bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024–06–23
27 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Guardians and Mediators of Metastasis: Exploring T Lymphocytes, Myeloid-Derived Suppressor Cells, and Tumor-Associated Macrophages in the Breast Cancer Microenvironment.
  2. Tumor-Associated Senescent Macrophages, Their Markers, and Their Role in Tumor Microenvironment.
  3. Macrophage polarization in the tumor microenvironment: Emerging roles and therapeutic potentials.
  4. Tumor microenvironment as niche constructed by cancer stem cells: Breaking the ecosystem to combat cancer.
  5. Tumor glucose metabolism and the T cell glycocalyx: implication for T cell function.
  6. Recapitulating the tumor microenvironment in a dish, one cell type at a time.
  7. Metabolic Reprogramming in Tumor Immune Microenvironment: Impact on Immune Cell Function and Therapeutic Implications.
  8. Recent advances in understanding the immune microenvironment in ovarian cancer.
  9. Dissecting the multifaceted roles of autophagy in cancer initiation, growth, and metastasis: from molecular mechanisms to therapeutic applications.
  10. A dual-enzyme-like photosensitive nanozyme for remodeling the tumor immunosuppressive microenvironment to enhance immunotherapy.
  11. The role of RNA methylation in tumor immunity and its potential in immunotherapy.
  12. Glioma-derived M-CSF and IL-34 license M-MDSCs to suppress CD8 + T cells in a NOS-dependent manner.
  13. Apoptosis, a Metabolic "Head-to-Head" between Tumor and T Cells: Implications for Immunotherapy.
  14. The Role of Metabolic Reprogramming in the Tumor Immune Microenvironment: Mechanisms and Opportunities for Immunotherapy in Hepatocellular Carcinoma.
  15. Cancer stem cell-derived exosomes in CD8+ T cell exhaustion.
  16. Beyond the danger signal: RNA aggregates orchestrate immunotherapy.
  17. CD39 transforming cancer therapy by modulating tumor microenvironment.
  18. Application and prospect of microfluidic devices for rapid assay of cell activities in the tumor microenvironment.
  19. The roles of branched-chain amino acids metabolism in tumorigenesis and progression.
  20. Engineering nanoparticles-enabled tumor-associated macrophages repolarization and phagocytosis restoration for enhanced cancer immunotherapy.
  21. Drug-Loaded Mesoporous Silica Nanoparticles Enhance Antitumor Immunotherapy by Regulating MDSCs.
  22. Mechanisms, combination therapy, and biomarkers in cancer immunotherapy resistance.
  23. Editorial: Polarization of cellular immune response in the context of inflammation and cancer.
  24. Exportin 1 governs the immunosuppressive functions of myeloid-derived suppressor cells in tumors through ERK1/2 nuclear export.
  25. The role of CD4+ CAR T cells in cancer immunotherapy.
  26. Essentials of CAR-T Therapy and Associated Microbial Challenges in Long Run Immunotherapy.
  27. Hypoxic tumor-derived exosomal miR-4488 induces macrophage M2 polarization to promote liver metastasis of pancreatic neuroendocrine neoplasm through RTN3/FABP5 mediated fatty acid oxidation.
  1. Int J Mol Sci. 2024 Jun 05. pii: 6224. [Epub ahead of print]25(11):
    Guardians and Mediators of Metastasis: Exploring T Lymphocytes, Myeloid-Derived Suppressor Cells, and Tumor-Associated Macrophages in the Breast Cancer Microenvironment.
    Maria Rosaria Ruocco, Armando Gisonna, Vittoria Acampora, Anna D'Agostino, Barbara Carrese, Jessie Santoro, Alessandro Venuta, Rosarita Nasso, Nicola Rocco, Daniela Russo, Annachiara Cavaliere, Giovanna Giuseppina Altobelli, Stefania Masone, Angelica Avagliano, Alessandro Arcucci, Giuseppe Fiume.
      Breast cancers (BCs) are solid tumors composed of heterogeneous tissues consisting of cancer cells and an ever-changing tumor microenvironment (TME). The TME includes, among other non-cancer cell types, immune cells influencing the immune context of cancer tissues. In particular, the cross talk of immune cells and their interactions with cancer cells dramatically influence BC dissemination, immunoediting, and the outcomes of cancer therapies. Tumor-infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) represent prominent immune cell populations of breast TMEs, and they have important roles in cancer immunoescape and dissemination. Therefore, in this article we review the features of TILs, TAMs, and MDSCs in BCs. Moreover, we highlight the mechanisms by which these immune cells remodel the immune TME and lead to breast cancer metastasis.
    Keywords:  breast cancers; metastasis; myeloid-derived suppressor cells; tumor microenvironment; tumor-associated macrophages; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.3390/ijms25116224
  2. Biochemistry (Mosc). 2024 May;89(5): 839-852
    Tumor-Associated Senescent Macrophages, Their Markers, and Their Role in Tumor Microenvironment.
    Tamara V Pukhalskaia, Taisiya R Yurakova, Daria A Bogdanova, Oleg N Demidov.
      Tumor-associated macrophages (TAMs) are an important component of the tumor microenvironment (TME) and the most abundant population of immune cells infiltrating a tumor. TAMs can largely determine direction of anti-tumor immune response by promoting it or, conversely, contribute to formation of an immunosuppressive TME that allows tumors to evade immune control. Through interactions with tumor cells or other cells in the microenvironment and, as a result of action of anti-cancer therapy, macrophages can enter senescence. In this review, we have attempted to summarize information available in the literature on the role of senescent macrophages in tumors. With the recent development of senolytic therapeutic strategies aimed at removing senescent cells from an organism, it seems important to discuss functions of the senescent macrophages and potential role of the senolytic drugs in reprogramming TAMs to enhance anti-tumor immune response and improve efficacy of cancer treatment.
    Keywords:  CD206; CXCR1; immunosuppression; p16INK4; p21cip1; senescent cells; tumor microenvironment
    DOI:  https://doi.org/10.1134/S0006297924050055
  3. Biomed Pharmacother. 2024 Jun 14. pii: S0753-3322(24)00814-X. [Epub ahead of print]177 116930
    Macrophage polarization in the tumor microenvironment: Emerging roles and therapeutic potentials.
    Wenru Zhang, Mengmeng Wang, Chonghao Ji, Xiaohui Liu, Bowen Gu, Ting Dong.
      The tumor microenvironment (TME) is a combination of tumor cells and indigenous host stroma, which consists of tumor-infiltrating immune cells, endothelial cells, fibroblasts, pericytes, and non-cellular elements. Tumor-associated macrophages (TAMs) represent the major tumor-infiltrating immune cell type and are generally polarized into two functionally contradictory subtypes, namely classical activated M1 macrophages and alternatively activated M2 macrophages. Macrophage polarization refers to how macrophages are activated at a given time and space. The interplay between the TME and macrophage polarization can influence tumor initiation and progression, making TAM a potential target for cancer therapy. Here, we review the latest investigations on factors orchestrating macrophage polarization in the TME, how macrophage polarization affects tumor progression, and the perspectives in modulating macrophage polarization for cancer immunotherapy.
    Keywords:  Immunotherapy; Macrophage; Macrophage polarization; Tumor microenvironment; Tumor-associated macrophage
    DOI:  https://doi.org/10.1016/j.biopha.2024.116930
  4. J Adv Res. 2024 Jun 10. pii: S2090-1232(24)00251-0. [Epub ahead of print]
    Tumor microenvironment as niche constructed by cancer stem cells: Breaking the ecosystem to combat cancer.
    Hao Zhong, Shiyue Zhou, Shuangshuang Yin, Yuling Qiu, Bo Liu, Haiyang Yu.
       BACKGROUND: Cancer stem cells (CSCs) are a distinct subpopulation of cancer cells with the capacity to constantly self-renew and differentiate, and they are the main driver in the progression of cancer resistance and relapse. The tumor microenvironment (TME) constructed by CSCs is the "soil" adapted to tumor growth, helping CSCs evade immune killing, enhance their chemical resistance, and promote cancer progression.
    AIM OF REVIEW: We aim to elaborate the tight connection between CSCs and immunosuppressive components of the TME. We attempt to summarize and provide a therapeutic strategy to eradicate CSCs based on the destruction of the tumor ecological niche.
    KEY SCIENTIFIC CONCEPTS OF REVIEW: This review is focused on three main key concepts. First, we highlight that CSCs recruit and transform normal cells to construct the TME, which further provides ecological niche support for CSCs. Second, we describe the main characteristics of the immunosuppressive components of the TME, targeting strategies and summarize the progress of corresponding drugs in clinical trials. Third, we explore the multilevel insights of the TME to serve as an ecological niche for CSCs.
    Keywords:  Cancer associated fibroblasts; Cancer stem cells; Myeloid-derived suppressor cells; Regulatory T cells; Tumor associated macrophages; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.jare.2024.06.014
  5. Front Immunol. 2024 ;15 1409238
    Tumor glucose metabolism and the T cell glycocalyx: implication for T cell function.
    Fabian Schuurmans, Kyra E Wagemans, Gosse J Adema, Lenneke A M Cornelissen.
      The T cell is an immune cell subset highly effective in eliminating cancer cells. Cancer immunotherapy empowers T cells and occupies a solid position in cancer treatment. The response rate, however, remains relatively low (<30%). The efficacy of immunotherapy is highly dependent on T cell infiltration into the tumor microenvironment (TME) and the ability of these infiltrated T cells to sustain their function within the TME. A better understanding of the inhibitory impact of the TME on T cells is crucial to improve cancer immunotherapy. Tumor cells are well described for their switch into aerobic glycolysis (Warburg effect), resulting in high glucose consumption and a metabolically distinct TME. Conversely, glycosylation, a predominant posttranslational modification of proteins, also relies on glucose molecules. Proper glycosylation of T cell receptors influences the immunological synapse between T cells and tumor cells, thereby affecting T cell effector functions including their cytolytic and cytostatic activities. This review delves into the complex interplay between tumor glucose metabolism and the glycocalyx of T cells, shedding light on how the TME can induce alterations in the T cell glycocalyx, which can subsequently influence the T cell's ability to target and eliminate tumor cells.
    Keywords:  T cell glycocalyx; glycobiology; metabolism; tumor immunity; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1409238
  6. Cell Rep Methods. 2024 Jun 17. pii: S2667-2375(24)00156-5. [Epub ahead of print]4(6): 100800
    Recapitulating the tumor microenvironment in a dish, one cell type at a time.
    Benjamin N Ostendorf.
      The tumor microenvironment harbors a variety of different cell types that differentially impact tumor biology. In this issue of Cell Reports Methods, Raffo-Romero et al. standardized and optimized 3D tumor organoids to model the interactions between tumor-associated macrophages and tumor cells in vitro.
    Keywords:  CP: cancer biology; CP: stem cell
    DOI:  https://doi.org/10.1016/j.crmeth.2024.100800
  7. Cancer Lett. 2024 Jun 19. pii: S0304-3835(24)00471-3. [Epub ahead of print] 217076
    Metabolic Reprogramming in Tumor Immune Microenvironment: Impact on Immune Cell Function and Therapeutic Implications.
    Yuqiang Liu, Yu Zhao, Huisheng Song, Yunting Li, Zihao Liu, Zhiming Ye, Jianzhu Zhao, Yuzheng Wu, Jun Tang, Maojin Yao.
      Understanding of the metabolic reprogramming has revolutionized our insights into tumor progression and potential treatment. This review concentrates on the aberrant metabolic pathways in cancer cells within the tumor microenvironment (TME). Cancer cells differ from normal cells in their metabolic processing of glucose, amino acids, and lipids in order to adapt to heightened biosynthetic and energy needs. These metabolic shifts, which crucially alter lactic acid, amino acid and lipid metabolism, affect not only tumor cell proliferation but also TME dynamics. This review also explores the reprogramming of various immune cells in the TME. From a therapeutic standpoint, targeting these metabolic alterations represents a novel cancer treatment strategy. This review also discusses approaches targeting the regulation of metabolism of different nutrients in tumor cells and influencing the tumor microenvironment to enhance the immune response. In summary, this review summarizes metabolic reprogramming in cancer and its potential as a target for innovative therapeutic strategies, offering fresh perspectives on cancer treatment.
    Keywords:  Immune cell; Immunotherapy; Tumor metabolic reprogramming; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2024.217076
  8. Front Immunol. 2024 ;15 1412328
    Recent advances in understanding the immune microenvironment in ovarian cancer.
    Jinxin Chen, Lu Yang, Yiming Ma, Ye Zhang.
      The occurrence of ovarian cancer (OC) is a major factor in women's mortality rates. Despite progress in medical treatments, like new drugs targeting homologous recombination deficiency, survival rates for OC patients are still not ideal. The tumor microenvironment (TME) includes cancer cells, fibroblasts linked to cancer (CAFs), immune-inflammatory cells, and the substances these cells secrete, along with non-cellular components in the extracellular matrix (ECM). First, the TME mainly plays a role in inhibiting tumor growth and protecting normal cell survival. As tumors progress, the TME gradually becomes a place to promote tumor cell progression. Immune cells in the TME have attracted much attention as targets for immunotherapy. Immune checkpoint inhibitor (ICI) therapy has the potential to regulate the TME, suppressing factors that facilitate tumor advancement, reactivating immune cells, managing tumor growth, and extending the survival of patients with advanced cancer. This review presents an outline of current studies on the distinct cellular elements within the OC TME, detailing their main functions and possible signaling pathways. Additionally, we examine immunotherapy rechallenge in OC, with a specific emphasis on the biological reasons behind resistance to ICIs.
    Keywords:  immune cells; immune checkpoint inhibitor; immunotherapy; ovarian cancer; tumor environment
    DOI:  https://doi.org/10.3389/fimmu.2024.1412328
  9. Med Oncol. 2024 Jun 20. 41(7): 183
    Dissecting the multifaceted roles of autophagy in cancer initiation, growth, and metastasis: from molecular mechanisms to therapeutic applications.
    Afia Ayub, Md Kamrul Hasan, Zimam Mahmud, Md Sabbir Hossain, Yearul Kabir.
      Autophagy is a cytoplasmic defense mechanism that cells use to break and reprocess their intracellular components. This utilization of autophagy is regarded as a savior in nutrient-deficient and other stressful conditions. Hence, autophagy keeps contact with and responds to miscellaneous cellular tensions and diverse pathways of signal transductions, such as growth signaling and cellular death. Importantly, autophagy is regarded as an effective tumor suppressor because regular autophagic breakdown is essential for cellular maintenance and minimizing cellular damage. However, paradoxically, autophagy has also been observed to promote the events of malignancies. This review discussed the dual role of autophagy in cancer, emphasizing its influence on tumor survival and progression. Possessing such a dual contribution to the malignant establishment, the prevention of autophagy can potentially advocate for the advancement of malignant transformation. In contrast, for the context of the instituted tumor, the agents of preventing autophagy potently inhibit the advancement of the tumor. Key regulators, including calpain 1, mTORC1, and AMPK, modulate autophagy in response to nutritional conditions and stress. Oncogenic mutations like RAS and B-RAF underscore autophagy's pivotal role in cancer development. The review also delves into autophagy's context-dependent roles in tumorigenesis, metastasis, and the tumor microenvironment (TME). It also discusses the therapeutic effectiveness of autophagy for several cancers. The recent implication of autophagy in the control of both innate and antibody-mediated immune systems made it a center of attention to evaluating its role concerning tumor antigens and treatments of cancer.
    Keywords:  Autophagosome; Autophagy; Cancer immunotherapy; Epithelial to mesenchymal transition; Metastatic-cascade; Tumor antigens; Tumor microenvironment; Tumorigenesis
    DOI:  https://doi.org/10.1007/s12032-024-02417-2
  10. Biomaterials. 2024 Jun 07. pii: S0142-9612(24)00194-7. [Epub ahead of print]311 122660
    A dual-enzyme-like photosensitive nanozyme for remodeling the tumor immunosuppressive microenvironment to enhance immunotherapy.
    Jiahao Zheng, Wangyang Meng, Zepeng Cui, Jia Tian, Weian Zhang.
      In "immune-cold" tumors, the upregulation of immunosuppressive cells and insufficient infiltration of lymphocytes contribute to the resistance against immune therapy. Herein, we have developed a dual-enzyme-like photosensitive nanozyme (PBAF) to remodel the tumor immunosuppressive microenvironment (TIME) and induce the tumor infiltration of cytotoxic T lymphocytes (CTLs). Specifically, PBAF exhibits peroxidase (POD)-like activity and glutathione oxidase (GSHOx)-like activity and can be stimulated by 750 nm laser, promoting oxidative stress at the tumor site. Consequently, this process further leads to the reconstruction of TIME in animal experiments, inducing tumor-associated macrophages (TAMs) toward the immunostimulatory M1 phenotype, eliminating myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). Simultaneously, PBAF also promotes dendritic cells (DCs) maturation to enhance CTLs infiltration into the tumor. The remodeled TIME and enhanced immune responses by PBAF demonstrate significant post-administration inhibition of recurrence and metastasis in the treatment of malignant tumors.
    Keywords:  Immunosuppressive microenvironment; Immunotherapy; Photosensitive nanozyme
    DOI:  https://doi.org/10.1016/j.biomaterials.2024.122660
  11. Mol Cancer. 2024 Jun 20. 23(1): 130
    The role of RNA methylation in tumor immunity and its potential in immunotherapy.
    Yan Li, Haoer Jin, Qingling Li, Liangrong Shi, Yitao Mao, Luqing Zhao.
      RNA methylation, a prevalent post-transcriptional modification, has garnered considerable attention in research circles. It exerts regulatory control over diverse biological functions by modulating RNA splicing, translation, transport, and stability. Notably, studies have illuminated the substantial impact of RNA methylation on tumor immunity. The primary types of RNA methylation encompass N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), and N7-methylguanosine (m7G), and 3-methylcytidine (m3C). Compelling evidence underscores the involvement of RNA methylation in regulating the tumor microenvironment (TME). By affecting RNA translation and stability through the "writers", "erasers" and "readers", RNA methylation exerts influence over the dysregulation of immune cells and immune factors. Consequently, RNA methylation plays a pivotal role in modulating tumor immunity and mediating various biological behaviors, encompassing proliferation, invasion, metastasis, etc. In this review, we discussed the mechanisms and functions of several RNA methylations, providing a comprehensive overview of their biological roles and underlying mechanisms within the tumor microenvironment and among immunocytes. By exploring how these RNA modifications mediate tumor immune evasion, we also examine their potential applications in immunotherapy. This review aims to provide novel insights and strategies for identifying novel targets in RNA methylation and advancing cancer immunotherapy efficacy.
    Keywords:  Immunotherapy; RNA methylation; Tumor immune evasion; Tumor immunity; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1186/s12943-024-02041-8
  12. bioRxiv. 2024 Jun 06. pii: 2024.06.05.597474. [Epub ahead of print]
    Glioma-derived M-CSF and IL-34 license M-MDSCs to suppress CD8 + T cells in a NOS-dependent manner.
    Gregory P Takacs, Julia S Garcia, Caitlyn A Hodges, Christian J Kreiger, Alexandra Sherman, Jeffrey K Harrison.
      Glioblastoma (GBM) is the most common malignant primary brain tumor, resulting in poor survival despite aggressive therapies. GBM is characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME) made up predominantly of infiltrating peripheral immune cells. One significant immune cell type that contributes to glioma immune evasion is a population of immunosuppressive cells, termed myeloid-derived suppressor cells (MDSCs). Previous studies suggest that a subset of myeloid cells, expressing monocytic (M)-MDSC markers and dual expression of chemokine receptors CCR2 and CX3CR1, utilize CCR2 to infiltrate the TME. This study evaluated the mechanism of CCR2 + /CX3CR1 + M-MDSC differentiation and T cell suppressive function in murine glioma models. We determined that bone marrow-derived CCR2 + /CX3CR1 + cells adopt an immune suppressive cell phenotype when cultured with glioma-derived factors. Glioma secreted CSF1R ligands M-CSF and IL-34 were identified as key drivers of M-MDSC differentiation while adenosine and iNOS pathways were implicated in M-MDSC suppression of T cells. Mining a human GBM spatial RNAseq database revealed a variety of different pathways that M-MDSCs utilize to exert their suppressive function that are driven by complex niches within the microenvironment. These data provide a more comprehensive understanding of the mechanism of M-MDSCs in glioblastoma.
    Simple Summary: Currently there are no effective therapies for glioblastoma. Infiltrating myeloid cells contribute significantly to the immune suppressive tumor microenvironment that is characteristic of GBM. Monocytic myeloid derived suppressor cells are chief immune suppressive cells found in the glioma microenvironment. Understanding the mechanisms of M-MDSC differentiation and T cell suppression is imperative for generating therapies that target this tumor supportive cell population. In this study we found that glioma secreted CSF1R ligands, M-CSF and IL-34, license M-MDSCs to suppress CD8 T cells. These M-MDSCs partially utilize nitric oxide synthase to illicit their suppressive activity. However, spatial RNAseq points to glioma microenvironment niches driving M-MDSC heterogeneity. Our findings identify key regulators of differentiation and suppressive mechanisms of M-MDSCs and confirm the importance of targeting this cell population in glioma.
    DOI:  https://doi.org/10.1101/2024.06.05.597474
  13. Cells. 2024 May 27. pii: 924. [Epub ahead of print]13(11):
    Apoptosis, a Metabolic "Head-to-Head" between Tumor and T Cells: Implications for Immunotherapy.
    Ornella Franzese, Pietro Ancona, Nicoletta Bianchi, Gianluca Aguiari.
      Induction of apoptosis represents a promising therapeutic approach to drive tumor cells to death. However, this poses challenges due to the intricate nature of cancer biology and the mechanisms employed by cancer cells to survive and escape immune surveillance. Furthermore, molecules released from apoptotic cells and phagocytes in the tumor microenvironment (TME) can facilitate cancer progression and immune evasion. Apoptosis is also a pivotal mechanism in modulating the strength and duration of anti-tumor T-cell responses. Combined strategies including molecular targeting of apoptosis, promoting immunogenic cell death, modulating immunosuppressive cells, and affecting energy pathways can potentially overcome resistance and enhance therapeutic outcomes. Thus, an effective approach for targeting apoptosis within the TME should delicately balance the selective induction of apoptosis in tumor cells, while safeguarding survival, metabolic changes, and functionality of T cells targeting crucial molecular pathways involved in T-cell apoptosis regulation. Enhancing the persistence and effectiveness of T cells may bolster a more resilient and enduring anti-tumor immune response, ultimately advancing therapeutic outcomes in cancer treatment. This review delves into the pivotal topics of this multifaceted issue and suggests drugs and druggable targets for possible combined therapies.
    Keywords:  T cells; apoptosis; cancer
    DOI:  https://doi.org/10.3390/cells13110924
  14. Int J Mol Sci. 2024 May 21. pii: 5584. [Epub ahead of print]25(11):
    The Role of Metabolic Reprogramming in the Tumor Immune Microenvironment: Mechanisms and Opportunities for Immunotherapy in Hepatocellular Carcinoma.
    Nan Hu, Haiyang Li, Changcheng Tao, Ting Xiao, Weiqi Rong.
      As one of the emerging hallmarks of tumorigenesis and tumor progression, metabolic remodeling is common in the tumor microenvironment. Hepatocellular carcinoma (HCC) is the third leading cause of global tumor-related mortality, causing a series of metabolic alterations in response to nutrient availability and consumption to fulfill the demands of biosynthesis and carcinogenesis. Despite the efficacy of immunotherapy in treating HCC, the response rate remains unsatisfactory. Recently, research has focused on metabolic reprogramming and its effects on the immune state of the tumor microenvironment, and immune response rate. In this review, we delineate the metabolic reprogramming observed in HCC and its influence on the tumor immune microenvironment. We discuss strategies aimed at enhancing response rates and overcoming immune resistance through metabolic interventions, focusing on targeting glucose, lipid, or amino acid metabolism, as well as systemic regulation.
    Keywords:  hepatocellular carcinoma; immunotherapy; metabolic intervention; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms25115584
  15. Int Immunopharmacol. 2024 Jun 17. pii: S1567-5769(24)01030-0. [Epub ahead of print]137 112509
    Cancer stem cell-derived exosomes in CD8+ T cell exhaustion.
    Amir Gholami.
      Tumor-derived extracellular vesicles (EVs) are one of the most important ways of intercellular communication and signaling. Cancer stem cells (CSCs) secrete EVs to modulate immune checkpoint molecules and evade immune surveillance. Activated CD8+ T cells known as cytotoxic T lymphocytes (CTLs) are the most powerful anti-cancer adaptive cells. Their activity is compromised upon encountering cells and signaling within the tumor microenvironment (TME), resulting in hyporesponsiveness called exhaustion. CSC-derived exosomes express programmed death ligand-1 (PD-L1) and upregulate programmed death-1 (PD-1) on CD8+ T cells to promote their exhaustion. PD-L1 expression on tumor-derived exosomes appears to be induced by CSC-derived exosomes containing transforming growth factor (TGF)-β. Tenascin-C is another constituent of CSC exosomes that acts on mammalian target of rapamycin (mTOR) signaling in T cells. Glycolysis is a metabolic event promoted by the inducing effect of CSC-derived exosomes on hypoxia-inducible factor-1α (HIF-1α). CSC interaction with CD8+ T cells is even more complex as the CSC-derived exosomes contain Notch1 to stimulate stemness in non-tumor cells, and the inducible effect of Notch1 on PD-1 promotes CD8+ T cell exhaustion. CSC exosome targeting has not been extensively studied yet. Advances in the field will open up new therapeutic windows and shape the future of cancer immunotherapy.
    Keywords:  CD8(+) T cell; Cancer stem cell; Exhaustion; Exosome; Programmed death-1 (PD-1)
    DOI:  https://doi.org/10.1016/j.intimp.2024.112509
  16. Trends Mol Med. 2024 Jun 11. pii: S1471-4914(24)00154-0. [Epub ahead of print]
    Beyond the danger signal: RNA aggregates orchestrate immunotherapy.
    Quazi T H Shubhra, Tivadar Feczkó, Qiang Cai.
      Mendez-Gomez et al. recently demonstrated the transformative potential of RNA-lipid particle aggregates (RNA-LPAs) in immunotherapy. By reprogramming the tumor microenvironment (TME) and potentiating antitumor immunity, RNA-LPAs target primary tumors and elicit robust systemic immunity. This innovative platform holds promise for translating preclinical success into tangible clinical benefits.
    Keywords:  cancer vaccine; immunotherapy; lipid particle aggregates (LPAs); mRNA; tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.molmed.2024.05.018
  17. Cancer Lett. 2024 Jun 15. pii: S0304-3835(24)00467-1. [Epub ahead of print] 217072
    CD39 transforming cancer therapy by modulating tumor microenvironment.
    Suling Xu, Yuhan Ma, Xinyu Jiang, Qingqing Wang, Wenxue Ma.
      CD39 is a pivotal enzyme in cancer, regulating immune response and tumor progression via extracellular ATP and adenosine in the tumor microenvironment (TME). Beyond its established immunoregulatory function, CD39 influences cancer cell angiogenesis and metabolism, opening new frontiers for therapeutic interventions. Current research faces gaps in understanding CD39's full impact across cancer types, with ongoing debates about its potential beyond modulating immune evasion. This review distills CD39's multifaceted roles, examining its dual actions and implications for cancer prognosis and treatment. We analyze the latest therapeutic strategies, highlighting the need for an integrated approach that combines molecular insights with TME dynamics to innovate cancer care. This synthesis underscores CD39's integral role, charting a course for precision oncology that seeks to unravel controversies and harness CD39's therapeutic promise for improved cancer outcomes.
    Keywords:  Angiogenesis; CD39; Immunoregulation; Metabolic Reprogramming; Therapeutic Targets; Tumor Microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.canlet.2024.217072
  18. Biomicrofluidics. 2024 May;18(3): 031506
    Application and prospect of microfluidic devices for rapid assay of cell activities in the tumor microenvironment.
    Linjing Zhu, Xueling Cui, Lingling Jiang, Fang Fang, Boyang Liu.
      The global impact of cancer on human health has raised significant concern. In this context, the tumor microenvironment (TME) plays a pivotal role in the tumorigenesis and malignant progression. In order to enhance the accuracy and efficacy of therapeutic outcomes, there is an imminent requirement for in vitro models that can accurately replicate the intricate characteristics and constituents of TME. Microfluidic devices exhibit notable advantages in investigating the progression and treatment of tumors and have the potential to become a novel methodology for evaluating immune cell activities in TME and assist clinicians in assessing the prognosis of patients. In addition, it shows great advantages compared to traditional cell experiments. Therefore, the review first outlines the applications and advantages of microfluidic chips in facilitating tumor cell culture, constructing TME and investigating immune cell activities. Second, the roles of microfluidic devices in the analysis of circulating tumor cells, tumor prognosis, and drug screening have also been mentioned. Moreover, a forward-looking perspective is discussed, anticipating the widespread clinical adoption of microfluidic devices in the future.
    DOI:  https://doi.org/10.1063/5.0206058
  19. Yi Chuan. 2024 Jun 20. 46(6): 438-451
    The roles of branched-chain amino acids metabolism in tumorigenesis and progression.
    Shen Yuan, Li Jin-Tao, Yin Miao, Lei Qun-Ying.
      Branched-chain amino acids (BCAAs), including leucine, valine, and isoleucine, play crucial roles in regulating metabolic balance and maintaining physiological functions in the body. Extensive studies have been focused on their implications in obesity, diabetes, and cardiovascular diseases. Nevertheless, accumulating evidence suggests that BCAAs metabolism also plays significant roles in tumorigenesis and progression. In this review, we overview recent progress of the study on BCAAs metabolism including its relationship with epigenetic regulation. Particularly, we discuss the metabolic reprogramming and metabolic sensing of BCAAs and its intermediate metabolites in tumor cells and microenvironment to decipher their functions. An enhanced understanding of the roles and mechanism of BCAAs metabolism in tumorigenesis and progression will contribute to development of novel therapeutic strategies against tumor.
    Keywords:  BCAAs; epigenetics; metabolic reprogramming; metabolic sensing; tumor cells; tumor microenvironment
    DOI:  https://doi.org/10.16288/j.yczz.24-095
  20. J Nanobiotechnology. 2024 Jun 18. 22(1): 341
    Engineering nanoparticles-enabled tumor-associated macrophages repolarization and phagocytosis restoration for enhanced cancer immunotherapy.
    Yonghua Gong, Wenyue Gao, Jinyang Zhang, Xia Dong, Dunwan Zhu, Guilei Ma.
      Tumor-associated macrophages (TAMs) are pivotal within the immunosuppressive tumor microenvironment (TME), and recently, have attracted intensive attention for cancer treatment. However, concurrently to promote TAMs repolarization and phagocytosis of cancer cells remains challenging. Here, a TAMs-targeted albumin nanoparticles-based delivery system (M@SINPs) was constructed for the co-delivery of photosensitizer IR820 and SHP2 inhibitor SHP099 to potentiate macrophage-mediated cancer immunotherapy. M@SINPs under laser irradiation can generate the intracellular reactive oxygen species (ROS) and facilitate M2-TAMs to an M1 phenotype. Meanwhile, inhibition of SHP2 could block the CD47-SIRPa pathway to restore M1 macrophage phagocytic activity. M@SINPs-mediated TAMs remodeling resulted in the immunostimulatory TME by repolarizing TAMs to an M1 phenotype, restoring its phagocytic function and facilitating intratumoral CTLs infiltration, which significantly inhibited tumor growth. Furthermore, M@SINPs in combination with anti-PD-1 antibody could also improve the treatment outcomes of PD-1 blockade and exert the synergistic anticancer effects. Thus, the macrophage repolarization/phagocytosis restoration combination through M@SINPs holds promise as a strategy to concurrently remodel TAMs in TME for improving the antitumor efficiency of immune checkpoint block and conventional therapy.
    Keywords:  Cancer immunotherapy; Combination; Nanoparticles; Phagocytosis; Polarization; Tumor-associated macrophages
    DOI:  https://doi.org/10.1186/s12951-024-02622-1
  21. Molecules. 2024 May 22. pii: 2436. [Epub ahead of print]29(11):
    Drug-Loaded Mesoporous Silica Nanoparticles Enhance Antitumor Immunotherapy by Regulating MDSCs.
    Changlin Xu, Nida Amna, Yuchen Shi, Rong Sun, Chenhui Weng, Jiaoyu Chen, Huaxing Dai, Chao Wang.
      Myeloid-derived suppressor cells (MDSCs) are recognized as major immune suppressor cells in the tumor microenvironment that may inhibit immune checkpoint blockade (ICB) therapy. Here, we developed a Stattic-loaded mesoporous silica nanoparticle (PEG-MSN-Stattic) delivery system to tumor sites to reduce the number of MDSCs in tumors. This approach is able to significantly deplete intratumoral MSDCs and thereby increase the infiltration of T lymphocytes in tumors to enhance ICB therapy. Our approach may provide a drug delivery strategy for regulating the tumor microenvironment and enhancing cancer immunotherapy efficacy.
    Keywords:  ICB therapy; PEG-MSN; myeloid-derived suppressor cells; stattic; tumor therapy
    DOI:  https://doi.org/10.3390/molecules29112436
  22. Cell Commun Signal. 2024 Jun 19. 22(1): 338
    Mechanisms, combination therapy, and biomarkers in cancer immunotherapy resistance.
    Manshi Yang, Mengying Cui, Yang Sun, Shui Liu, Weibo Jiang.
      Anti-programmed death 1/programmed death ligand 1 (anti-PD-1/PD-L1) antibodies exert significant antitumor effects by overcoming tumor cell immune evasion and reversing T-cell exhaustion. However, the emergence of drug resistance causes most patients to respond poorly to these immune checkpoint inhibitors (ICIs). Studies have shown that insufficient T-cell infiltration, lack of PD-1 expression, deficient interferon signaling, loss of tumor antigen presentation, and abnormal lipid metabolism are all considered to be closely associated with immunotherapy resistance. To address drug resistance in tumor immunotherapy, a lot of research has concentrated on developing combination therapy strategies. Currently, ICIs such as anti-PD-1 /PD-L1 antibody combined with chemotherapy and targeted therapy have been approved for clinical treatment. In this review, we analyze the mechanisms of resistance to anti-PD-1/PD-L1 therapy in terms of the tumor microenvironment, gut microbiota, epigenetic regulation, and co-inhibitory immune checkpoint receptors. We also discuss various promising combination therapeutic strategies to address resistance to anti-PD-1/PD-L1 drugs, including combining these therapies with traditional Chinese medicine, non-coding RNAs, targeted therapy, other ICIs, and personalized cancer vaccines. Moreover, we focus on biomarkers that predict resistance to anti-PD-1/PD-L1 therapy as well as combination therapy efficacy. Finally, we suggest ways to further expand the application of immunotherapy through personalized combination strategies using biomarker systems.
    Keywords:  Biomarker; Cancer; Combination therapy; Immunotherapy resistance; Mechanism
    DOI:  https://doi.org/10.1186/s12964-024-01711-w
  23. Front Immunol. 2024 ;15 1433808
    Editorial: Polarization of cellular immune response in the context of inflammation and cancer.
    Elisa Wirthgen, Grazyna Domanska.
      
    Keywords:  cancer; chronic inflammation; immune response; inflammasome; macrophages; polarization
    DOI:  https://doi.org/10.3389/fimmu.2024.1433808
  24. Cell Mol Immunol. 2024 Jun 20.
    Exportin 1 governs the immunosuppressive functions of myeloid-derived suppressor cells in tumors through ERK1/2 nuclear export.
    Saeed Daneshmandi, Qi Yan, Jee Eun Choi, Eriko Katsuta, Cameron R MacDonald, Mounika Goruganthu, Nathan Roberts, Elizabeth A Repasky, Prashant K Singh, Kristopher Attwood, Jianmin Wang, Yosef Landesman, Philip L McCarthy, Hemn Mohammadpour.
      Myeloid-derived suppressor cells (MDSCs) are a main driver of immunosuppression in tumors. Understanding the mechanisms that determine the development and immunosuppressive function of these cells could provide new therapeutic targets to improve antitumor immunity. Here, using preclinical murine models, we discovered that exportin 1 (XPO1) expression is upregulated in tumor MDSCs and that this upregulation is induced by IL-6-induced STAT3 activation during MDSC differentiation. XPO1 blockade transforms MDSCs into T-cell-activating neutrophil-like cells, enhancing the antitumor immune response and restraining tumor growth. Mechanistically, XPO1 inhibition leads to the nuclear entrapment of ERK1/2, resulting in the prevention of ERK1/2 phosphorylation following the IL-6-mediated activation of the MAPK signaling pathway. Similarly, XPO1 blockade in human MDSCs induces the formation of neutrophil-like cells with immunostimulatory functions. Therefore, our findings revealed a critical role for XPO1 in MDSC differentiation and suppressive functions; exploiting these new discoveries revealed new targets for reprogramming immunosuppressive MDSCs to improve cancer therapeutic responses.
    Keywords:  Exportin 1; MAPK pathway; MDSCs; Tumor
    DOI:  https://doi.org/10.1038/s41423-024-01187-1
  25. Transl Cancer Res. 2024 May 31. 13(5): 2580-2586
    The role of CD4+ CAR T cells in cancer immunotherapy.
    Camilla Bove, John Maher, Maya Glover.
      
    Keywords:  CD4+ T cells; IFN-γ; cancer; chimeric antigen receptor; immunotherapy
    DOI:  https://doi.org/10.21037/tcr-23-2044
  26. J Cell Immunol. 2024 ;6(1): 22-50
    Essentials of CAR-T Therapy and Associated Microbial Challenges in Long Run Immunotherapy.
    Muhammad Kalim, Rui Jing, Xin Li, Zhiwu Jiang, Ningbo Zheng, Ziyu Wang, Guo Wei, Yong Lu.
      Chimeric antigen receptor (CAR)-T cell therapy has shown potential in improving outcomes for individuals with hematological malignancies. However, achieving long-term full remission for blood cancer remains challenging due to severe life-threatening toxicities such as limited anti-tumor efficacy, antigen escape, trafficking restrictions, and limited tumor invasion. Furthermore, the interactions between CAR-T cells and their host tumor microenvironments have a significant impact on CAR-T function. To overcome these considerable hurdles, fresh methodologies and approaches are needed to produce more powerful CAR-T cells with greater anti-tumor activity and less toxicity. Despite advances in CAR-T research, microbial resistance remains a significant obstacle. In this review, we discuss and describe the basics of CAR-T structures, generations, challenges, and potential risks of infections in CAR-T cell therapy.
    Keywords:  Adoptive cellular therapy; CAR-T; COVID-19; Immunotherapy; Infection
    DOI:  https://doi.org/10.33696/immunology.6.189
  27. Int J Biol Sci. 2024 ;20(8): 3201-3218
    Hypoxic tumor-derived exosomal miR-4488 induces macrophage M2 polarization to promote liver metastasis of pancreatic neuroendocrine neoplasm through RTN3/FABP5 mediated fatty acid oxidation.
    Feiyu Lu, Mujie Ye, Yikai Shen, Yanling Xu, Chunhua Hu, Jinhao Chen, Ping Yu, Bingyan Xue, Danyang Gu, Lin Xu, Lingyi Chen, Yi Ding, Jianan Bai, Ye Tian, Qiyun Tang.
      Tumor-associated macrophages (TAMs) represent a predominant cellular component within the tumor microenvironment (TME) of pancreatic neuroendocrine neoplasms (pNENs). There is a growing body of evidence highlighting the critical role of exosomes in facilitating communication between tumor cells and TAMs, thereby contributing to the establishment of the premetastatic niche. Nonetheless, the specific mechanisms through which exosomes derived from tumor cells influence macrophage polarization under hypoxic conditions in pNENs, and the manner in which these interactions support cancer metastasis, remain largely unexplored. Recognizing the capacity of exosomes to transfer miRNAs that can modify cellular behaviors, our research identified a significant overexpression of miR-4488 in exosomes derived from hypoxic pNEN cells. Furthermore, we observed that macrophages that absorbed circulating exosomal miR-4488 underwent M2-like polarization. Our investigations revealed that miR-4488 promotes M2-like polarization by directly targeting and suppressing RTN3 in macrophages. This suppression of RTN3 enhances fatty acid oxidation and activates the PI3K/AKT/mTOR signaling pathway through the interaction and downregulation of FABP5. Additionally, M2 polarized macrophages contribute to the formation of the premetastatic niche and advance pNENs metastasis by releasing MMP2, thereby establishing a positive feedback loop involving miR-4488, RTN3, FABP5, and MMP2 in pNEN cells. Together, these findings shed light on the role of exosomal miRNAs from hypoxic pNEN cells in mediating interactions between pNEN cells and intrahepatic macrophages, suggesting that miR-4488 holds potential as a valuable biomarker and therapeutic target for pNENs.
    Keywords:  FABP5; M2-like polarization; MMP2; RTN3; exosomes; fatty acid oxidation; hypoxia; miR-4488; pancreatic neuroendocrine neoplasms
    DOI:  https://doi.org/10.7150/ijbs.96831
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