bims-trytim Biomed News
on Tryptophan metabolism in tumour-immune microenvironment
Issue of 2024–06–16
seven papers selected by
Jialin Feng, University of Dundee
  1. The Mutual Regulatory Role of Ferroptosis and Immunotherapy in Anti-tumor Therapy.
  2. Cholesterol-ferroptosis nexus: Unveiling novel cancer therapeutic avenues.
  3. Research progress on the mechanism and signalling pathway of ferroptosis and its potential role in dermatosis research.
  4. Targeting ferroptosis regulators by natural products in colorectal cancer.
  5. CRISPR activation screens identify the SWI/SNF ATPases as suppressors of ferroptosis.
  6. Exploiting ferroptosis vulnerabilities in cancer.
  7. Chemo-immunotherapy by nanoliposomal epacadostat and docetaxel combination to IDO1 inhibition and tumor microenvironment suppression.
  1. Apoptosis. 2024 Jun 09.
    The Mutual Regulatory Role of Ferroptosis and Immunotherapy in Anti-tumor Therapy.
    Zhiguo Mao, Yilong Hu, Yinan Zhao, Xiaolei Zhang, Lin Guo, Xiaoran Wang, Jinying Zhang, Mingsan Miao.
      Ferroptosis is a form of cell death that is triggered by the presence of ferrous ions and is characterized by lipid peroxidation induced by these ions. The mechanism exhibits distinct morphological characteristics compared to apoptosis, autophagy, and necrosis. A notable aspect of ferroptosis is its ability to inhibit uncontrolled tumor replication and immortalization, especially in malignant, drug-resistant, and metastatic tumors. Additionally, immunotherapy, a novel therapeutic approach for tumors, has been found to have a reciprocal regulatory relationship with ferroptosis in the context of anti-tumor therapy. A comprehensive analysis of ferroptosis and immunotherapy in tumor therapy is presented in this paper, highlighting the potential for mutual adjuvant effects. Specifically, we discuss the mechanisms underlying ferroptosis and immunotherapy, emphasizing their ability to improve the tumor immune microenvironment and enhance immunotherapeutic effects. Furthermore, we investigate how immunotherapeutic factors may increase the sensitivity of tumor cells to ferroptosis. We aim to provide a prospective view of the promising value of combined ferroptosis and immunotherapy in anticancer therapy by elucidating the mutual regulatory network between each.
    Keywords:  Combined therapy; Ferroptosis; Immune checkpoint; Immunotherapy; Tumor
    DOI:  https://doi.org/10.1007/s10495-024-01988-9
  2. Cancer Lett. 2024 Jun 08. pii: S0304-3835(24)00440-3. [Epub ahead of print]597 217046
    Cholesterol-ferroptosis nexus: Unveiling novel cancer therapeutic avenues.
    Jaewang Lee, Jong-Lyel Roh.
      Ferroptosis, a novel form of regulated cell death characterized by iron-mediated lipid peroxidation, holds immense potential in cancer therapeutics due to its role in tumor progression and resistance. This review predominantly explores the intricate relationship between ferroptosis and cholesterol metabolism pathways, mainly focusing on the cholesterol biosynthesis pathway. This review highlights the therapeutic implications of targeting cholesterol metabolism pathways for cancer treatment by delving into the mechanisms underlying ferroptosis regulation. Strategies such as inhibiting HMG-CoA reductase and suppressing squalene synthesis offer promising avenues for inducing ferroptosis in cancer cells. Moreover, insights into targeting the 7-dehydrocholesterol pathway provide novel perspectives on modulating ferroptosis susceptibility and managing ferroptosis-associated diseases. Understanding the interplay between ferroptosis and cholesterol metabolism pathways underscores the potential of lipid metabolism modulation as an innovative therapeutic approach in cancer treatment.
    Keywords:  Biosynthesis; Cancer; Cholesterol; Ferroptosis; Lipid peroxidation
    DOI:  https://doi.org/10.1016/j.canlet.2024.217046
  3. Exp Dermatol. 2024 Jun;33(6): e15114
    Research progress on the mechanism and signalling pathway of ferroptosis and its potential role in dermatosis research.
    Min Li, Jian Gong, Qiao Liu, Weiwei Wu.
      Ferroptosis is a novel type of cell death that is dependent on lipid peroxidation and iron accumulation, which distinguishes it from other types of programmed cell death. Current research indicates a significant association between ferroptosis and various pathological conditions, including cancer, neurological disorders, and cardiovascular diseases, albeit with a relatively unexplored role in dermatological afflictions. This paper elaborates on the mechanisms and signalling pathways of ferroptosis, summarizing the recent studies on ferroptosis and its related factors in dermatosis. Our objective is to shed light on novel perspectives and therapeutic strategies for dermatosis, enhancing the understanding of this under-researched area through this comprehensive review.
    Keywords:  dermatosis; ferroptosis; mechanism; research progress; signalling pathway
    DOI:  https://doi.org/10.1111/exd.15114
  4. Front Pharmacol. 2024 ;15 1374722
    Targeting ferroptosis regulators by natural products in colorectal cancer.
    Yiping Zhang, Jun Xie.
      Colorectal cancer (CRC) poses a significant global health challenge, ranking as the third most diagnosed cancer and the second leading cause of cancer-related deaths. Despite advancements in treatment, challenges such as delayed diagnosis, multidrug resistance, and limited therapeutic effectiveness persist, emphasizing the need for innovative approaches. This review explores the potential of natural products, nutraceuticals, and phytochemicals for targeting ferroptosis-related regulators as a novel strategy in CRC. Ferroptosis, a form of regulated cell death characterized by iron-dependent lethal lipid peroxide accumulation, holds substantial importance in CRC progression and therapy resistance. Natural products, known for their diverse bioactive effects and favorable safety profiles, emerge as promising candidates to induce ferroptosis in CRC cells. Exploring amino acid, iron, lipid metabolism regulators, and oxidative stress regulators reveals promising avenues for inducing cell death in CRC. This comprehensive review provides insights into the multifaceted effects of natural products on proteins integral to ferroptosis regulation, including GPX4, SLC7A11, ACSL4, NCOA4, and HO-1. By elucidating the intricate mechanisms through which natural products modulate these proteins, this review lays the foundation for a promising therapeutic strategy in CRC.
    Keywords:  ROS; colorectal cancer; ferroptosis; iron; natural products
    DOI:  https://doi.org/10.3389/fphar.2024.1374722
  5. Cell Rep. 2024 Jun 11. pii: S2211-1247(24)00673-9. [Epub ahead of print]43(6): 114345
    CRISPR activation screens identify the SWI/SNF ATPases as suppressors of ferroptosis.
    Kamakoti P Bhat, Jinchu Vijay, Caroline K Vilas, Jyoti Asundi, Jun Zou, Ted Lau, Xiaoyu Cai, Musaddeque Ahmed, Michal Kabza, Julie Weng, Jean-Philippe Fortin, Aaron Lun, Steffen Durinck, Marc Hafner, Michael R Costa, Xin Ye.
      Ferroptosis is an iron-dependent cell death mechanism characterized by the accumulation of toxic lipid peroxides and cell membrane rupture. GPX4 (glutathione peroxidase 4) prevents ferroptosis by reducing these lipid peroxides into lipid alcohols. Ferroptosis induction by GPX4 inhibition has emerged as a vulnerability of cancer cells, highlighting the need to identify ferroptosis regulators that may be exploited therapeutically. Through genome-wide CRISPR activation screens, we identify the SWI/SNF (switch/sucrose non-fermentable) ATPases BRM (SMARCA2) and BRG1 (SMARCA4) as ferroptosis suppressors. Mechanistically, they bind to and increase chromatin accessibility at NRF2 target loci, thus boosting NRF2 transcriptional output to counter lipid peroxidation and confer resistance to GPX4 inhibition. We further demonstrate that the BRM/BRG1 ferroptosis connection can be leveraged to enhance the paralog dependency of BRG1 mutant cancer cells on BRM. Our data reveal ferroptosis induction as a potential avenue for broadening the efficacy of BRM degraders/inhibitors and define a specific genetic context for exploiting GPX4 dependency.
    Keywords:  CP: Cancer; CP: Molecular biology
    DOI:  https://doi.org/10.1016/j.celrep.2024.114345
  6. Nat Cell Biol. 2024 Jun 10.
    Exploiting ferroptosis vulnerabilities in cancer.
    Toshitaka Nakamura, Marcus Conrad.
      Ferroptosis is a distinct lipid peroxidation-dependent form of necrotic cell death. This process has been increasingly contemplated as a new target for cancer therapy because of an intrinsic or acquired ferroptosis vulnerability in difficult-to-treat cancers and tumour microenvironments. Here we review recent advances in our understanding of the molecular mechanisms that underlie ferroptosis and highlight available tools for the modulation of ferroptosis sensitivity in cancer cells and communication with immune cells within the tumour microenvironment. We further discuss how these new insights into ferroptosis-activating pathways can become new armouries in the fight against cancer.
    DOI:  https://doi.org/10.1038/s41556-024-01425-8
  7. Int Immunopharmacol. 2024 Jun 12. pii: S1567-5769(24)00958-5. [Epub ahead of print]137 112437
    Chemo-immunotherapy by nanoliposomal epacadostat and docetaxel combination to IDO1 inhibition and tumor microenvironment suppression.
    Rahimeh Khoshkhabar, Mona Yazdani, Seyedeh Hoda Alavizadeh, Zahra Saberi, Leila Arabi, Mahmoud Reza Jaafari.
      The over-activation of tryptophan (Trp) metabolism to kynurenine (Kyn) catalyzed by Indoleamine 2,3-dioxygenase-1 (IDO1) enzyme, is one of the main metabolic pathways involved in tumor microenvironment (TME) immune escape and cancer treatment failure. The most efficient of IDO1 inhibitors is Epacadostat (EPA). Since monotherapy with single-agent IDO1 inhibitor regimen has led to an insufficient anti-tumor activity, we examined the efficacy of simultaneous treatment by Liposomal epacadostat (Lip-EPA) as a potent IDO inhibitor, in combination with docetaxel (DTX) as a complement immunogenic cell death (ICD) agent against B16F10 model. First, the in vitro combination index (CI) of epacadostat (EPA) and DTX was investigated by using the unified theory. Then, the in vivo efficacy of the combination therapy was assessed. Results indicated the synergestic cytotoxic effect of the combination on B16F10 compared to normal fibroblast cells (NIH). The immune profiling demonstrated a significant increase in the percentage of infiltrated T lymphocytes and IFN-γ release, a significant decrease in the percentage of regulatory T cells (Treg) population and the subsequent low levels of IL-10 generation in mice treated with Lip-EPA + DTX. Further, a significant tumor growth delay (TGD = 69.15 %) and an increased life span (ILS > 47.83 %) was observed with the combination strategy. Histopathology analysis revealed a remarkable increase in the Trp concentration following combination treatment, while Kyn levels significantly decreased. Results showed that the nano-liposomal form of IDO1 inhibitor in combination with chemotherapy could significantly improve the imunity response and dominate the tumor immuno-suppressive micro-environment, which merits further investigations.
    Keywords:  Chemo-immunotherapy; Docetaxel; IDO1 inhibitor; Melanoma; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.intimp.2024.112437
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