bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2025–03–23
seven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Reducing Dietary Protein Enhances the Antitumor Effects of Chemotherapy through Immune-Mediated Mechanisms.
  2. Metabolic mechanisms of immunotherapy resistance.
  3. Extracellular Vesicles Secreted by Cancer-Associated Fibroblasts Drive Non-Invasive Cancer Cell Progression to Metastasis via TGF-β Signalling Hyperactivation.
  4. Mammary tumor development induces perturbation of liver glucose metabolism with inflammation and fibrosis.
  5. The tumor microenvironment is an ecosystem sustained by metabolic interactions.
  6. Phosphorylation of eIF2α suppresses the impairment of GSH/NADPH homeostasis and mitigates the activation of cell death pathways, including ferroptosis, during ER stress.
  7. AMPK is necessary for Treg functional adaptation to microenvironmental stress during malignancy and viral pneumonia.
  1. Mol Cancer Ther. 2025 Mar 19.
    Reducing Dietary Protein Enhances the Antitumor Effects of Chemotherapy through Immune-Mediated Mechanisms.
    Samantha C Mulkeen, Suchandrima Saha, Carmen R Ferrara, Vladimira Bibeva, Michael C Wood, Ji Dong K Bai, Tanara V Peres, Daniel Martinez-Martinez, Alex Montoya, Pavel Shliaha, Filipe Cabreiro, David C Montrose.
      Diet is believed to be an important mediator of oncogenesis and response to anti-cancer therapies, although no evidence-based dietary guidelines exist for patients with cancer. Limiting protein intake can suppress tumor growth by both inducing nutrient stress and enhancing anti-tumor immunity. However, little is known about the impact of reducing dietary protein on the efficacy of chemotherapy, the most widely used anti-cancer treatment. Here, we present evidence that reducing protein intake in mice by 50% stops the growth of established tumors, in parallel with inducing a stress response and DNA damage. Further, a reduced protein (RP) diet enhances tumor regression upon treatment with 5-fluorouracil (5-FU). This effect is accompanied by elevated apoptosis and suppressed mitosis of tumor cells. Proteomic analysis of tumors revealed marked differences between 5-FU treated mice fed control or RP diet including decreased abundance of proteins that mediate DNA repair and replication in mice consuming RP. In vitro studies mimicking amino acid changes found in tumors from RP-fed mice showed that cGAS/STING1 signaling, including transcription of Interferon beta 1, was maximally increased in 5-FU treated cells cultured in modified amino acid medium. These findings correlated with enhanced immune cell influx into tumors from mice treated with 5-FU while consuming a RP diet, an effect that was causally linked to improved response to chemotherapy. Collectively, these findings suggest that reducing dietary protein in cancer patients may enhance the efficacy of chemotherapy by promoting anti-tumor immunity.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-24-0545
  2. Explor Target Antitumor Ther. 2025 ;6 1002297
    Metabolic mechanisms of immunotherapy resistance.
    Luis Cabezón-Gutiérrez, Magda Palka-Kotlowska, Sara Custodio-Cabello, Beatriz Chacón-Ovejero, Vilma Pacheco-Barcia.
      Immunotherapy has revolutionized cancer treatment, yet its efficacy is frequently compromised by metabolic mechanisms that drive resistance. Understanding how tumor metabolism shapes the immune microenvironment is essential for developing effective therapeutic strategies. This review examines key metabolic pathways influencing immunotherapy resistance, including glucose, lipid, and amino acid metabolism. We discuss their impact on immune cell function and tumor progression, highlighting emerging therapeutic strategies to counteract these effects. Tumor cells undergo metabolic reprogramming to sustain proliferation, altering the availability of essential nutrients and generating toxic byproducts that impair cytotoxic T lymphocytes (CTLs) and natural killer (NK) cell activity. The accumulation of lactate, deregulated lipid metabolism, and amino acid depletion contribute to an immunosuppressive tumor microenvironment (TME). Targeting metabolic pathways, such as inhibiting glycolysis, modulating lipid metabolism, and restoring amino acid balance, has shown promise in enhancing immunotherapy response. Addressing metabolic barriers is crucial to overcoming immunotherapy resistance. Integrating metabolic-targeted therapies with immune checkpoint inhibitors may improve clinical outcomes. Future research should focus on personalized strategies to optimize metabolic interventions and enhance antitumor immunity.
    Keywords:  Immune resistance; cancer; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.37349/etat.2025.1002297
  3. J Extracell Vesicles. 2025 Mar;14(3): e70055
    Extracellular Vesicles Secreted by Cancer-Associated Fibroblasts Drive Non-Invasive Cancer Cell Progression to Metastasis via TGF-β Signalling Hyperactivation.
    Adilson Fonseca Teixeira, Yanhong Wang, Josephine Iaria, Peter Ten Dijke, Hong-Jian Zhu.
      Metastasis is the leading cause of cancer-related deaths. Cancer-associated fibroblasts (CAFs) are abundant components within the tumour microenvironment, playing critical roles in metastasis. Although increasing evidence supports a role for small extracellular vesicles (sEVs) in this process, their precise contribution and molecular mechanisms remain unclear, compromising the development of antimetastatic therapies. Here, we establish that CAF-sEVs drive metastasis by mediating CAF-cancer cell interaction and hyperactivating TGF-β signalling in tumour cells. Metastasis is abolished by genetically targeting CAF-sEV secretion and consequent reduction of TGF-β signalling in cancer cells. Pharmacological treatment with dimethyl amiloride (DMA) decreases CAFs' sEV secretion, reduces TGF-β signalling levels in tumour cells and abrogates metastasis and tumour self-seeding. This work defines a new mechanism required by CAFs to drive cancer progression, supporting the therapeutic targeting of EV trafficking to disable the driving forces of metastasis.
    Keywords:  TGF‐β; cancer‐associated fibroblasts; circulating tumour cells; extracellular vesicles; metastasis; therapy; tumour microenvironment
    DOI:  https://doi.org/10.1002/jev2.70055
  4. Am J Physiol Endocrinol Metab. 2025 Mar 19.
    Mammary tumor development induces perturbation of liver glucose metabolism with inflammation and fibrosis.
    Anouk Charlot, Anthony Bringolf, Joris Mallard, Amélie Jaulin, Emilie Crouchet, Anne-Laure Charles, Delphine Duteil, Fabien Alpy, Catherine-Laure Tomasetto, Thomas F Baumert, Joffrey Zoll.
      Cancer cells rely on glycolysis and lactic fermentation for ATP production, inducing an abnormal glucose uptake in tumors. However, it is largely unknown whether the increased tumor glucose consumption affects overall body glucose homeostasis including perturbation of the liver glucose production pathways. The effect of mammary tumor development on liver metabolism pathway was examined by using a mouse model based on FVB/N wild-type (WT-SD) and FVB/N-Tg(MMTV-PyVT)634Mul/J mice (Tg-SD), who develop spontaneous mammary tumors. Blood and livers were analyzed for metabolic changes, by measuring histological staining, signaling and insulin sensitivity. Tg-SD mice developed mammary tumors with an average weight of 6g, and cancer development increased total food intake without impacting body weight gain. Tumor development did not affect blood glycemia and lactate levels but increased insulin and HOMA-IR index (p=0.06). In the liver, Tg-SD mice with tumors exhibited a decrease in glycogen content, and an increase in gluconeogenesis gene expression, as G6pc, Pgc1α and Foxo1 (p<0.05), as well as Pepck and Ldha (p<0.01). Moreover, the phosphorylation of AMPK and AKT was significantly decreased (respectively (p<0.01 and p<0.05)). Surprisingly, liver fibrosis was markedly increased in Tg mice (p<0.05) alongside elevated inflammatory gene expression, such as IL1β (p<0.01) or IL6 (p<0.05). Here we found that the development of non-metastatic mammary tumors using the MMTV-PyMT mouse model disrupts liver function through the development of inflammation, fibrosis and metabolic perturbation, including an increase in glucose production and insulin resistance. Finally, these observations unravel a previously unknown metabolic crosstalk between the tumors and the liver.
    Keywords:  Breast cancer; Gluconeogenesis; Insulin resistance; Liver; Warburg effect
    DOI:  https://doi.org/10.1152/ajpendo.00498.2024
  5. Cell Rep. 2025 Mar 13. pii: S2211-1247(25)00203-7. [Epub ahead of print]44(3): 115432
    The tumor microenvironment is an ecosystem sustained by metabolic interactions.
    Emily Jane Kay, Sara Zanivan.
      Cancer-associated fibroblasts (CAFs) and immune cells make up two major components of the tumor microenvironment (TME), contributing to an ecosystem that can either support or restrain cancer progression. Metabolism is a key regulator of the TME, providing a means for cells to communicate with and influence each other, modulating tumor progression and anti-tumor immunity. Cells of the TME can metabolically interact directly through metabolite secretion and consumption or by influencing other aspects of the TME that, in turn, stimulate metabolic rewiring in target cells. Recent advances in understanding the subtypes and plasticity of cells in the TME both open up new avenues and create challenges for metabolically targeting the TME to hamper tumor growth and improve response to therapy. This perspective explores ways in which the CAF and immune components of the TME could metabolically influence each other, based on current knowledge of their metabolic states, interactions, and subpopulations.
    Keywords:  CAFs; CP: Cancer; CP: Metabolism; immune cells; metabolism; stroma immune; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2025.115432
  6. Mol Cells. 2025 Mar 13. pii: S1016-8478(25)00034-2. [Epub ahead of print] 100210
    Phosphorylation of eIF2α suppresses the impairment of GSH/NADPH homeostasis and mitigates the activation of cell death pathways, including ferroptosis, during ER stress.
    Hien Thi Le, Yong Hwan Kim, Mi-Jeong Kim, Seung Hwa Hyun, Hyeeun Kim, Su Wol Chung, Yeonsoo Joe, Hun Taeg Chung, Dong-Myung Shin, Sung Hoon Back.
      eIF2α phosphorylation helps maintain cellular homeostasis and overcome endoplasmic reticulum (ER) stress through transcriptional and translational reprogramming. This study aims to elucidate the transcriptional regulation of glutathione (GSH) and NADPH homeostasis through eIF2α phosphorylation and its impact on cell death during ER stress. eIF2α phosphorylation-deficient (A/A) cells exhibited decreased expression of multiple genes involved in GSH synthesis and NADPH production, leading to an exacerbated depletion of both cellular and mitochondrial GSH, as well as mitochondrial NADPH, during ER stress. Impaired GSH homeostasis resulted from deficient expression of ATF4 and/or its dependent factor, Nrf2, which are key transcription factors in the antioxidant response during ER stress. In contrast, the exacerbation of NADPH depletion may primarily be attributed to the dysregulated expression of mitochondrial serine-driven one-carbon metabolism pathway genes, which are regulated by an unidentified eIF2α phosphorylation-dependent mechanism during ER stress. Moreover, the eIF2α phosphorylation-ATF4 axis was responsible for upregulation of ferroptosis-inhibiting genes and downregulation of ferroptosis-activating genes upon ER stress. Therefore, ER stress strongly induced ferroptosis of A/A cells, which was significantly inhibited by treatments with cell-permeable GSH and the ferroptosis inhibitor ferrostatin-1 (Fer-1). ATF4 overexpression suppressed impairment of GSH homeostasis in A/A cells during ER stress by promoting expression of downstream target genes. Consequently, ATF4 overexpression mitigated ferroptosis as well as apoptosis of A/A cells during ER stress. Our findings underscore the importance of eIF2α phosphorylation in maintaining GSH/NADPH homeostasis and inhibiting ferroptosis through ATF4 and unidentified eIF2α phosphorylation-dependent target(s)-mediated transcriptional reprogramming during ER stress.
    Keywords:  ATF4; ER stress; Ferroptosis; Glutathione; Nrf2; eIF2α phosphorylation
    DOI:  https://doi.org/10.1016/j.mocell.2025.100210
  7. J Clin Invest. 2025 Mar 18. pii: e179572. [Epub ahead of print]
    AMPK is necessary for Treg functional adaptation to microenvironmental stress during malignancy and viral pneumonia.
    Manuel A Torres Acosta, Jonathan K Gurkan, Qianli Liu, Nurbek Mambetsariev, Carla Reyes Flores, Kathryn A Helmin, Anthony M Joudi, Luisa Morales-Nebreda, Kathleen Cheng, Hiam Abdala-Valencia, Samuel E Weinberg, Benjamin D Singer.
      CD4+FOXP3+ regulatory T (Treg) cells maintain self-tolerance, suppress the immune response to cancer, and protect against tissue injury during acute inflammation. Treg cells require mitochondrial metabolism to function, but how Treg cells adapt their metabolic programs to optimize their function during an immune response occurring in a metabolically stressed microenvironment remains unclear. Here, we tested whether Treg cells require the energy homeostasis-maintaining enzyme AMPK to adapt to metabolically aberrant microenvironments caused by malignancy or lung injury, finding that AMPK is dispensable for Treg cell immune-homeostatic function but is necessary for full Treg cell function in B16 melanoma tumors and during influenza virus pneumonia. AMPK-deficient Treg cells had lower mitochondrial mass and exhibited an impaired ability to maximize aerobic respiration. Mechanistically, we found that AMPK regulates DNA methyltransferase 1 to promote transcriptional programs associated with mitochondrial function in the tumor microenvironment. During viral pneumonia, we found that AMPK sustains metabolic homeostasis and mitochondrial activity. Induction of DNA hypomethylation was sufficient to rescue mitochondrial mass in AMPK-deficient Treg cells, linking AMPK function to mitochondrial metabolism via DNA methylation. These results define AMPK as a determinant of Treg cell adaptation to metabolic stress and offer potential therapeutic targets in cancer and tissue injury.
    Keywords:  Immunology; Intermediary metabolism; Mitochondria; Oncology; Pulmonology; T cells
    DOI:  https://doi.org/10.1172/JCI179572
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