adaptation of myeloid cells in the glioblastoma microenvironment.
    Nora Essakhi, Alexandre Bertucci, Nathalie Baeza-Kallee, Carole Colin, Rosario Lavignolle-Heguy, Paulina Garcia-Gonzalez, Rafael J Argüello, Aurélie Tchoghandjian, Emeline Tabouret.
      In recent decades, immunometabolism in cancers has emerged as an interesting target for treatment development. Indeed, the tumor microenvironment (TME) unique characteristics such as hypoxia and limitation of nutrients availability lead to a switch in metabolic pathways in both tumor and TME cells in order to support their adaptation and grow. Glioblastoma (GBM), the most frequent and aggressive primary brain tumor in adults, has been extensively studied in multiple aspects regarding its immune population, but research focused on immunometabolism remains limited. Here, we provide an overview of immunometabolism adaptation of myeloid cells in cancers with a specific focus on GBM and other brain tumors, before describing current therapeutic strategies targeting metabolic pathways. The main myeloid cells composing the GBM TME include tumor-associated macrophages (TAMs), which comprise both peripheral macrophages and local microglia, as well as myeloid-derived suppressor cells. The metabolic pathways involved in myeloid cell remodeling encompass the tricarboxylic acid cycle (TCA cycle), the lipid, glucose and amino acid metabolism and hypoxia. Developing treatments that target these metabolic pathways in tumor growth and its TME is a promising and increasing field. It includes both drug-repurposing and the development of innovative metabolic therapies. We finally provide an overview of all clinical trials in neuro-oncology involving treatments modifying cell metabolism and provide the preclinical rationale for both drugs already evaluated within clinical trials and potential candidates for future trials.
    Keywords:  TCA cycle; glioblastoma; glycolysis; lipid metabolism; metabolism; myeloid cells
    DOI:  https://doi.org/10.3389/fimmu.2024.1431112
  10. JCI Insight. 2025 Jan 07. pii: e186000. [Epub ahead of print]
    Metabolic Fitness of NAC1-Deficient Regulatory T Cells in the Tumor Microenvironment Fuels Tumor Growth.
    Anil Kumar, Jugal Das, Hao-Yun Peng, Liqing Wang, Darby Ballard, Yijie Ren, Xiaofang Xiong, Xingcong Ren, Jin-Ming Yang, Paul de Figueiredo, Jianxun Song.
      The nucleus accumbens-associated protein-1 (NAC1) has recently emerged as a pivotal factor in oncogenesis by promoting glycolysis. Deletion of NAC1 in regulatory T cells (Tregs) has been shown to enhance FoxP3 stability, a suppressor of glycolysis. This study delves into the intriguing dual role of NAC1, uncovering that Tregs-specific deletion of NAC1 fosters metabolic fitness in Tregs, thereby promoting tumorigenesis. Our results unveil that NAC1-deficient Tregs exhibit prolonged survival and heightened function, particularly in acidic environments. Mechanistically, we find that NAC1-deficient Tregs adapt to adverse conditions by upregulating FoxP3 expression, engaging in CD36-mediated lipid metabolism, and enhancing PGC-1α-regulated mitochondrial function. In mouse tumor xenograft models, NAC1-deficient mice demonstrate increased susceptibility to tumor growth. Notably, Tregs lacking NAC1 not only display elevated lipid metabolism and mitochondrial fitness but also exhibit enhanced tumoral infiltration. Adoptive Treg transfer experiments further underscore the supportive role of NAC1-deficient Tregs in tumor growth. These findings suggest that modulating NAC1 expression in FoxP3+ Tregs could serve as a promising approach to augment antitumor immunity. Understanding the intricate interplay between NAC1 and Tregs opens avenues for potential therapeutic strategies targeting the tumor microenvironment (TME).
    Keywords:  Cancer; Immunology
    DOI:  https://doi.org/10.1172/jci.insight.186000
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