bims-tumime Biomed News
on Tumor microenvironment and metabolism
Issue of 2024‒03‒10
nine papers selected by
Alex Muir, University of Chicago

  1. Cold Spring Harb Perspect Med. 2024 Mar 04. pii: a041547. [Epub ahead of print]
      Tumors consist of cancer cells and a wide range of tissue resident and infiltrating cell types. Tumor metabolism, however, has largely been studied on whole tumors or cancer cells and the metabolism of infiltrating immune cells remains poorly understood. It is now clear from a range of analyses and metabolite rescue studies that metabolic adaptations to the tumor microenvironment (TME) directly impede T-cell and macrophage effector functions. The drivers of metabolic adaptation to the TME and metabolic immune suppression include depletion of essential nutrients, accumulation of waste products or immune suppression metabolites, and metabolic signaling through altered posttranslational modifications. Each infiltrating immune cell subset differs, however, with specific metabolic requirements and adaptations that can be maladaptive for antitumor immunity. Here, we review T-cell and macrophage adaptation and metabolic immune suppression in solid tumors. Ultimately, understanding and addressing these challenges will improve cancer immunotherapy and adoptive chimeric antigen receptor T-cell therapies.
  2. Immunol Rev. 2024 Mar 09.
      Natural Killer (NK) cells are a top contender in the development of adoptive cell therapies for cancer due to their diverse antitumor functions and ability to restrict their activation against nonmalignant cells. Despite their success in hematologic malignancies, NK cell-based therapies have been limited in the context of solid tumors. Tumor cells undergo various metabolic adaptations to sustain the immense energy demands that are needed to support their rapid and uncontrolled proliferation. As a result, the tumor microenvironment (TME) is depleted of nutrients needed to fuel immune cell activity and contains several immunosuppressive metabolites that hinder NK cell antitumor functions. Further, we now know that NK cell metabolic status is a main determining factor of their effector functions. Hence, the ability of NK cells to withstand and adapt to these metabolically hostile conditions is imperative for effective and sustained antitumor activity in the TME. With this in mind, we review the consequences of metabolic hostility in the TME on NK cell metabolism and function. We also discuss tumor-like metabolic programs in NK cell induced by STAT3-mediated expansion that adapt NK cells to thrive in the TME. Finally, we examine how other approaches can be applied to enhance NK cell metabolism in tumors.
    Keywords:  cancer immunotherapy; immunometabolism; metabolic reprogramming; natural killer cells; tumor metabolism
  3. Innovation (Camb). 2024 Mar 04. 5(2): 100583
      The tumor microenvironment is composed of a complex mixture of different cell types interacting under conditions of nutrient deprivation, but the metabolism therein is not fully understood due to difficulties in measuring metabolic fluxes and exchange of metabolites between different cell types in vivo. Genome-scale metabolic modeling enables estimation of such exchange fluxes as well as an opportunity to gain insight into the metabolic behavior of individual cell types. Here, we estimated the availability of nutrients and oxygen within the tumor microenvironment using concentration measurements from blood together with a metabolite diffusion model. In addition, we developed an approach to efficiently apply enzyme usage constraints in a comprehensive metabolic model of human cells. The combined modeling reproduced severe hypoxic conditions and the Warburg effect, and we found that limitations in enzymatic capacity contribute to cancer cells' preferential use of glutamine as a substrate to the citric acid cycle. Furthermore, we investigated the common hypothesis that some stromal cells are exploited by cancer cells to produce metabolites useful for the cancer cells. We identified over 200 potential metabolites that could support collaboration between cancer cells and cancer-associated fibroblasts, but when limiting to metabolites previously identified to participate in such collaboration, no growth advantage was observed. Our work highlights the importance of enzymatic capacity limitations for cell behaviors and exemplifies the utility of enzyme-constrained models for accurate prediction of metabolism in cells and tumor microenvironments.
  4. J Transl Med. 2024 Mar 03. 22(1): 229
      Natural killer (NK) cells are unique from other immune cells in that they can rapidly kill multiple neighboring cells without the need for antigenic pre-sensitization once the cells display surface markers associated with oncogenic transformation. Given the dynamic role of NK cells in tumor surveillance, NK cell-based immunotherapy is rapidly becoming a "new force" in tumor immunotherapy. However, challenges remain in the use of NK cell immunotherapy in the treatment of solid tumors. Many metabolic features of the tumor microenvironment (TME) of solid tumors, including oxygen and nutrient (e.g., glucose, amino acids) deprivation, accumulation of specific metabolites (e.g., lactate, adenosine), and limited availability of signaling molecules that allow for metabolic reorganization, multifactorial shaping of the immune-suppressing TME impairs tumor-infiltrating NK cell function. This becomes a key barrier limiting the success of NK cell immunotherapy in solid tumors. Restoration of endogenous NK cells in the TME or overt transfer of functionally improved NK cells holds great promise in cancer therapy. In this paper, we summarize the metabolic biology of NK cells, discuss the effects of TME on NK cell metabolism and effector functions, and review emerging strategies for targeting metabolism-improved NK cell immunotherapy in the TME to circumvent these barriers to achieve superior efficacy of NK cell immunotherapy.
    Keywords:  Immunotherapy; Natural killer cells; Solid tumors; Tumor microenvironment
  5. Nat Commun. 2024 Mar 05. 15(1): 1987
      Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster of metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs macrophage migration and lactate dehydrogenase inhibitor stiripentol emerges as the top hit. Combined profiling and functional studies demonstrate that lactate dehydrogenase A (LDHA)-directed extracellular signal-regulated kinase (ERK) pathway activates yes-associated protein 1 (YAP1)/ signal transducer and activator of transcription 3 (STAT3) transcriptional co-activators in glioblastoma cells to upregulate C-C motif chemokine ligand 2 (CCL2) and CCL7, which recruit macrophages into the tumor microenvironment. Reciprocally, infiltrating macrophages produce LDHA-containing extracellular vesicles to promote glioblastoma cell glycolysis, proliferation, and survival. Genetic and pharmacological inhibition of LDHA-mediated tumor-macrophage symbiosis markedly suppresses tumor progression and macrophage infiltration in glioblastoma mouse models. Analysis of tumor and plasma samples of glioblastoma patients confirms that LDHA and its downstream signals are potential biomarkers correlating positively with macrophage density. Thus, LDHA-mediated tumor-macrophage symbiosis provides therapeutic targets for glioblastoma.
  6. J Exp Clin Cancer Res. 2024 Mar 08. 43(1): 74
      Glutamine metabolism plays a pivotal role in cancer progression, immune cell function, and the modulation of the tumor microenvironment. Dysregulated glutamine metabolism has been implicated in cancer development and immune responses, supported by mounting evidence. Cancer cells heavily rely on glutamine as a critical nutrient for survival and proliferation, while immune cells require glutamine for activation and proliferation during immune reactions. This metabolic competition creates a dynamic tug-of-war between cancer and immune cells. Targeting glutamine transporters and downstream enzymes involved in glutamine metabolism holds significant promise in enhancing anti-tumor immunity. A comprehensive understanding of the intricate molecular mechanisms underlying this interplay is crucial for developing innovative therapeutic approaches that improve anti-tumor immunity and patient outcomes. In this review, we provide a comprehensive overview of recent advances in unraveling the tug-of-war of glutamine metabolism between cancer and immune cells and explore potential applications of basic science discoveries in the clinical setting. Further investigations into the regulation of glutamine metabolism in cancer and immune cells are expected to yield valuable insights, paving the way for future therapeutic interventions.
    Keywords:  Cancer; Glutamine metabolism; Immune cells; Therapeutic strategies; Tumor microenvironment
  7. Nat Biomed Eng. 2024 Mar 04.
      Extracellular pH impacts many molecular, cellular and physiological processes, and hence is tightly regulated. Yet, in tumours, dysregulated cancer cell metabolism and poor vascular perfusion cause the tumour microenvironment to become acidic. Here by leveraging fluorescent pH nanoprobes with a transistor-like activation profile at a pH of 5.3, we show that, in cancer cells, hydronium ions are excreted into a small extracellular region. Such severely polarized acidity (pH <5.3) is primarily caused by the directional co-export of protons and lactate, as we show for a diverse panel of cancer cell types via the genetic knockout or inhibition of monocarboxylate transporters, and also via nanoprobe activation in multiple tumour models in mice. We also observed that such spot acidification in ex vivo stained snap-frozen human squamous cell carcinoma tissue correlated with the expression of monocarboxylate transporters and with the exclusion of cytotoxic T cells. Severely spatially polarized tumour acidity could be leveraged for cancer diagnosis and therapy.
  8. J Clin Invest. 2024 Mar 05. pii: e170071. [Epub ahead of print]
      Antitumor responses of CD8+ T cells are tightly regulated by distinct metabolic fitness. High levels of glutathione (GSH) are observed in the majority of tumors contributing to cancer progression and treatment resistance in part by preventing glutathione peroxidase 4 (GPX4) dependent ferroptosis. Here, we show the necessity of the adenosine A2A receptor (A2AR) signaling and the glutathione (GSH)-GPX4 axis in orchestrating metabolic fitness and survival of functionally competent CD8+ T cells. Activated CD8+ T cells treated ex vivo with simultaneous inhibition of A2AR and lipid peroxidation acquire a superior capacity to proliferate and persist in vivo, demonstrating a translatable means to prevent ferroptosis in adoptive cell therapy (ACT). Additionally, we identify a particular cluster of intratumoral CD8+ T cells expressing a putative gene signature of GSH metabolism (GMGS) in association with clinical response and survival across several human cancers. Our study addresses a key role of GSH-GPX4 and adenosinergic pathways in fine-tuning the metabolic fitness of antitumor CD8+ T cells.
    Keywords:  Cancer immunotherapy; Immunology; Metabolism; T cells
  9. Cell Death Discov. 2024 Mar 07. 10(1): 118
      Colorectal cancer (CRC) is a malignancy that is widely prevalent worldwide. Due to its unsatisfactory treatment outcome and extremely poor prognosis, many studies on the molecular mechanisms and pathological mechanisms of CRC have been published in recent years. The tumor microenvironment (TME) is an extremely important feature of tumorigenesis and one of the hallmarks of tumor development. Metabolic reprogramming is currently a hot topic in tumor research, and studies on this topic have provided important insights into CRC development. In particular, metabolic reprogramming in cancer causes changes in the composition of energy and nutrients in the TME. Furthermore, it can alter the complex crosstalk between immune cells and associated immune factors, such as associated macrophages and T cells, which play important immune roles in the TME, in turn affecting the immune escape of tumors by altering immune surveillance. In this review, we summarize several metabolism-related processes affecting the immune microenvironment of CRC tumors. Our results showed that the immune microenvironment is regulated by metabolic reprogramming and influences the development of CRC.