bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2025–01–05
eight papers selected by
Oltea Sampetrean, Keio University
  1. Targeting glutamine metabolism crosstalk with tumor immune response.
  2. Lipids guide T cell antitumor immunity by shaping their metabolic and functional fitness.
  3. Metabolism of cancer cells and immune cells in the initiation, progression, and metastasis of cancer.
  4. Iron metabolism and the tumor microenvironment: A new perspective on cancer intervention and therapy (Review).
  5. The protein circPETH-147aa regulates metabolic reprogramming in hepatocellular carcinoma cells to remodel immunosuppressive microenvironment.
  6. FOXP3 Transcriptionally Activates Fatty Acid Scavenger Receptor CD36 in Tumour-Induced Treg Cells.
  7. Engineering immunity using metabolically active polymeric nanoparticles.
  8. Effects of metabolism upon immunity: Targeting myeloid-derived suppressor cells for the treatment of breast cancer is a promising area of study.
  1. Biochim Biophys Acta Rev Cancer. 2024 Dec 31. pii: S0304-419X(24)00188-4. [Epub ahead of print] 189257
    Targeting glutamine metabolism crosstalk with tumor immune response.
    Chenshuang Dong, Yan Zhao, Yecheng Han, Ming Li, Guiling Wang.
      Glutamine, akin to glucose, is a fundamental nutrient for human physiology. Tumor progression is often accompanied by elevated glutamine consumption, resulting in a disrupted nutritional balance and metabolic reprogramming within the tumor microenvironment. Furthermore, immune cells, which depend on glutamine for metabolic support, may experience functional impairments and dysregulation. Although the role of glutamine in tumors has been extensively studied, the specific impact of glutamine competition on immune responses, as well as the precise cellular alterations within immune cells, remains incompletely understood. In this review, we summarize the consequences of glutamine deprivation induced by tumor-driven glutamine uptake on immune cells, assessing the underlying mechanisms from the perspective of various components of the immune microenvironment. Additionally, we discuss the potential synergistic effects of glutamine supplementation and immunotherapy, offering insights into future research directions. This review provides compelling evidence for the integration of glutamine metabolism and immunotherapy as a promising strategy in cancer therapy.
    Keywords:  Glutamine deprivation; Glutamine therapy; Immune cells; Immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2024.189257
  2. Trends Endocrinol Metab. 2024 Dec 31. pii: S1043-2760(24)00321-7. [Epub ahead of print]
    Lipids guide T cell antitumor immunity by shaping their metabolic and functional fitness.
    Letizia Rumiano, Teresa Manzo.
      Lipids are metabolic messengers essential for energy production, membrane structure, and signal transduction. Beyond their recognized role, lipids have emerged as metabolic rheostats of T cell responses, with distinct species differentially modulating CD8+ T cell (CTL) fate and function. Indeed, lipids can influence T cell signaling by altering their membrane composition; in addition, they can affect the differentiation path of T cells through cellular metabolism. This Review discusses the ability of lipids to shape T cell phenotypes and functions. Based on this link between lipid metabolism, metabolic fitness and immunosurveillance, we suggest that lipid could be rationally integrated in the context of immunotherapies to fine-tune fitness and function of adoptive T cell therapy (ACT) products.
    Keywords:  CD8 T cells; antitumor immunity; immunotherapy; lipids; metabolism
    DOI:  https://doi.org/10.1016/j.tem.2024.11.014
  3. Theranostics. 2025 ;15(1): 155-188
    Metabolism of cancer cells and immune cells in the initiation, progression, and metastasis of cancer.
    Mingxia Jiang, Huapan Fang, Huayu Tian.
      The metabolism of cancer and immune cells plays a crucial role in the initiation, progression, and metastasis of cancer. Cancer cells often undergo metabolic reprogramming to sustain their rapid growth and proliferation, along with meeting their energy demands and biosynthetic needs. Nevertheless, immune cells execute their immune response functions through the specific metabolic pathways, either to recognize, attack, and eliminate cancer cells or to promote the growth or metastasis of cancer cells. The alteration of cancer niches will impact the metabolism of both cancer and immune cells, modulating the survival and proliferation of cancer cells, and the activation and efficacy of immune cells. This review systematically describes the key characteristics of cancer cell metabolism and elucidates how such metabolic traits influence the metabolic behavior of immune cells. Moreover, this article also highlights the crucial role of immune cell metabolism in anti-tumor immune responses, particularly in priming T cell activation and function. By comprehensively exploring the metabolic crosstalk between cancer and immune cells in cancer niche, the aim is to discover novel strategies of cancer immunotherapy and provide effective guidance for clinical research in cancer treatment. In addition, the review also discusses current challenges such as the inadequacy of relevant diagnostic technologies and the issue of multidrug resistance, and proposes potential solutions including bolstering foundational cancer research, fostering technological innovation, and implementing precision medicine approaches. In-depth research into the metabolic effects of cancer niches can improve cancer treatment outcomes, prolong patients' survival period and enhance their quality of life.
    Keywords:  Anti-tumor immune responses; Cancer immunotherapy; Cancer niches; Metabolic reprogramming; Metabolism of cancer and immune cells
    DOI:  https://doi.org/10.7150/thno.103376
  4. Int J Mol Med. 2025 Mar;pii: 39. [Epub ahead of print]55(3):
    Iron metabolism and the tumor microenvironment: A new perspective on cancer intervention and therapy (Review).
    Xiaorui Bu, Lufang Wang.
      Iron metabolism plays a crucial role in the tumor microenvironment, influencing various aspects of cancer cell biology and tumor progression. This review discusses the regulatory mechanisms of iron metabolism within the tumor microenvironment and highlights how tumor cells and associated stromal cells manage iron uptake, accumulation and regulation. The sources of iron within tumors and the biological importance of ferroptosis in cancer were explored, focusing on its mechanisms, biological effects and, in particular, its tumor‑suppressive properties. Furthermore, the protective strategies employed by cancer cells to evade ferroptosis were examined. This review also delves into the intricate relationship between iron metabolism and immune modulation within the tumor microenvironment, detailing the impact on tumor‑associated immune cells and immune evasion. The interplay between ferroptosis and immunotherapy is discussed and potential strategies to enhance cancer immunotherapy by modulating iron metabolism are presented. Finally, the current ferroptosis‑based cancer therapeutic approaches were summarized and future directions for therapies that target iron metabolism were proposed.
    Keywords:  cancer immunotherapy; cancer therapy; ferroptosis; iron metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3892/ijmm.2024.5480
  5. Nat Commun. 2025 Jan 02. 16(1): 333
    The protein circPETH-147aa regulates metabolic reprogramming in hepatocellular carcinoma cells to remodel immunosuppressive microenvironment.
    Tian Lan, Fengwei Gao, Yunshi Cai, Yinghao Lv, Jiang Zhu, Hu Liu, Sinan Xie, Haifeng Wan, Haorong He, Kunlin Xie, Chang Liu, Hong Wu.
      Metabolic reprogramming fuels cancer cell metastasis and remodels the immunosuppressive tumor microenvironment (TME). We report here that circPETH, a circular RNA (circRNA) transported via extracellular vesicles (EVs) from tumor-associated macrophages (TAMs) to hepatocellular carcinoma (HCC) cells, facilitates glycolysis and metastasis in recipient HCC cells. Mechanistically, circPETH-147aa, encoded by circPETH in an m6A-driven manner, promotes PKM2-catalyzed ALDOA-S36 phosphorylation via the MEG pocket. Furthermore, circPETH-147aa impairs anti-HCC immunity by increasing HuR-dependent SLC43A2 mRNA stability and driving methionine and leucine deficiency in cytotoxic CD8+ T cells. Importantly, through virtual and experimental screening, we find that a small molecule, Norathyriol, is an effective inhibitor that targets the MEG pocket on the circPETH-147aa surface. Norathyriol reverses circPETH-147aa-facilitated acquisition of metabolic and metastatic phenotypes by HCC cells, increases anti-PD1 efficacy, and enhances cytotoxic CD8+ T-cell function. Here we show that Norathyriol is a promising anti-HCC agent that contributes to attenuating the resistance of advanced HCC to immune checkpoint blocker (ICB) therapies.
    DOI:  https://doi.org/10.1038/s41467-024-55577-0
  6. Immunology. 2024 Dec 30.
    FOXP3 Transcriptionally Activates Fatty Acid Scavenger Receptor CD36 in Tumour-Induced Treg Cells.
    Subhanki Dhar, Tania Sarkar, Sayantan Bose, Subhadip Pati, Dwaipayan Chakraborty, Dia Roy, Abir K Panda, Aharna Guin, Sumon Mukherjee, Kuladip Jana, Diptendra K Sarkar, Gaurisankar Sa.
      The host immune system is adapted in a variety of ways by tumour microenvironment and growing tumour interacts to promote immune escape. One of these adaptations is manipulating the metabolic processes of cells in the tumour microenvironment. The growing tumour aggressively utilise glucose, its primary energy source available in tumour site, and produce lactate by Warburg effect. In such a hostile environment, tumour-infiltrating immune cells are unable to survive metabolically. Tumour-infiltrating CD4+ Treg cells, on the other hand, adapted to an alternative energy-generating system, switching from the highly-competitive glucose to the fatty-acid metabolic pathway, by down-regulating glucose-metabolising genes and up-regulating fatty-acid metabolising genes. Tregs with high-levels of the fatty acid scavenger receptor CD36, a key component of the fatty-acid metabolic pathway, aided this metabolic shift. Treg cell formation was hampered when the fatty-acid metabolic pathway was disrupted, showing that it is necessary for Treg cell development. FOXP3, the Treg lineage-specific transcription factor, regulates fatty-acid metabolism by inducing CD36 transcription. A high-fat diet enhanced Treg development while suppressing anti-tumour immunity, whereas a low-fat diet suppressed Treg development. The altered metabolism of tumour-infiltrating Treg cells enables their rapid generation and survival in the hostile tumour microenvironment, aiding cancer progression. Fascinatingly, mice fed with a low-fat diet showed a positive prognosis with chemotherapy than mice fed with a high-fat diet. Thus, a maximum efficacy of chemotherapy might be achieved by altering diet composition during chemotherapy, providing a promising indication for future cancer treatment.
    Keywords:  CD36; Treg; cancer; metabolism; tumour microenvironment
    DOI:  https://doi.org/10.1111/imm.13887
  7. Trends Biotechnol. 2024 Dec 27. pii: S0167-7799(24)00345-7. [Epub ahead of print]
    Engineering immunity using metabolically active polymeric nanoparticles.
    Kate V Griffin, Michael N Saunders, Costas A Lyssiotis, Lonnie D Shea.
      Immune system functions play crucial roles in both health and disease, and these functions are regulated by their metabolic programming. The field of immune engineering has emerged to develop therapeutic strategies, including polymeric nanoparticles (NPs), that can direct immune cell phenotype and function by directing immunometabolic changes. Precise control of bioenergetic processes may offer the opportunity to prevent undesired immune activity and improve disease-specific outcomes. In this review we discuss the role that polymeric NPs can play in shaping immunometabolism and subsequent immune system activity through particle-mediated delivery of metabolically active agents as either structural components or cargo.
    Keywords:  immunoengineering; immunometabolism; metabolic reprogramming; polymeric nanoparticle
    DOI:  https://doi.org/10.1016/j.tibtech.2024.11.016
  8. Int Immunopharmacol. 2024 Dec 30. pii: S1567-5769(24)02414-7. [Epub ahead of print]147 113892
    Effects of metabolism upon immunity: Targeting myeloid-derived suppressor cells for the treatment of breast cancer is a promising area of study.
    Yulin Wang, Qiutong Dong, Menghan Yuan, Jingxian Hu, Peizhe Lin, Yijing Yan, Yu Wang, Yanyan Wang.
      Breast cancer (BC) ranks among the most prevalent malignancies affecting women, with advanced-stage patients facing an increased mortality risk. Myeloid-derived suppressor cells (MDSCs) contribute significantly to poor prognostic outcomes. Research has concentrated predominantly on the immunological mechanisms underlying MDSC functions, but a comprehensive investigation into the metabolic interactions between BC cells and MDSCs is lacking. In a hypoxic tumor microenvironment (TME), BC cells can enhance aerobic-glycolysis rates, upregulate expression of key lipid metabolism enzymes such as cluster of differentiation (CD) 36 and 5-lipoxygenase (5-LOX), accelerate glutamine (Gln) uptake, and elevate extracellular adenosine (eADO) levels, thereby fostering MDSC proliferation and amplifying immune suppression. Concurrently, alterations in the metabolic state of MDSCs also influence BC progression. To ensure adequate proliferative resources, MDSCs upregulate the pentose phosphate pathway and expedite glycolysis for energy supply while increasing the expression of fatty acid transport proteins (FATPs) such as CD36 and fatty acid transporter 2 (FATP2) to maintain intracellular lipid availability, thereby enhancing their adaptability within the TME. Furthermore, MDSCs undermine T-cell anti-tumor efficacy by depleting essential amino acids (AAs), such as arginine (Arg), tryptophan (Trp), and cysteine (Cys), required for T-cell function. This review elucidates how pharmacological agents such as metformin, liver X receptor (LXR) agonists, and 6-diazo-5-oxo-L-norleucine (DON) can augment anti-cancer treatment efficacy by targeting metabolic pathways in MDSCs. We systematically delineate the mechanisms governing interactions between BC cells and MDSCs from a metabolic standpoint while summarizing therapeutic strategies to modulate metabolism within MDSCs. Our review provides a framework for optimizing MDSC applications in BC immunotherapy.
    Keywords:  Breast cancer; Immunity; Metabolism; Myeloid-derived suppressor cells; Targeted therapy
    DOI:  https://doi.org/10.1016/j.intimp.2024.113892
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