bims-trytim Biomed News
on Tryptophan metabolism in tumour-immune microenvironment
Issue of 2024–07–21
ten papers selected by
Jialin Feng, University of Dundee
  1. Regulation of gut microbiota on immune cell ferroptosis: A novel insight for immunotherapy against tumor.
  2. Engineered small extracellular vesicle-mediated ferroptosis: A new frontier in cancer immunotherapy.
  3. Metabolic heterogeneity in tumor microenvironment - A novel landmark for immunotherapy.
  4. The regulation and function of Nrf2 signaling in ferroptosis-activated cancer therapy.
  5. Immunomodulatory molecules in colorectal cancer liver metastasis.
  6. Ferroptosis contributes to the progression of female-specific neoplasms, from breast cancer to gynecological malignancies in a manner regulated by non-coding RNAs: Mechanistic implications.
  7. Ferroptosis regulation by Cap'n'collar family transcription factors.
  8. Aryl hydrocarbon receptor (AhR)-mediated immune responses to degeneration of the retinal pigment epithelium.
  9. Targeting ferroptosis: a new therapeutic opportunity for kidney diseases.
  10. Exploring the relationship between anastasis and mitochondrial ROS-mediated ferroptosis in metastatic chemoresistant cancers: a call for investigation.
  1. Cancer Lett. 2024 Jul 16. pii: S0304-3835(24)00510-X. [Epub ahead of print] 217115
    Regulation of gut microbiota on immune cell ferroptosis: A novel insight for immunotherapy against tumor.
    Ruobing Liu, Juanjuan Wang, Yuqing Liu, Yunhuan Gao, Rongcun Yang.
      Gut microbiota contributes to the homeostasis of immune system and is related to various diseases such as tumorigenesis. Ferroptosis, a new type of cell death, is also involved in the disease pathogenesis. Recent studies have found the correlations of gut microbiota mediated ferroptosis and immune cell death. Gut microbiota derived immunosuppressive metabolites, which can promote differentiation and function of immune cells, tend to inhibit ferroptosis through their receptors, whereas inflammatory metabolites from gut microbiota also affect the differentiation and function of immune cells and their ferroptosis. Thus, it is possible for gut microbiota to regulate immune cell ferroptosis. Indeed, gut microbiota metabolite receptor aryl hydrocarbon receptor (AhR) can affect ferroptosis of intestinal intraepithelial lymphocytes, leading to disease pathogenesis. Since immune cell ferroptosis in tumor microenvironment (TME) affects the occurrence and development of tumor, the modulation of gut microbiota in these cell ferroptosis might influence on the tumorigenesis, and also immunotherapy against tumors. Here we will summarize the recent advance of ferroptosis mediated by gut microbiota metabolites, which potentially acts as regulator(s) on immune cells in TME for therapy against tumor.
    DOI:  https://doi.org/10.1016/j.canlet.2024.217115
  2. Int Immunopharmacol. 2024 Jul 15. pii: S1567-5769(24)01142-1. [Epub ahead of print]139 112621
    Engineered small extracellular vesicle-mediated ferroptosis: A new frontier in cancer immunotherapy.
    Xiao-Qi He, Ya-Jun Wu.
      Ferroptosis is a novel iron-dependent form of cell death discovered in recent years, characterized by the accumulation of ferrous iron, the production of reactive oxygen species (ROS) through the Fenton reaction, and lipid peroxidation, ultimately leading to the disruption of the antioxidant system and cell membrane damage. Extensive research has found that ferroptosis plays a significant role in regulating tumor cell immune evasion, tumor development, and remodeling the tumor microenvironment. Small Extracellular vesicles (sEVs), carrying various bioactive molecules (ncRNA, DNA, proteins), are key nanoscale mediators of intercellular communication. Increasing evidence confirms that EVs can regulate the ferroptosis pathway in tumors, promoting tumor cell immune evasion and reshaping the tumor microenvironment. This article aims to comprehensively review the key mechanisms by which sEVs mediate ferroptosis in cancer and provide new insights into targeting tumor immunotherapy.
    Keywords:  EVs; Ferroptosis; Immunotherapy; Mechanism
    DOI:  https://doi.org/10.1016/j.intimp.2024.112621
  3. Autoimmun Rev. 2024 Jul 12. pii: S1568-9972(24)00070-3. [Epub ahead of print] 103579
    Metabolic heterogeneity in tumor microenvironment - A novel landmark for immunotherapy.
    Chen Chen, Peng Han, Yanping Qing.
      The surrounding non-cancer cells and tumor cells that make up the tumor microenvironment (TME) have various metabolic rhythms. TME metabolic heterogeneity is influenced by the intricate network of metabolic control within and between cells. DNA, protein, transport, and microbial levels are important regulators of TME metabolic homeostasis. The effectiveness of immunotherapy is also closely correlated with alterations in TME metabolism. The response of a tumor patient to immunotherapy is influenced by a variety of variables, including intracellular metabolic reprogramming, metabolic interaction between cells, ecological changes within and between tumors, and general dietary preferences. Although immunotherapy and targeted therapy have made great strides, their use in the accurate identification and treatment of tumors still has several limitations. The function of TME metabolic heterogeneity in tumor immunotherapy is summarized in this article. It focuses on how metabolic heterogeneity develops and is regulated as a tumor progresses, the precise molecular mechanisms and potential clinical significance of imbalances in intracellular metabolic homeostasis and intercellular metabolic coupling and interaction, as well as the benefits and drawbacks of targeted metabolism used in conjunction with immunotherapy. This offers insightful knowledge and important implications for individualized tumor patient diagnosis and treatment plans in the future.
    Keywords:  Immunotherapy; Metabolic crosstalk; Metabolic heterogeneity; Metabolic reprogramming; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.autrev.2024.103579
  4. Acta Pharmacol Sin. 2024 Jul 17.
    The regulation and function of Nrf2 signaling in ferroptosis-activated cancer therapy.
    Xin Jiang, Min Yu, Wei-Kai Wang, Li-Yuan Zhu, Xian Wang, Hong-Chuan Jin, Li-Feng Feng.
      Ferroptosis is an iron-dependent programmed cell death process that involves lipid oxidation via the Fenton reaction to produce lipid peroxides, causing disruption of the lipid bilayer, which is essential for cellular survival. Ferroptosis has been implicated in the occurrence and treatment response of various types of cancer, and targeting ferroptosis has emerged as a promising strategy for cancer therapy. However, cancer cells can escape cellular ferroptosis by activating or remodeling various signaling pathways, including oxidative stress pathways, thereby limiting the efficacy of ferroptosis-activating targeted therapy. The key anti-oxidative transcription factor, nuclear factor E2 related factor 2 (Nrf2 or NFE2L2), plays a dominant role in defense machinery by reprogramming the iron, intermediate, and glutathione peroxidase 4 (GPX4)-related network and the antioxidant system to attenuate ferroptosis. In this review, we summarize the recent advances in the regulation and function of Nrf2 signaling in ferroptosis-activated cancer therapy and explore the prospect of combining Nrf2 inhibitors and ferroptosis inducers as a promising cancer treatment strategy.
    Keywords:  antioxidant system; cancer therapy; drug resistance; ferroptosis; iron metabolism; nuclear factor E2 related factor 2 (Nrf2)
    DOI:  https://doi.org/10.1038/s41401-024-01336-2
  5. Cancer Lett. 2024 Jul 14. pii: S0304-3835(24)00508-1. [Epub ahead of print]598 217113
    Immunomodulatory molecules in colorectal cancer liver metastasis.
    Wei-Shuai Kong, Jia-Jun Li, Yu-Qing Deng, Huai-Qiang Ju, Rui-Hua Xu.
      Colorectal cancer (CRC) ranks as the third most common cancer and the second leading cause of cancer-related deaths. According to clinical diagnosis and treatment, liver metastasis occurs in approximately 50 % of CRC patients, indicating a poor prognosis. The unique immune tolerance of the liver fosters an immunosuppressive tumor microenvironment (TME). In the context of tumors, numerous membrane and secreted proteins have been linked to tumor immune evasion as immunomodulatory molecules, but much remains unknown about how these proteins contribute to immune evasion in colorectal cancer liver metastasis (CRLM). This article reviews recently discovered membrane and secreted proteins with roles as both immunostimulatory and immunosuppressive molecules within the TME that influence immune evasion in CRC primary and metastatic lesions, particularly their mechanisms in promoting CRLM. This article also addresses screening strategies for identifying proteins involved in immune evasion in CRLM and provides insights into potential protein targets for treating CRLM.
    Keywords:  Colorectal cancer liver metastasis; Immunomodulatory molecule; Membrane protein; Secreted protein; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2024.217113
  6. Noncoding RNA Res. 2024 Dec;9(4): 1159-1177
    Ferroptosis contributes to the progression of female-specific neoplasms, from breast cancer to gynecological malignancies in a manner regulated by non-coding RNAs: Mechanistic implications.
    Kiavash Hushmandi, Daniel J Klionsky, Amir Reza Aref, Mojtaba Bonyadi, Russel J Reiter, Noushin Nabavi, Shokooh Salimimoghadam, Seyed Hassan Saadat.
      Ferroptosis, a recently identified type of non-apoptotic cell death, triggers the elimination of cells in the presence of lipid peroxidation and in an iron-dependent manner. Indeed, ferroptosis-stimulating factors have the ability of suppressing antioxidant capacity, leading to the accumulation of reactive oxygen species (ROS) and the subsequent oxidative death of the cells. Ferroptosis is involved in the pathophysiological basis of different maladies, such as multiple cancers, among which female-oriented malignancies have attracted much attention in recent years. In this context, it has also been unveiled that non-coding RNA transcripts, including microRNAs, long non-coding RNAs, and circular RNAs have regulatory interconnections with the ferroptotic flux, which controls the pathogenic development of diseases. Furthermore, the potential of employing these RNA transcripts as therapeutic targets during the onset of female-specific neoplasms to modulate ferroptosis has become a research hotspot; however, the molecular mechanisms and functional alterations of ferroptosis still require further investigation. The current review comprehensively highlights ferroptosis and its association with non-coding RNAs with a focus on how this crosstalk affects the pathogenesis of female-oriented malignancies, from breast cancer to ovarian, cervical, and endometrial neoplasms, suggesting novel therapeutic targets to decelerate and even block the expansion and development of these tumors.
    Keywords:  Breast neoplasms; Endometrial neoplasms; Ferroptosis; Noncoding RNAs; Ovarian neoplasms; Signal transduction; Uterine cervical neoplasms
    DOI:  https://doi.org/10.1016/j.ncrna.2024.05.008
  7. J Biol Chem. 2024 Jul 16. pii: S0021-9258(24)02084-2. [Epub ahead of print] 107583
    Ferroptosis regulation by Cap'n'collar family transcription factors.
    Magdalena B Murray, Scott J Dixon.
      Ferroptosis is an iron-dependent cell death mechanism that may be important to prevent tumor formation and useful as a target for new cancer therapies. Transcriptional networks play a crucial role in shaping ferroptosis sensitivity by regulating the expression of transporters, metabolic enzymes, and other proteins. The Cap'n'collar (CNC) protein nuclear factor erythroid 2 like 2 (NFE2L2, also known as NRF2) is a key regulator of ferroptosis in many cells and contexts. Emerging evidence indicates that the related CNC family members BTB and CNC homology 1 (BACH1) and nuclear factor erythroid 2 like 1 (NFE2L1) also have non-redundant roles in ferroptosis regulation. Here, we comprehensively review the role of CNC transcription factors in governing cellular sensitivity to ferroptosis. We describe how CNC family members regulate ferroptosis sensitivity through modulation of iron, lipid, and redox metabolism. We also use examples of ferroptosis regulation by CNC proteins to illustrate the flexible and highly context-dependent nature of the ferroptosis mechanism between cells and conditions.
    Keywords:  BACH1; NFE2L1; NRF2; Nuclear factor 2 (erythroid‐derived 2‐like factor) (NFE2L2); Oxidative stress; glycosylation; iron metabolism; lipid peroxidation
    DOI:  https://doi.org/10.1016/j.jbc.2024.107583
  8. Biochim Biophys Acta Mol Basis Dis. 2024 Jul 14. pii: S0925-4439(24)00344-2. [Epub ahead of print]1870(7): 167351
    Aryl hydrocarbon receptor (AhR)-mediated immune responses to degeneration of the retinal pigment epithelium.
    James Regun Karmoker, Sarah E Bounds, Jiyang Cai.
      Injuries to the retinal pigment epithelium (RPE) trigger immune responses, orchestrating interactions within the innate and adaptive immune systems in the outer retina and choroid. We previously reported that interleukin 17 (IL-17) is a pivotal signaling molecule originating from choroidal γδ T cells, exerting protective effects by mediating functional connections between the RPE and subretinal microglia. In this current study, we generated mice with aryl hydrocarbon receptor (AhR) knockout specifically in IL-17-producing cells. These animals had deficiency in IL-17 production from γδ T cells, and exhibited increased sensitivity to both acute and chronic insults targeting the RPE. These findings imply that IL-17 plays a crucial role as a signaling cytokine in preserving the homeostasis of the outer retina and choroid.
    Keywords:  Age-related macular degeneration; Aryl hydrocarbon receptor; Immune response; RPE
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167351
  9. Front Immunol. 2024 ;15 1435139
    Targeting ferroptosis: a new therapeutic opportunity for kidney diseases.
    Zhiyong Long, Yanfang Luo, Min Yu, Xiaoyan Wang, Liuting Zeng, Kailin Yang.
      Ferroptosis is a form of non-apoptotic regulated cell death (RCD) that depends on iron and is characterized by the accumulation of lipid peroxides to lethal levels. Ferroptosis involves multiple pathways including redox balance, iron regulation, mitochondrial function, and amino acid, lipid, and glycometabolism. Furthermore, various disease-related signaling pathways also play a role in regulating the process of iron oxidation. In recent years, with the emergence of the concept of ferroptosis and the in-depth study of its mechanisms, ferroptosis is closely associated with various biological conditions related to kidney diseases, including kidney organ development, aging, immunity, and cancer. This article reviews the development of the concept of ferroptosis, the mechanisms of ferroptosis (including GSH-GPX4, FSP1-CoQ1, DHODH-CoQ10, GCH1-BH4, and MBOAT1/2 pathways), and the latest research progress on its involvement in kidney diseases. It summarizes research on ferroptosis in kidney diseases within the frameworks of metabolism, reactive oxygen biology, and iron biology. The article introduces key regulatory factors and mechanisms of ferroptosis in kidney diseases, as well as important concepts and major open questions in ferroptosis and related natural compounds. It is hoped that in future research, further breakthroughs can be made in understanding the regulation mechanism of ferroptosis and utilizing ferroptosis to promote treatments for kidney diseases, such as acute kidney injury(AKI), chronic kidney disease (CKD), diabetic nephropathy(DN), and renal cell carcinoma. This paves the way for a new approach to research, prevent, and treat clinical kidney diseases.
    Keywords:  acute kidney disease; chronic kidney disease; ferroptosis; iron metabolism; natural compounds
    DOI:  https://doi.org/10.3389/fimmu.2024.1435139
  10. Front Immunol. 2024 ;15 1428920
    Exploring the relationship between anastasis and mitochondrial ROS-mediated ferroptosis in metastatic chemoresistant cancers: a call for investigation.
    Yu Cao, Chang Lu, Narasimha M Beeraka, Sergey Efetov, Mikhail Enikeev, Yu Fu, Xinyi Yang, Basappa Basappa, Mingze He, Zhi Li.
      Ferroptosis induces significant changes in mitochondrial morphology, including membrane condensation, volume reduction, cristae alteration, and outer membrane rupture, affecting mitochondrial function and cellular fate. Recent reports have described the intrinsic cellular iron metabolism and its intricate connection to ferroptosis, a significant kind of cell death characterized by iron dependence and oxidative stress regulation. Furthermore, updated molecular insights have elucidated the significance of mitochondria in ferroptosis and its implications in various cancers. In the context of cancer therapy, understanding the dual role of anastasis and ferroptosis in chemoresistance is crucial. Targeting the molecular pathways involved in anastasis may enhance the efficacy of ferroptosis inducers, providing a synergistic approach to overcome chemoresistance. Research into how DNA damage response (DDR) proteins, metabolic changes, and redox states interact during anastasis and ferroptosis can offer new insights into designing combinatorial therapeutic regimens against several cancers associated with stemness. These treatments could potentially inhibit anastasis while simultaneously inducing ferroptosis, thereby reducing the likelihood of cancer cells evading death and developing resistance to chemotherapy. The objective of this study is to explore the intricate interplay between anastasis, ferroptosis, EMT and chemoresistance, and immunotherapeutics to better understand their collective impact on cancer therapy outcomes. We searched public research databases including google scholar, PubMed, relemed, and the national library of medicine related to this topic. In this review, we discussed the interplay between the tricarboxylic acid cycle and glycolysis implicated in modulating ferroptosis, adding complexity to its regulatory mechanisms. Additionally, the regulatory role of reactive oxygen species (ROS) and the electron transport chain (ETC) in ferroptosis has garnered significant attention. Lipid metabolism, particularly involving GPX4 and System Xc- plays a significant role in both the progression of ferroptosis and cancer. There is a need to investigate the intricate interplay between anastasis, ferroptosis, and chemoresistance to better understand cancer therapy clinical outcomes. Integrating anastasis, and ferroptosis into strategies targeting chemoresistance and exploring its potential synergy with immunotherapy represent promising avenues for advancing chemoresistant cancer treatment. Understanding the intricate interplay among mitochondria, anastasis, ROS, and ferroptosis is vital in oncology, potentially revolutionizing personalized cancer treatment and drug development.
    Keywords:  EMT; anastasis; chemoresistance; ferroptosis; mitochondria
    DOI:  https://doi.org/10.3389/fimmu.2024.1428920
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