bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2025–01–26
thirteen papers selected by
Oltea Sampetrean, Keio University
  1. Mannose: A game-changer for T cell immunotherapy.
  2. Biomimetic calcium-chelation nanoparticles reprogram tumor metabolism to enhance antitumor immunity.
  3. Selective deficiency of mitochondrial respiratory complex I subunits Ndufs4/6 causes tumor immunogenicity.
  4. Fuel for thought: targeting metabolism in lung cancer.
  5. Metabolic interplays between the tumour and the host shape the tumour macroenvironment.
  6. Immune evasion through mitochondrial transfer in the tumour microenvironment.
  7. Impaired oxidative phosphorylation drives primary tumor escape and metastasis.
  8. Neutrophil extracellular traps in tumor metabolism and microenvironment.
  9. Exercise-induced extracellular vesicles in reprogramming energy metabolism in cancer.
  10. Intratumoral microbiota, fatty acid metabolism, and tumor microenvironment constitute an unresolved trinity in colon adenocarcinoma.
  11. Glut3 overexpression improves environmental glucose uptake and antitumor efficacy of CAR-T cells in solid tumors.
  12. Comparison of Lean, Obese, and Weight Loss Models Reveals TREM2 Deficiency Attenuates Breast Cancer Growth Uniquely in Lean Mice and Alters Clonal T Cell Populations.
  13. Fine-tuning tumor immunogenicity with mitochondrial complex I.
  1. Cell Metab. 2025 Jan 15. pii: S1550-4131(24)00496-0. [Epub ahead of print]
    Mannose: A game-changer for T cell immunotherapy.
    Jingwei Ma, Shuai Tong, Jingxuan Xiao, Bo Huang.
      Metabolism influences the behavior of various immune cell types. In a recent Cancer Cell study, Qiu et al. revealed mannose metabolism as a prominent metabolic feature of tumor precursor exhausted T cells (Tpex) that is crucial for maintaining T cell stemness. Their work uncovers a novel metabolic mechanism that decouples T cell proliferation from differentiation, providing valuable insights into how metabolic modulation can be used to generate "better" T cells during the manufacturing process.
    DOI:  https://doi.org/10.1016/j.cmet.2024.12.014
  2. J Control Release. 2025 Jan 18. pii: S0168-3659(25)00056-2. [Epub ahead of print]
    Biomimetic calcium-chelation nanoparticles reprogram tumor metabolism to enhance antitumor immunity.
    Zheng Wang, Ming Wu, Yingmeng Jiang, Junjie Zhou, Sai Chen, Qizhi Wang, Honghao Sun, Yueyang Deng, Zhanwei Zhou, Minjie Sun.
      Metabolic reprogramming within the tumor microenvironment poses a significant obstacle to the therapeutic efficacy of antitumor immunity. Here, inspired by the diverse programme of cholesterol metabolism between tumor and immune cells, a biocompatible carboxy-modified cyclodextrin carrier equipped with a biomimetic surface was developed to encapsulate FX11 and Avasimibe (RM-CDC@FX11&Ava) for synergistic antitumor metabolic therapy and immunotherapy. Through the manipulation of calcium levels using poly-carboxylic compounds to initiate cholesterol biosynthesis, RM-CDC@FX11&Ava dynamically regulates glycolysis and blocks cholesterol esterification to navigate metabolic reprogramming. The resultant cholesterol augmentation triggered by RM-CDC@FX11&Ava could not only specifically induce 34.3 % tumor cell apoptosis but also promote 57.8 % dendritic cell maturation for antigen presentation and improve the effector function of T cells. Furthermore, the tumor immunosuppressive microenvironment was also reprogrammed by impairing Treg cells through the blockade of lactic acid. As a result, RM-CDC@FX11&Ava showed superior antitumor efficacy in mastadenoma and melanoma models.
    Keywords:  Antitumor immunotherapy; Biomimetic delivery system; Cholesterol metabolism; Glucose metabolism; Metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.jconrel.2025.01.046
  3. Nat Cancer. 2025 Jan 17.
    Selective deficiency of mitochondrial respiratory complex I subunits Ndufs4/6 causes tumor immunogenicity.
    Jiaxin Liang, Tevis Vitale, Xixi Zhang, Thomas D Jackson, Deyang Yu, Mark Jedrychowski, Steve P Gygi, Hans R Widlund, Kai W Wucherpfennig, Pere Puigserver.
      Cancer cells frequently rewire their metabolism to support proliferation and evade immune surveillance, but little is known about metabolic targets that could increase immune surveillance. Here we show a specific means of mitochondrial respiratory complex I (CI) inhibition that improves tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB). Targeted genetic deletion of either Ndufs4 or Ndufs6, but not other CI subunits, induces an immune-dependent growth attenuation in melanoma and breast cancer models. We show that deletion of Ndufs4 induces expression of the major histocompatibility complex (MHC) class I co-activator Nlrc5 and antigen presentation machinery components, most notably H2-K1. This induction of MHC-related genes is driven by a pyruvate dehydrogenase-dependent accumulation of mitochondrial acetyl-CoA, which leads to an increase in histone H3K27 acetylation within the Nlrc5 and H2-K1 promoters. Taken together, this work shows that selective CI inhibition restricts tumor growth and that specific targeting of Ndufs4 or Ndufs6 increases T cell surveillance and ICB responsiveness.
    DOI:  https://doi.org/10.1038/s43018-024-00895-x
  4. Transl Lung Cancer Res. 2024 Dec 31. 13(12): 3692-3717
    Fuel for thought: targeting metabolism in lung cancer.
    Jaime L Schneider, SeongJun Han, Christopher S Nabel.
      For over a century, we have appreciated that the biochemical processes through which micro- and macronutrients are anabolized and catabolized-collectively referred to as "cellular metabolism"-are reprogrammed in malignancies. Cancer cells in lung tumors rewire pathways of nutrient acquisition and metabolism to meet the bioenergetic demands for unchecked proliferation. Advances in precision medicine have ushered in routine genotyping of patient lung tumors, enabling a deeper understanding of the contribution of altered metabolism to tumor biology and patient outcomes. This paradigm shift in thoracic oncology has spawned a new enthusiasm for dissecting oncogenotype-specific metabolic phenotypes and creates opportunity for selective targeting of essential tumor metabolic pathways. In this review, we discuss metabolic states across histologic and molecular subtypes of lung cancers and the additional changes in tumor metabolic pathways that occur during acquired therapeutic resistance. We summarize the clinical investigation of metabolism-specific therapies, addressing successes and limitations to guide the evaluation of these novel strategies in the clinic. Beyond changes in tumor metabolism, we also highlight how non-cellular autonomous processes merit particular consideration when manipulating metabolic processes systemically, such as efforts to disentangle how lung tumor cells influence immunometabolism. As the future of metabolic therapeutics hinges on use of models that faithfully recapitulate metabolic rewiring in lung cancer, we also discuss best practices for harmonizing workflows to capture patient specimens for translational metabolic analyses.
    Keywords:  Lung cancer; immunometabolism; metabolism; resistance
    DOI:  https://doi.org/10.21037/tlcr-24-662
  5. Nat Rev Cancer. 2025 Jan 20.
    Metabolic interplays between the tumour and the host shape the tumour macroenvironment.
    Patricia Altea-Manzano, Amanda Decker-Farrell, Tobias Janowitz, Ayelet Erez.
      Metabolic reprogramming of cancer cells and the tumour microenvironment are pivotal characteristics of cancers, and studying these processes offer insights and avenues for cancer diagnostics and therapeutics. Recent advancements have underscored the impact of host systemic features, termed macroenvironment, on facilitating cancer progression. During tumorigenesis, these inherent features of the host, such as germline genetics, immune profile and the metabolic status, influence how the body responds to cancer. In parallel, as cancer grows, it induces systemic effects beyond the primary tumour site and affects the macroenvironment, for example, through inflammation, the metabolic end-stage syndrome of cachexia, and metabolic dysregulation. Therefore, understanding the intricate metabolic interplay between the tumour and the host is a growing frontier in advancing cancer diagnosis and therapy. In this Review, we explore the specific contribution of the metabolic fitness of the host to cancer initiation, progression and response to therapy. We then delineate the complex metabolic crosstalk between the tumour, the microenvironment and the host, which promotes disease progression to metastasis and cachexia. The metabolic relationships among the host, cancer pathogenesis and the consequent responsive systemic manifestations during cancer progression provide new perspectives for mechanistic cancer therapy and improved management of patients with cancer.
    DOI:  https://doi.org/10.1038/s41568-024-00786-4
  6. Nature. 2025 Jan 22.
    Immune evasion through mitochondrial transfer in the tumour microenvironment.
    Hideki Ikeda, Katsushige Kawase, Tatsuya Nishi, Tomofumi Watanabe, Keizo Takenaga, Takashi Inozume, Takamasa Ishino, Sho Aki, Jason Lin, Shusuke Kawashima, Joji Nagasaki, Youki Ueda, Shinichiro Suzuki, Hideki Makinoshima, Makiko Itami, Yuki Nakamura, Yasutoshi Tatsumi, Yusuke Suenaga, Takao Morinaga, Akiko Honobe-Tabuchi, Takehiro Ohnuma, Tatsuyoshi Kawamura, Yoshiyasu Umeda, Yasuhiro Nakamura, Yukiko Kiniwa, Eiki Ichihara, Hidetoshi Hayashi, Jun-Ichiro Ikeda, Toyoyuki Hanazawa, Shinichi Toyooka, Hiroyuki Mano, Takuji Suzuki, Tsuyoshi Osawa, Masahito Kawazu, Yosuke Togashi.
      Cancer cells in the tumour microenvironment use various mechanisms to evade the immune system, particularly T cell attack1. For example, metabolic reprogramming in the tumour microenvironment and mitochondrial dysfunction in tumour-infiltrating lymphocytes (TILs) impair antitumour immune responses2-4. However, detailed mechanisms of such processes remain unclear. Here we analyse clinical specimens and identify mitochondrial DNA (mtDNA) mutations in TILs that are shared with cancer cells. Moreover, mitochondria with mtDNA mutations from cancer cells are able to transfer to TILs. Typically, mitochondria in TILs readily undergo mitophagy through reactive oxygen species. However, mitochondria transferred from cancer cells do not undergo mitophagy, which we find is due to mitophagy-inhibitory molecules. These molecules attach to mitochondria and together are transferred to TILs, which results in homoplasmic replacement. T cells that acquire mtDNA mutations from cancer cells exhibit metabolic abnormalities and senescence, with defects in effector functions and memory formation. This in turn leads to impaired antitumour immunity both in vitro and in vivo. Accordingly, the presence of an mtDNA mutation in tumour tissue is a poor prognostic factor for immune checkpoint inhibitors in patients with melanoma or non-small-cell lung cancer. These findings reveal a previously unknown mechanism of cancer immune evasion through mitochondrial transfer and can contribute to the development of future cancer immunotherapies.
    DOI:  https://doi.org/10.1038/s41586-024-08439-0
  7. bioRxiv. 2025 Jan 09. pii: 2025.01.08.631936. [Epub ahead of print]
    Impaired oxidative phosphorylation drives primary tumor escape and metastasis.
    Emily N Arner, Erin Q Jennings, Daniel R Crooks, Christopher J Ricketts, Melissa M Wolf, Matthew A Cottam, Emilie L Fisher-Gupta, Martin Lang, Nunziata Maio, Yuki Shibata, Evan S Krystofiak, Logan M Vlach, Zaid Hatem, Alexander M Blatt, Darren R Heintzman, Allison E Sewell, Emma S Hathaway, KayLee K Steiner, Xiang Ye, Samuel Schaefer, Zachary A Bacigalupa, W Marston Linehan, Kathryn E Beckermann, Frank M Mason, Kamran Idrees, W Kimryn Rathmell, Jeffrey C Rathmell.
      Metastasis causes most cancer deaths and reflects transitions from primary tumor escape to seeding and growth at metastatic sites. Epithelial-to-mesenchymal transition (EMT) is important early in metastasis to enable cancer cells to detach from neighboring cells, become migratory, and escape the primary tumor. While different phases of metastasis expose cells to variable nutrient environments and demands, the metabolic requirements and plasticity of each step are uncertain. Here we show that EMT and primary tumor escape are stimulated by disrupted oxidative metabolism. Using Renal Cell Carcinoma (RCC) patient samples, we identified the mitochondrial electron transport inhibitor NDUFA4L2 as upregulated in cells undergoing EMT. Deletion of NDUFA4L2 enhanced oxidative metabolism and prevented EMT and metastasis while NDUFA4L2 overexpression enhanced these processes. Mechanistically, NDUFA4L2 suppressed oxidative phosphorylation and caused citric acid cycle intermediates to accumulate, which modified chromatin accessibility of EMT-related loci to drive primary tumor escape. The effect of impaired mitochondrial metabolism to drive EMT appeared general, as renal cell carcinoma patient tumors driven by fumarate hydratase mutations with disrupted oxidative phosphorylation were highly metastatic and also had robust EMT. These findings highlight the importance of dynamic shifts in metabolism for cell migration and metastasis, with mitochondrial impairment driving early phases of this process. Understanding mitochondrial dynamics may have important implications in both basic and translational efforts to prevent cancer deaths.
    DOI:  https://doi.org/10.1101/2025.01.08.631936
  8. Biomark Res. 2025 Jan 23. 13(1): 12
    Neutrophil extracellular traps in tumor metabolism and microenvironment.
    Zhanrui Liu, Yuanyao Dou, Conghua Lu, Rui Han, Yong He.
      Neutrophil extracellular traps (NETs) are intricate, web-like formations composed of DNA, histones, and antimicrobial proteins, released by neutrophils. These structures participate in a wide array of physiological and pathological activities, including immune rheumatic diseases and damage to target organs. Recently, the connection between NETs and cancer has garnered significant attention. Within the tumor microenvironment and metabolism, NETs exhibit multifaceted roles, such as promoting the proliferation and migration of tumor cells, influencing redox balance, triggering angiogenesis, and driving metabolic reprogramming. This review offers a comprehensive analysis of the link between NETs and tumor metabolism, emphasizing areas that remain underexplored. These include the interaction of NETs with tumor mitochondria, their effect on redox states within tumors, their involvement in metabolic reprogramming, and their contribution to angiogenesis in tumors. Such insights lay a theoretical foundation for a deeper understanding of the role of NETs in cancer development. Moreover, the review also delves into potential therapeutic strategies that target NETs and suggests future research directions, offering new perspectives on the treatment of cancer and other related diseases.
    Keywords:  Angiogenesis; Metabolic reprogramming; Mitochondria; Neutrophil Extracellular traps; ROS; Redox reaction; Tumor metabolism
    DOI:  https://doi.org/10.1186/s40364-025-00731-z
  9. Front Oncol. 2024 ;14 1480074
    Exercise-induced extracellular vesicles in reprogramming energy metabolism in cancer.
    Marju Puurand, Alicia Llorente, Aija Linē, Tuuli Kaambre.
      Cancer is caused by complex interactions between genetic, environmental, and lifestyle factors, making prevention strategies, including exercise, a promising avenue for intervention. Physical activity is associated with reduced cancer incidence and progression and systemic anti-cancer effects, including improved tumor suppression and prolonged survival in preclinical models. Exercise impacts the body's nutrient balance and stimulates the release of several exercise-induced factors into circulation. The mechanisms of how exercise modulates cancer energy metabolism and the tumor microenvironment through systemic effects mediated, in part, by extracellular vesicles (EVs) are still unknown. By transferring bioactive cargo such as miRNAs, proteins and metabolites, exercise-induced EVs may influence cancer cells by altering glycolysis and oxidative phosphorylation, potentially shifting metabolic plasticity - a hallmark of cancer. This short review explores the roles of EVs in cancer as mediators to reprogram cellular energy metabolism through exchanging information inside the tumor microenvironment, influencing immune cells, fibroblast and distant cells. Considering this knowledge, further functional studies into exercise-induced EVs and cellular energy production pathways could inform more specific exercise interventions to enhance cancer therapy and improve patient outcomes.
    Keywords:  cancer; cancer microenvironment; energy metabolism; extracellular vesicles; physical exercise
    DOI:  https://doi.org/10.3389/fonc.2024.1480074
  10. Sci Rep. 2025 Jan 20. 15(1): 2568
    Intratumoral microbiota, fatty acid metabolism, and tumor microenvironment constitute an unresolved trinity in colon adenocarcinoma.
    Guangyi Liu, Kun Liu, Lei Ji, Yang Li.
      The intratumoral microbiota, fatty acid metabolism (FAM), and tumor microenvironment (TME) all provide insights into the management of colon adenocarcinoma (COAD). But the biological link among the three remains unclear. Here, we analyzed intratumoral microbiome samples and matched host transcriptome samples from 420 patients with COAD in The Cancer Genome Atlas (TCGA). All patients were divided into two subtypes (FAM_high and FAM_low) based on the Gene set variation analysis (GSVA) score of FAM pathway. Furthermore, we found significant difference in the intratumoral microbiota signatures between the two subtypes. In-depth analysis suggested that specific microbes in tumors may indirectly modify the TME, particularly stromal cell populations, by modulating the FAM process. More importantly, the crosstalk between the three can have a significant impact on prognosis, response to immunotherapy, and drug sensitivity of patients. Pathological image profiling showed that changes in the TME originating from intratumoral microbiota disturbance could be reflected in pathological image features. In summary, our study provides novel insights into the biological links among the intratumoral microbiota, FAM, and the TME in COAD, and offer guidance for the therapeutic opportunities that target intratumoral microbes.
    Keywords:  Colon adenocarcinoma; Fatty acid metabolism; Intratumoral microbiota; Tumor microenvironment
    DOI:  https://doi.org/10.1038/s41598-025-87194-2
  11. J Immunother Cancer. 2025 Jan 16. pii: e010540. [Epub ahead of print]13(1):
    Glut3 overexpression improves environmental glucose uptake and antitumor efficacy of CAR-T cells in solid tumors.
    Wenhao Hu, Feng Li, Yue Liang, Shasha Liu, Shumin Wang, Chunyi Shen, Yuyu Zhao, Hui Wang, Yi Zhang.
       BACKGROUND: Glucose deprivation inhibits T-cell metabolism and function. Glucose levels are low in the tumor microenvironment of solid tumors and insufficient glucose uptake limits the antitumor response of T cells. Furthermore, glucose restriction can contribute to the failure of chimeric antigen receptor T (CAR-T) cell therapy for solid tumors. However, the impact of glucose restriction remains unknown in CAR-T cell therapy.
    METHODS: Glucose transporters were detected and overexpressed in CAR-T cells. The impacts of glucose restriction on CAR-T cells were checked in vitro and in vivo.
    RESULTS: Glucose restriction significantly decreased CAR-T cell activation, effector function, and expansion. CAR-T cells expressed high levels of the glucose transporter Glut1, which has a low affinity for glucose. Overexpression of Glut1 failed to improve CAR-T cell function under glucose-restricted conditions. In contrast, the function and antitumor potential of CAR-T cells was enhanced by the overexpression of Glut3, which has the highest affinity for glucose among the Glut transporter family and is expressed in minor parts of CAR-T cells. Glut3-overexpressing CAR-T cells demonstrated increased tumoricidal efficacy in multiple xenografts and syngenetic mouse models. Furthermore, Glut3 overexpression activated the PI3K/Akt pathway and increased OXPHOS and mitochondrial fitness.
    CONCLUSIONS: We provide a direct and effective approach to enhance low glucose uptake levels by CAR-T cells and improve their antitumor efficacy against solid tumors.
    Keywords:  Chimeric antigen receptor - CAR; Mitochondria; Nutrition; Solid tumor
    DOI:  https://doi.org/10.1136/jitc-2024-010540
  12. Cancer Res. 2025 Jan 22.
    Comparison of Lean, Obese, and Weight Loss Models Reveals TREM2 Deficiency Attenuates Breast Cancer Growth Uniquely in Lean Mice and Alters Clonal T Cell Populations.
    Elysa W Pierro, Matthew A Cottam, Hanbing An, Brian D Lehmann, Jennifer A Pietenpol, Kathryn E Wellen, Liza Makowski, Jeffrey C Rathmell, Barbara Fingleton, Alyssa H Hasty.
      Obesity is an established risk factor for breast cancer development and poor prognosis. The adipose environment surrounding breast tumors, which is inflamed in obesity, has been implicated in tumor progression, and TREM2, a transmembrane receptor expressed on macrophages in adipose tissue and tumors, is an emerging therapeutic target for cancer. A better understanding of the mechanisms for the obesity-breast cancer association and the potential benefits of weight loss could help inform treatment strategies. Here, we utilized lean, obese, and weight loss mouse models to examine the impacts of TREM2 deficiency (Trem2+/+ and Trem2-/-) on postmenopausal breast cancer depending on weight history conditions. Trem2 deficiency constrained tumor growth in lean, but not obese or weight loss, mice. Single-cell RNA sequencing, in conjunction with VDJ sequencing of tumor and tumor-adjacent mammary adipose tissue (mATTum-adj) immune cells, revealed differences in the immune landscapes across the different models. Tumors of lean Trem2-/- mice exhibited a shift in clonal CD8+ T cells from an exhausted to an effector memory state, accompanied increased clonality of CD4+ Th1 cells, that was not observed in any other diet-genotype group. Notably, identical T cell clonotypes were identified in the tumor and mATTum-adj of the same mouse. Finally, anti-PD-1 therapy restricted tumor growth in lean and weight loss, but not obese, mice. These findings indicate that weight history could impact the efficacy of TREM2 inhibition in postmenopausal breast cancer. The reported immunological interactions between tumors and the surrounding adipose tissue highlight significant differences under obese and weight loss conditions.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-3511
  13. Nat Cancer. 2025 Jan 17.
    Fine-tuning tumor immunogenicity with mitochondrial complex I.
    Désirée Schatton, Christian Frezza.
      
    DOI:  https://doi.org/10.1038/s43018-024-00874-2
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