bims-trytim 2024-06-02 papers

bims-trytim

Biomed News

on Tryptophan metabolism in tumour-immune microenvironment

Issue of 2024‒06‒02
eight papers selected by
Jialin Feng, University of Dundee

Targeting metabolism to enhance immunotherapy within tumor microenvironment.
Targeting ferroptosis in neuroimmune and neurodegenerative disorders for the development of novel therapeutics.
Tumor Microenvironment Specific Regulation Ca-Fe-Nanospheres for Ferroptosis-Promoted Domino Synergistic Therapy and Tumor Immune Response.
The aryl hydrocarbon receptor as a tumor modulator: mechanisms to therapy.
Ferroptosis in glioma therapy: advancements in sensitizing strategies and the complex tumor-promoting roles.
FLI1 promotes IFN-γ-induced kynurenine production to impair anti-tumor immunity.
LC3-associated phagocytosis of neutrophils triggers tumor ferroptotic cell death in glioblastoma.
Ferroptosis: A double-edged sword.

Acta Pharmacol Sin. 2024 May 29.

Targeting metabolism to enhance immunotherapy within tumor microenvironment.

Xiao-Hui Liang, Xin-Yi Chen, Yue Yan, Ao-Yu Cheng, Jia-Yi Lin, Yi-Xin Jiang, Hong-Zhuan Chen, Jin-Mei Jin, Xin Luan.

  Cancer metabolic reprogramming has been considered an emerging hallmark in tumorigenesis and the antitumor immune response. Like cancer cells, immune cells within the tumor microenvironment or premetastatic niche also undergo extensive metabolic reprogramming, which profoundly impacts anti-tumor immune responses. Numerous evidence has illuminated that immunosuppressive TME and the metabolites released by tumor cells, including lactic acid, Prostaglandin E2 (PGE2), fatty acids (FAs), cholesterol, D-2-Hydroxyglutaric acid (2-HG), adenosine (ADO), and kynurenine (KYN) can contribute to CD8+ T cell dysfunction. Dynamic alterations of these metabolites between tumor cells and immune cells can similarly initiate metabolic competition in the TME, leading to nutrient deprivation and subsequent microenvironmental acidosis, which impedes immune response. This review summarizes the new landscape beyond the classical metabolic pathways in tumor cells, highlighting the pivotal role of metabolic disturbance in the immunosuppressive microenvironment, especially how nutrient deprivation in TME leads to metabolic reprogramming of CD8+ T cells. Likewise, it emphasizes the current therapeutic targets or strategies related to tumor metabolism and immune response, providing therapeutic benefits for tumor immunotherapy and drug development in the future. Cancer metabolic reprogramming has been considered an emerging hallmark in tumorigenesis and the antitumor immune response. Dynamic alterations of metabolites between tumor cells and immune cells initiate metabolic competition in the TME, leading to nutrient deprivation and subsequent microenvironmental acidosis, which impedes immune response.

Keywords:  dynamic interplay; immune response; metabolic reprogramming; targeted strategies; tumor microenvironment

DOI:  https://doi.org/10.1038/s41401-024-01304-w
Biomed Pharmacother. 2024 May 24. pii: S0753-3322(24)00661-9. [Epub ahead of print]176 116777

Targeting ferroptosis in neuroimmune and neurodegenerative disorders for the development of novel therapeutics.

Zihao Li, Ye Zhang, Meiling Ji, Chenglong Wu, Yanxing Zhang, Senlin Ji.

  Neuroimmune and neurodegenerative ailments impose a substantial societal burden. Neuroimmune disorders involve the intricate regulatory interactions between the immune system and the central nervous system. Prominent examples of neuroimmune disorders encompass multiple sclerosis and neuromyelitis optica. Neurodegenerative diseases result from neuronal degeneration or demyelination in the brain or spinal cord, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. The precise underlying pathogenesis of these conditions remains incompletely understood. Ferroptosis, a programmed form of cell death characterised by lipid peroxidation and iron overload, plays a pivotal role in neuroimmune and neurodegenerative diseases. In this review, we provide a detailed overview of ferroptosis, its mechanisms, pathways, and regulation during the progression of neuroimmune and neurodegenerative diseases. Furthermore, we summarise the impact of ferroptosis on neuroimmune-related cells (T cells, B cells, neutrophils, and macrophages) and neural cells (glial cells and neurons). Finally, we explore the potential therapeutic implications of ferroptosis inhibitors in diverse neuroimmune and neurodegenerative diseases.

Keywords:  Ferroptosis; Inhibitor; Neurodegenerative disorders; Neuroimmune disorders; Signaling

DOI:  https://doi.org/10.1016/j.biopha.2024.116777
Small. 2024 May 27. e2312141

Tumor Microenvironment Specific Regulation Ca-Fe-Nanospheres for Ferroptosis-Promoted Domino Synergistic Therapy and Tumor Immune Response.

Xu Chu, Hua-Ying Hou, Meng-Die Duan, Yu-Juan Zhang, Yu-Ying Zhu, Yi Liu, Shu-Lan Li.

  Reactive oxygen species (ROS)-mediated emerging treatments exhibit unique advantages in cancer therapy in recent years. While the efficacy of ROS-involved tumor therapy is greatly restricted by complex tumor microenvironment (TME). Herein, a dual-metal CaO2@CDs-Fe (CCF) nanosphere, with TME response and regulation capabilities, are proposed to improve ROS lethal power by a multiple cascade synergistic therapeutic strategy with domino effect. In response to weak acidic TME, CCF will decompose, accompanied with intracellular Ca2+ upregulated and abundant H2O2 and O2 produced to reverse antitherapeutic TME. Then the exposed CF cores can act as both Fenton agent and sonosensitizer to generate excessive ROS in the regulated TME for enhanced synergistic CDT/SDT. In combination with calcium overloading, the augmented ROS induced oxidative stress will cause more severe mitochondrial damage and cellular apoptosis. Furthermore, CCF can also reduce GPX4 expression and enlarge the lipid peroxidation, causing ferroptosis and apoptosis in parallel. These signals of damage will finally initiate damage-associated molecular patterns to activate immune response and to realize excellent antitumor effect. This outstanding domino ROS/calcium loading synergistic effect endows CCF with excellent anticancer effect to efficiently eliminate tumor by apoptosis/ferroptosis/ICD both in vitro and in vivo.

Keywords:  calcium overloading; enhanced oxidative stress; ferroptosis; synergistic therapy; tumor immune response

DOI:  https://doi.org/10.1002/smll.202312141
Front Oncol. 2024 ;14 1375905

The aryl hydrocarbon receptor as a tumor modulator: mechanisms to therapy.

Kanita A Chaudhry, Anna Bianchi-Smiraglia.

  The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is widely recognized to play important, but complex, modulatory roles in a variety of tumor types. In this review, we comprehensively summarize the increasingly controversial role of AhR as a tumor regulator and the mechanisms by which it alters tumor progression based on the cancer cell type. Finally, we discuss new and emerging strategies to therapeutically modulate AhR, focusing on novel agents that hold promise in current human clinical trials as well as existing FDA-approved drugs that could potentially be repurposed for cancer therapy.

Keywords:  AhR; cancer biology; immune regulation; therapeutics; tumor promoter; tumor suppressor; xenobiotic

DOI:  https://doi.org/10.3389/fonc.2024.1375905
Brain Res. 2024 May 29. pii: S0006-8993(24)00299-3. [Epub ahead of print] 149045

Ferroptosis in glioma therapy: advancements in sensitizing strategies and the complex tumor-promoting roles.

Soo Yeon Kim, Miaolu Tang, Tong Lu, Stephen Y Chih, Wei Li.

  Ferroptosis, an iron-dependent form of non-apoptotic regulated cell death, is induced by the accumulation of lipid peroxides on cellular membranes. Over the past decade, ferroptosis has emerged as a crucial process implicated in various physiological and pathological systems. Positioned as an alternative modality of cell death, ferroptosis holds promise for eliminating cancer cells that have developed resistance to apoptosis induced by conventional therapeutics. This has led to a growing interest in leveraging ferroptosis for cancer therapy across diverse malignancies. Gliomas are tumors arising from glial or precursor cells, with glioblastoma (GBM) being the most common malignant primary brain tumor that is associated with a dismal prognosis. This review provides a summary of recent advancements in the exploration of ferroptosis-sensitizing methods, with a specific focus on their potential application in enhancing the treatment of gliomas. In addition to summarizing the therapeutic potential, this review also discusses the intricate interplay of ferroptosis and its potential tumor-promoting roles within gliomas. Recognizing these dual roles is essential, as they could potentially complicate the therapeutic benefits of ferroptosis. Exploring strategies aimed at circumventing these tumor-promoting roles could enhance the overall therapeutic efficacy of ferroptosis in the context of glioma treatment.

Keywords:  Ferroptosis; Ferroptosis-sensitizing methods; Glioblastoma; Glioma; Regulated cell death; neUroinflammation

DOI:  https://doi.org/10.1016/j.brainres.2024.149045
Nat Commun. 2024 May 30. 15(1): 4590

FLI1 promotes IFN-γ-induced kynurenine production to impair anti-tumor immunity.

Enni Chen, Jiawei Wu, Jiajia Huang, Wancui Zhu, Haohui Sun, Xiaonan Wang, Dagui Lin, Xiaodi Li, Dingbo Shi, Zhiqiao Liu, Jinsheng Huang, Miao Chen, Fangyun Xie, Wuguo Deng.

Nasopharyngeal carcinoma (NPC)-mediated immunosuppression within the tumor microenvironment (TME) frequently culminates in the failure of otherwise promising immunotherapies. In this study, we identify tumor-intrinsic FLI1 as a critical mediator in impairing T cell anti-tumor immunity. A mechanistic inquiry reveals that FLI1 orchestrates the expression of CBP and STAT1, facilitating chromatin accessibility and transcriptional activation of IDO1 in response to T cell-released IFN-γ. This regulatory cascade ultimately leads to augmented IDO1 expression, resulting in heightened synthesis of kynurenine (Kyn) in tumor cells. This, in turn, fosters CD8+ T cell exhaustion and regulatory T cell (Treg) differentiation. Intriguingly, we find that pharmacological inhibition of FLI1 effectively obstructs the CBP/STAT1-IDO1-Kyn axis, thereby invigorating both spontaneous and checkpoint therapy-induced immune responses, culminating in enhanced tumor eradication. In conclusion, our findings delineate FLI1-mediated Kyn metabolism as an immune evasion mechanism in NPC, furnishing valuable insights into potential therapeutic interventions.

DOI: https://doi.org/10.1038/s41467-024-48397-9
EMBO J. 2024 May 28.

LC3-associated phagocytosis of neutrophils triggers tumor ferroptotic cell death in glioblastoma.

Tong Lu, Patricia P Yee, Stephen Y Chih, Miaolu Tang, Han Chen, Dawit G Aregawi, Michael J Glantz, Brad E Zacharia, Hong-Gang Wang, Wei Li.

  Necrosis in solid tumors is commonly associated with poor prognostic but how these lesions expand remains unclear. Studies have found that neutrophils associate with and contribute to necrosis development in glioblastoma by inducing tumor cell ferroptosis through transferring myeloperoxidase-containing granules. However, the mechanism of neutrophilic granule transfer remains elusive. We performed an unbiased small molecule screen and found that statins inhibit neutrophil-induced tumor cell death by blocking the neutrophilic granule transfer. Further, we identified a novel process wherein neutrophils are engulfed by tumor cells before releasing myeloperoxidase-containing contents into tumor cells. This neutrophil engulfment is initiated by integrin-mediated adhesion, and further mediated by LC3-associated phagocytosis (LAP), which can be blocked by inhibiting the Vps34-UVRAG-RUBCN-containing PI3K complex. Myeloperoxidase inhibition or Vps34 depletion resulted in reduced necrosis formation and prolonged mouse survival in an orthotopic glioblastoma mouse model. Thus, our study unveils a critical role for LAP-mediated neutrophil internalization in facilitating the transfer of neutrophilic granules, which in turn triggers tumor cell death and necrosis expansion. Targeting this process holds promise for improving glioblastoma prognosis.

Keywords:  Ferroptosis; Glioblastoma; LC3-associated Phagocytosis; Neutrophil; Tumor Necrosis

DOI:  https://doi.org/10.1038/s44318-024-00130-4
Cell Death Discov. 2024 May 30. 10(1): 265

Ferroptosis: A double-edged sword.

Shengmei Wang, Qiuyan Guo, Lili Zhou, Xinhua Xia.

Ferroptosis represents a form of programmed cell death that is propelled by iron-dependent lipid peroxidation, thereby being distinguished by the prominent features of iron accumulation and lipid peroxidation. Ferroptosis has been implicated in numerous physiological and pathological phenomena, with mounting indications that it holds significant implications for cancer and other medical conditions. On one side, it demonstrates anti-cancer properties by triggering ferroptosis within malignant cells, and on the other hand, it damages normal cells causing other diseases. Therefore, in this paper, we propose to review the paradoxical regulation of ferroptosis in tumors and other diseases. First, we introduce the development history, concept and mechanism of ferroptosis. The second part focuses on the methods of inducing ferroptosis in tumors. The third section emphasizes the utilization of ferroptosis in different medical conditions and strategies to inhibit ferroptosis. The fourth part elucidates the key contradictions in the control of ferroptosis. Finally, potential research avenues in associated domains are suggested.

DOI: https://doi.org/10.1038/s41420-024-02037-9