bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024–09–29
25 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Targeting tumor-associated macrophages with nanocarrier-based treatment for breast cancer: A step toward developing innovative anti-cancer therapeutics.
  2. Metabolic reprogramming of macrophages in cancer therapy.
  3. Recent advancements in improving the efficacy and safety of chimeric antigen receptor (CAR)-T cell therapy for hepatocellular carcinoma.
  4. New insights into SYK targeting in solid tumors.
  5. Treg Cell Therapeutic Strategies for Breast Cancer: Holistic to Local Aspects.
  6. Complex role of neutrophils in the tumor microenvironment: an avenue for novel immunotherapies.
  7. Hepatocellular carcinoma cells induce γδ T cells through metabolic reprogramming into tumor-progressive subpopulation.
  8. Mesenchymal Stem/Stromal cells in solid tumor Microenvironment: Orchestrating NK cell remodeling and therapeutic insights.
  9. Validation of a PD-1/CD28 chimeric switch receptor to augment CAR-T function in dogs with spontaneous B cell lymphoma.
  10. Enhancing cancer immunotherapy: Nanotechnology-mediated immunotherapy overcoming immunosuppression.
  11. Unraveling Th subsets: insights into their role in immune checkpoint inhibitor therapy.
  12. Tumor Microenvironment-Derived Exosomes: A Double-Edged Sword for Advanced T Cell-Based Immunotherapy.
  13. Targeted nanomedicine for reprogramming the tumor innate immune system: From bench to bedside.
  14. Recent advances and progress in immunotherapy of solid cancers.
  15. Role of Nutrients Regulating Myeloid Derived Suppressor Cells in Cancer: A Scoping Review.
  16. Engineering macrophage membrane-camouflaged nanoplatforms with enhanced macrophage function for mediating sonodynamic therapy of ovarian cancer.
  17. Crosstalk Between Cancer-associated Fibroblasts and Myeloid Cells Shapes the Heterogeneous Microenvironment of Gastric Cancer.
  18. Cellular Dynamics of Tumor Microenvironment Driving Immunotherapy Resistance in Non-Small-Cell Lung Carcinoma.
  19. The crossroad between tumor and endothelial cells.
  20. [Research Progresses on the Effects of CCL4 on Immune Escape 
in Tumor Microenvironment].
  21. Intricate relationship between cancer stemness, metastasis, and drug resistance.
  22. The missing link between cancer stem cells and immunotherapy.
  23. CD200 depletion in glioma enhances antitumor immunity and induces tumor rejection.
  24. The role of cholesterol metabolism in lung cancer.
  25. Host ANGPTL2 establishes an immunosuppressive tumor microenvironment and resistance to immune checkpoint therapy.
  1. Heliyon. 2024 Sep 30. 10(18): e37217
    Targeting tumor-associated macrophages with nanocarrier-based treatment for breast cancer: A step toward developing innovative anti-cancer therapeutics.
    Ghazala Muteeb, Doaa S R Khafaga, Manar T El-Morsy, Mohd Farhan, Mohammad Aatif, Mohamed Hosney.
      Tumor-associated macrophages (TAMs) promote tumor advancement in many ways, such as inducing angiogenesis and the formation of new blood vessels that provide tumors with nourishment and oxygen. TAMs also facilitate tumor invasion and metastasis by secreting enzymes that degrade the extracellular matrix and generating pro-inflammatory cytokines that enhance the migration of tumor cells. TAMs also have a role in inhibiting the immune response against malignancies. To accomplish this, they release immunosuppressive cytokines such as IL-10, and TAMs can hinder the function of T cells and natural killer cells, which play crucial roles in the immune system's ability to combat cancer. The role of TAMs in breast cancer advancement is a complex and dynamic field of research. Therefore, TAMs are a highly favorable focus for innovative breast cancer treatments. This review presents an extensive overview of the correlation between TAMs and breast cancer development as well as its role in the tumor microenvironment (TME) shedding light on their impact on tumor advancement and immune evasion mechanisms. Notably, our study provides an innovative approach to employing nanomedicine approaches for targeted TAM therapy in breast cancer, providing an in-depth overview of recent advances in this emerging field.
    Keywords:  Angiogenesis; Breast cancer progression; Immunosuppression; M1; M2; Metastasis; Tumor associated macrophages
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e37217
  2. Trends Endocrinol Metab. 2024 Sep 19. pii: S1043-2760(24)00244-3. [Epub ahead of print]
    Metabolic reprogramming of macrophages in cancer therapy.
    Xudong Wang, Shaolong Zhang, Dixuan Xue, Dante Neculai, Jin Zhang.
      Cancer presents a significant global public health challenge. Within the tumor microenvironment (TME), macrophages are the most abundant immune cell population. Tumor-associated macrophages (TAMs) undergo metabolic reprogramming through influence of the TME; thus, by manipulating key metabolic pathways such as glucose, lipid, or amino acid metabolism, it may be possible to shift TAMs towards an antitumor state, enhancing the immune response against tumors. Here, we highlight the metabolic reprogramming of macrophages as a potential approach for cancer immunotherapy. We explore the major pathways involved in the metabolic reprogramming of TAMs and offer new and valuable insights on the current technologies utilized for TAM reprogramming, including genome editing, antibodies, small molecules, nanoparticles and other in situ editing strategies.
    Keywords:  cancer therapy; macrophage; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.tem.2024.08.009
  3. Naunyn Schmiedebergs Arch Pharmacol. 2024 Sep 24.
    Recent advancements in improving the efficacy and safety of chimeric antigen receptor (CAR)-T cell therapy for hepatocellular carcinoma.
    Tuo Ren, Yonghui Huang.
      The liver is one of the most frequent sites of primary malignancies in humans. Hepatocellular carcinoma (HCC) is one of the most prevalent solid tumors with poor prognosis. Current treatments showed limited efficacy in some patients, and, therefore, alternative strategies, such as immunotherapy, cancer vaccines, adoptive cell therapy (ACT), and recently chimeric antigen receptors (CAR)-T cells, are developed to offer better efficacy and safety profile in patients with HCC. Unlike other ACTs like tumor-infiltrating lymphocytes (TILs), CAR-T cells are equipped with engineered CAR receptors that effectively identify tumor antigens and eliminate cancer cells without major histocompatibility complex (MHC) restriction. This process induces intracellular signaling, leading to T lymphocyte recruitment and subsequent activation of other effector cells in the tumor microenvironment (TME). Until today, novel approaches have been used to develop more potent CAR-T cells with robust persistence, specificity, trafficking, and safety. However, the clinical application of CAR-T cells in solid tumors is still challenging. Therefore, this study aims to review the advancement, prospects, and possible avenues of CAR-T cell application in HCC following an outline of the CAR structure and function.
    Keywords:  Adoptive cell therapy; CAR-T cell; Hepatocellular carcinoma; Immunotherapy
    DOI:  https://doi.org/10.1007/s00210-024-03443-7
  4. Trends Pharmacol Sci. 2024 Sep 24. pii: S0165-6147(24)00168-8. [Epub ahead of print]
    New insights into SYK targeting in solid tumors.
    Shweta Joshi.
      Spleen tyrosine kinase (SYK) is predominantly expressed in hematopoietic cells and has been extensively studied for its pivotal role in B cell malignancies and autoimmune diseases. In epithelial solid tumors, SYK shows a paradoxical role, acting as a tumor suppressor in some cancers while driving tumor growth in others. Recent preclinical studies have identified the role of SYK in the tumor microenvironment (TME), revealing that SYK signaling in immune cells, especially B cells, and myeloid cells, promote immunosuppression, tumor growth, and metastasis across various solid tumors. This review explores the emerging roles of SYK in solid tumors, the mechanisms of SYK activation, and findings from preclinical and clinical studies of SYK inhibitors as either standalone treatments or in combination with immunotherapy or chemotherapy for solid tumors.
    Keywords:  B cells; SYK; macrophages; myeloid cells; solid tumors; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.tips.2024.08.006
  5. Cells. 2024 Sep 11. pii: 1526. [Epub ahead of print]13(18):
    Treg Cell Therapeutic Strategies for Breast Cancer: Holistic to Local Aspects.
    Hanwen Zhang, Oliver Felthaus, Andreas Eigenberger, Silvan Klein, Lukas Prantl.
      Regulatory T cells (Tregs) play a key role in maintaining immune homeostasis and preventing autoimmunity through their immunosuppressive function. There have been numerous reports confirming that high levels of Tregs in the tumor microenvironment (TME) are associated with a poor prognosis, highlighting their role in promoting an immunosuppressive environment. In breast cancer (BC), Tregs interact with cancer cells, ultimately leading to the suppression of immune surveillance and promoting tumor progression. This review discusses the dual role of Tregs in breast cancer, and explores the controversies and therapeutic potential associated with targeting these cells. Researchers are investigating various strategies to deplete or inhibit Tregs, such as immune checkpoint inhibitors, cytokine antagonists, and metabolic inhibition. However, the heterogeneity of Tregs and the variable precision of treatments pose significant challenges. Understanding the functional diversity of Tregs and the latest advances in targeted therapies is critical for the development of effective therapies. This review highlights the latest approaches to Tregs for BC treatment that both attenuate Treg-mediated immunosuppression in tumors and maintain immune tolerance, and advocates precise combination therapy strategies to optimize breast cancer outcomes.
    Keywords:  breast cancer; regulatory T cells; treatment
    DOI:  https://doi.org/10.3390/cells13181526
  6. Cancer Biol Med. 2024 Sep 19. pii: j.issn.2095-3941.2024.0192. [Epub ahead of print]
    Complex role of neutrophils in the tumor microenvironment: an avenue for novel immunotherapies.
    Mao Zhang, Haokai Qin, Yingcheng Wu, Qiang Gao.
      Neutrophils, which originate from the bone marrow and are characterized by a segmented nucleus and a brief lifespan, have a crucial role in the body's defense against infections and acute inflammation. Recent research has uncovered the complex roles of neutrophils as regulators in tumorigenesis, during which neutrophils exhibit a dualistic nature that promotes or inhibits tumor progression. This adaptability is pivotal within the tumor microenvironment (TME). In this review, we provide a comprehensive characterization of neutrophil plasticity and heterogeneity, aiming to illuminate current research findings and discuss potential therapeutic avenues. By delineating the intricate interplay of neutrophils in the TME, this review further underscores the urgent need to understand the dual functions of neutrophils with particular emphasis on the anti-tumor effects to facilitate the development of effective therapeutic strategies against cancer.
    Keywords:  Neutrophil; immunotherapy; plasticity; tumor microenvironment
    DOI:  https://doi.org/10.20892/j.issn.2095-3941.2024.0192
  7. Front Oncol. 2024 ;14 1451650
    Hepatocellular carcinoma cells induce γδ T cells through metabolic reprogramming into tumor-progressive subpopulation.
    Jinkun Xia, Chaoyu Wang, Biao Li.
      Tumor immune microenvironment (TIME) is a tiny structure that contains multiple immune cell components around tumor cells, which plays an important role in tumorigenesis, and is also the potential core area of activated immunotherapy. How immune cells with tumor-killing capacity in TIME are hijacked by tumor cells during the progression of tumorigenesis and transformed into subpopulations that facilitate cancer advancement is a question that needs to be urgently addressed nowadays. γδ T cells (their T cell receptors are composed of γ and δ chains), a unique T cell subpopulation distinguished from conventional αβ T cells, are involved in a variety of immune response processes through direct tumor-killing effects and/or indirectly influencing the activity of other immune cells. However, the presence of γδ T cells in the tumor microenvironment (TME) has been reported to be associated with poor prognosis in some tumors, suggesting that certain γδ T cell subsets may also have pro-tumorigenic effects. Recent studies have revealed that metabolic pathways such as activation of glycolysis, increase of lipid metabolism, enhancement of mitochondrial biosynthesis, alterations of fatty acid metabolism reshape the local TME, and immune cells trigger metabolic adaptation through metabolic reprogramming to meet their own needs and play the role of anti-tumor or immunosuppression. Combining previous studies and our bioinformatics results, we hypothesize that γδT cells compete for resources with hepatocellular carcinoma (HCC) cells by means of fatty acid metabolic regulation in the TME, which results in the weakening or loss of their ability to recognize and kill HCC cells through genetic and epigenetic alterations, thus allowing γδT cells to be hijacked by HCC cells as a subpopulation that promotes HCC progression.
    Keywords:  fatty acid; hepatocellular carcinoma; metabolic reprogramming; tumor immune microenvironment; γδT cells
    DOI:  https://doi.org/10.3389/fonc.2024.1451650
  8. Int Immunopharmacol. 2024 Sep 20. pii: S1567-5769(24)01703-X. [Epub ahead of print]142(Pt B): 113181
    Mesenchymal Stem/Stromal cells in solid tumor Microenvironment: Orchestrating NK cell remodeling and therapeutic insights.
    Hao Zhang, Xiaoli Cao, Rulin Gui, Yuanyuan Li, Xinlan Zhao, Jingyu Mei, Baocheng Zhou, Mei Wang.
      Mesenchymal stem/stromal cells (MSCs), originating from normal tissues, possess the capacity to home to tumor sites and differentiate into tumor-associated MSCs (TA-MSCs), which are instrumental in shaping an immunosuppressive milieu within tumors. Natural killer (NK) cells, integral to the innate immune system, are endowed with the ability to eradicate target cells autonomously, serving as an immediate defense against neoplastic growths. Nonetheless, within the tumor microenvironment (TME), NK cells often exhibit a decline in both their numerical presence and functionality. TA-MSCs have been shown to exert profound inhibitory effects on the functions of tumor-infiltrating immune cells, notably NK cells. Understanding the mechanisms by which TA-MSCs contribute to NK cell dysfunction is critical for the advancement of immune surveillance and the enhancement of tumoricidal responses. This review summarizes existing literature on NK cell modulation by TA-MSCs within the TME and proposes innovative strategies to augment antitumor immunity.
    Keywords:  Mesenchymal stem/stromal cells; Natural killer cells; Therapeutic implications; Tumor immunology; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.intimp.2024.113181
  9. iScience. 2024 Sep 20. 27(9): 110863
    Validation of a PD-1/CD28 chimeric switch receptor to augment CAR-T function in dogs with spontaneous B cell lymphoma.
    Sho Yoshimoto, Ayano Kudo, Antonia Rotolo, Kay Foos, Lauren Olenick, Satoshi Takagi, Nicola J Mason.
      Chimeric antigen receptor (CAR) T cell therapy has achieved unprecedented clinical outcomes in patients with relapsed/refractory B cell leukemias; however, response rates in patients with large B cell lymphoma (LBCL) are less impressive. Expression of PD-1 on activated T cells and PD-L1 on malignant, stromal, and immune cells within the tumor microenvironment (TME) contribute to CAR-T exhaustion, hypofunction, and treatment failures. Here, a comparative approach is taken to develop a chimeric switch receptor (CSR) with potential to augment CAR-T persistence, function, and clinical efficacy in immune competent, pet dogs with spontaneous B cell lymphoma (BCL). We show that similar to human CAR-T cells, expression of a PD-1/CD28 CSR in canine CAR-T cells results in enhanced function against PD-L1+ targets and preserves central memory phenotype. We also demonstrate that these effects depend upon active CSR signaling. This work paves the way for in vivo studies in canine BCL patients to inform human trial design.
    Keywords:  Cancer; Therapeutics; Veterinary medicine
    DOI:  https://doi.org/10.1016/j.isci.2024.110863
  10. Acta Pharm Sin B. 2024 Sep;14(9): 3834-3854
    Enhancing cancer immunotherapy: Nanotechnology-mediated immunotherapy overcoming immunosuppression.
    Yunna Chen, Qianqian Zhou, Zongfang Jia, Nuo Cheng, Sheng Zhang, Weidong Chen, Lei Wang.
      Immunotherapy is an important cancer treatment method that offers hope for curing cancer patients. While immunotherapy has achieved initial success, a major obstacle to its widespread adoption is the inability to benefit the majority of patients. The success or failure of immunotherapy is closely linked to the tumor's immune microenvironment. Recently, there has been significant attention on strategies to regulate the tumor immune microenvironment in order to stimulate anti-tumor immune responses in cancer immunotherapy. The distinctive physical properties and design flexibility of nanomedicines have been extensively utilized to target immune cells (including tumor-associated macrophages (TAMs), T cells, myeloid-derived suppressor cells (MDSCs), and tumor-associated fibroblasts (TAFs)), offering promising advancements in cancer immunotherapy. In this article, we have reviewed treatment strategies aimed at targeting various immune cells to regulate the tumor immune microenvironment. The focus is on cancer immunotherapy models that are based on nanomedicines, with the goal of inducing or enhancing anti-tumor immune responses to improve immunotherapy. It is worth noting that combining cancer immunotherapy with other treatments, such as chemotherapy, radiotherapy, and photodynamic therapy, can maximize the therapeutic effects. Finally, we have identified the challenges that nanotechnology-mediated immunotherapy needs to overcome in order to design more effective nanosystems.
    Keywords:  Cancer; Extracellular matrix; Immune checkpoint inhibitors; Immunogenic cell death; Immunotherapy; Nanomedicine; T cells; Tumor immunosuppressive microenvironment
    DOI:  https://doi.org/10.1016/j.apsb.2024.05.032
  11. Cell Oncol (Dordr). 2024 Sep 26.
    Unraveling Th subsets: insights into their role in immune checkpoint inhibitor therapy.
    Monika Ryba-Stanisławowska.
      T helper (Th) cell subsets play pivotal roles in regulating immune responses within the tumor microenvironment, influencing both tumor progression and anti-tumor immunity. Among these subsets, Th1 cells promote cytotoxic responses through the production of IFN-γ, while Th2 cells and regulatory T cells (Tregs) exert immunosuppressive effects that support tumor growth. Th9 and Th17 cells have context-dependent roles, contributing to both pro-inflammatory and regulatory processes in tumor immunity. Tumor antigen-specific T cells within the tumor microenvironment often exhibit a dysfunctional phenotype due to increased expression of inhibitory receptors such as CTLA-4 and PD-1, leading to reduced antitumor activity. Monoclonal antibodies that block these inhibitory signals-collectively known as immune checkpoint inhibitors (ICIs)-can reactivate these T cells, enhancing their ability to target and destroy cancer cells. Recent advancements have highlighted the critical role of T helper subsets in modulating responses to ICIs, with their interactions remaining a focus of ongoing research. Both positive and negative effects of ICIs have been reported in relation to Th cell subsets, with some effects depending on the type of tumor microenvironment. This review summarizes the crucial roles of different T helper cell subsets in tumor immunity and their complex relationship with immune checkpoint inhibitor therapy.
    Keywords:  Anti-CTLA-4; Anti-PD1; ICI; Th subsets; Tumor immunity
    DOI:  https://doi.org/10.1007/s13402-024-00992-0
  12. ACS Nano. 2024 Sep 25.
    Tumor Microenvironment-Derived Exosomes: A Double-Edged Sword for Advanced T Cell-Based Immunotherapy.
    Ye Lu, Jiarong Zheng, Pei Lin, Yunfan Lin, Yucheng Zheng, Zizhao Mai, Xu Chen, Tian Xia, Xinyuan Zhao, Li Cui.
      The tumor microenvironment (TME) plays a crucial role in cancer progression and immune evasion, partially mediated by the activity of the TME-derived exosomes. These extracellular vesicles are pivotal in shaping immune responses through the transfer of proteins, lipids, and nucleic acids between cells, facilitating a complex interplay that promotes tumor growth and metastasis. This review delves into the dual roles of exosomes in the TME, highlighting both their immunosuppressive functions and their emerging therapeutic potential. Exosomes can inhibit T cell function and promote tumor immune escape by carrying immune-modulatory molecules, such as PD-L1, yet they also hold promise for cancer therapy as vehicles for delivering tumor antigens and costimulatory signals. Additionally, the review discusses the intricate crosstalk mediated by exosomes among various cell types within the TME, influencing both cancer progression and responses to immunotherapies. Moreover, this highlights current challenges and future directions. Collectively, elucidating the detailed mechanisms by which TME-derived exosomes mediate T cell function offers a promising avenue for revolutionizing cancer treatment. Understanding these interactions allows for the development of targeted therapies that manipulate exosomal pathways to enhance the immune system's response to tumors.
    Keywords:  Exosomes; Immune evasion; Immune response; Immunotherapy; Nanocarrier; T cell; Therapeutic target; Tumor microenvironment
    DOI:  https://doi.org/10.1021/acsnano.4c09190
  13. Eur J Pharm Biopharm. 2024 Sep 20. pii: S0939-6411(24)00336-9. [Epub ahead of print] 114510
    Targeted nanomedicine for reprogramming the tumor innate immune system: From bench to bedside.
    Kunal Pednekar, Julia Minnee, I Jolanda M de Vries, Jai Prakash.
      Tumor-associated innate immune cells such as tumor-associated macrophages, neutrophils, dendritic cells play a crucial role in tumor progression, angiogenesis and metastasis. These cells also control the efficacy of chemotherapy and immunotherapy by inducing drug resistance and immunosuppression, leading to therapeutic failures. Therefore, targeting the tumor-associated innate immune cells has gained high attention for the development of effective cancer therapy. Nanomedicine based strategies to target these cells are highly relevant and can be used to reprogram these cells. In this review, we discuss the fundamental roles of the tumor-associated innate immune cells in the tumor microenvironment and different strategies to modulate them. Then, nanomedicine-based strategies to target different tumor innate immune cells are explained in detail. While the clinical development of the targeted nanomedicine remains a great challenge in practice, we have provided our perspectives on various factors such as pharmaceutical aspects, preclinical testing and biological aspects which are crucial to consider before translating these targeting strategies to clinics.
    Keywords:  Cancer therapeutics; Immunotherapy; Innate immune cells; Nanomedicine; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.ejpb.2024.114510
  14. Adv Cancer Res. 2024 ;pii: S0065-230X(24)00014-9. [Epub ahead of print]164 111-190
    Recent advances and progress in immunotherapy of solid cancers.
    Amit Kumar, Luni Emdad, Swadesh K Das, Paul B Fisher.
      Adoptive cell therapy using chimeric antigen receptor (CAR) technology has become mainstream by employing advanced engineering platforms to promote cancer immunotherapy. CAR T cells have shown remarkable efficacy in the treatment of hematological malignancies; however, the value of this therapy remains inconclusive in the context of solid tumors. Immunotherapy of solid tumors is restrained by several obstacles including the presence of an immunosuppressive tumor microenvironment (TME), limited tumor trafficking, inhibited immune cell infiltration, absence of tumor-specific antigens, and off-target toxicity and adverse events associated with these therapies. Despite recent advances in CAR T cell construction, including the integration of co-stimulatory domains and the creation of armed CAR T cells, with promising outcomes in the treatment of some solid tumors, there are still many unresolved obstacles that need to be overcome. To surmount these impediments to effective CAR T cell therapies, other immune cells, such as natural killer cells and macrophages, have been engineered to serve as appealing alternatives for successful cancer immunotherapy of solid tumors. CAR NK cells demonstrate significant clinical advantages due to their ready availability and minimal toxicity. CAR macrophage (M) cells provide considerable therapeutic potential due to their ability to penetrate the TME of solid tumors. In this review, we comprehensively examine the latest developments and prospects of engineered immune cell-based cancer immunotherapies specifically designed for treating solid tumors. In addition, we provide a concise overview of current clinical trials that are examining the safety and effectiveness of modified immune cells, such as CAR T, CAR NK, and CAR M, in their ability to specifically target solid tumors and promote improved therapeutic outcomes in patients with diverse solid cancers.
    Keywords:  CAR NK cells; CAR T cells; CAR macrophages; Immunotherapy; Solid cancers
    DOI:  https://doi.org/10.1016/bs.acr.2024.05.004
  15. Curr Issues Mol Biol. 2024 Aug 23. 46(9): 9286-9297
    Role of Nutrients Regulating Myeloid Derived Suppressor Cells in Cancer: A Scoping Review.
    Beatriz Pérez-Peláez, Carlos Jiménez-Cortegana, Luis de la Cruz-Merino, Víctor Sánchez-Margalet.
      Myeloid-derived suppressor cells (MDSCs) are immature cells with an immunosuppressive function. MDSCs have been related to inflammation in many settings, including infections, transplantation, obesity, aging, or cancer. In oncological settings, MDSCs participate in tumor immunoescape, growth, and metastasis. Certain nutrients can modify chronic inflammation by their interaction with MDSCs. Therefore, the possible influence of certain nutrients on immune surveillance by their actions on MDSCs and how this may affect the prognosis of cancer patients were evaluated in this scoping review. We identified seven papers, six of which were murine model studies and only one was a human clinical trial. Globally, a significant reduction in cancer growth and progression was observed after achieving a reduction in both MDSCs and their immunosuppressive ability with nutrients such as selected vegetables, icaritin, retinoic acid, curdlan, active vitamin D, soy isoflavones, and green tea. In conclusion, the consumption of certain nutrients may have effects on MDSCs, with beneficial results not only in the prevention of tumor development and growth but also in improving patients' response.
    Keywords:  cancer; dietary supplements; myeloid-derived suppressor cells; neoplasms; nutrients; vitamins
    DOI:  https://doi.org/10.3390/cimb46090549
  16. Nanoscale. 2024 Sep 23.
    Engineering macrophage membrane-camouflaged nanoplatforms with enhanced macrophage function for mediating sonodynamic therapy of ovarian cancer.
    Xiaofei Wang, Hongling Wang, Yansheng Li, Zhihong Sun, Jie Liu, Chengming Sun, Xiaoli Cao.
      Cancer immunotherapy has demonstrated remarkable efficacy in the treatment of cancer, and it has been successfully applied in the treatment of various solid tumors. However, the response rates to immunotherapy in patients with ovarian cancer remain modest because of the immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages (TAMs) represent the predominant myeloid cell population within the TME, which adopt the protumorigenic M2 phenotype and are blinded by the "don't eat me" signals from tumor cells. These characteristics of TAMs result in insufficient phagocytic activation. In this study, we constructed a SIM@TR-NP-mediated combination therapy of sonodynamic and immunotherapy. SIM@TR-NPs were modified by engineered macrophage membranes with overexpressed sialic acid-binding Ig-like lectin 10 (Siglec-10), and were internally loaded with sonosensitizer 4,4',4'',4'''-(porphine-5,10,15,20-tetrayl)tetrakis(benzoic acid) and immune adjuvant resiquimod. SIM@TR-NPs can block "don't eat me" signals to enhance macrophage phagocytosis and trigger the polarization of TAMs toward the M1 phenotype, thereby improving the immunosuppressive TME. Simultaneously, upon ultrasound irradiation, SIM@TR-NP-mediated sonodynamic therapy (SDT) triggered immunogenic cell death in tumor cells, in combination with TAM-based immunotherapy, transforming the "immune cold tumor" into an "immune hot tumor". SIM@TR-NP-mediated sonodynamic immunotherapy exhibited potent antitumor efficacy in ovarian cancer and exhibited substantial potential for improving the immunosuppressive TME. This study presents an emerging therapeutic regimen for ovarian cancer that synergizes TAM-based antitumor immunotherapy and SDT.
    DOI:  https://doi.org/10.1039/d4nr01307g
  17. Curr Genomics. 2024 ;25(5): 390-411
    Crosstalk Between Cancer-associated Fibroblasts and Myeloid Cells Shapes the Heterogeneous Microenvironment of Gastric Cancer.
    Zhiwei Peng, Can Fang, Zhiwei Tong, Qiufan Rao, Zihao Ren, Kongwang Hu.
       Background: Targeted therapies have improved the clinical outcomes of most patients with cancer. However, the heterogeneity of gastric cancer remains a major hurdle for precision treatment. Further investigations into tumor microenvironment heterogeneity are required to resolve these problems.
    Methods: In this study, bioinformatic analyses, including metabolism analysis, pathway enrichment, differentiation trajectory inference, regulatory network construction, and survival analysis, were applied to gain a comprehensive understanding of tumor microenvironment biology within gastric cancer using single-cell RNA-seq and public datasets and experiments were carried out to confirm the conclusions of these analyses.
    Results: We profiled heterogeneous single-cell atlases and identified eight cell populations with differential expression patterns. We identified two cancer-associated fibroblasts (CAFs) subtypes, with particular emphasis on the role of inflammatory cancer-associated fibroblasts (iCAFs) in EMT and lipid metabolic crosstalk within the tumor microenvironment. Notably, we detected two differentiation states of iCAFs that existed in different tissues with discrepant expression of genes involved in immuno-inflammation or ECM remodeling. Moreover, investigation of tumor-infiltrating myeloid cells has revealed the functional diversity of myeloid cell lineages in gastric cancer. Of which a proliferative cell lineage named C1QC+MKI67+TAMs was recognized with high immunosuppressive capacities, suggesting it has immune suppression and cell proliferation functions in the tumor niche. Finally, we explored regulatory networks based on ligand-receptor pairs and found crucial pro-tumor crosstalk between CAFs and myeloid cells in the tumor microenvironment (TME).
    Conclusion: These findings provide insights for future cancer treatments and drug discovery.
    Keywords:  Single-cell sequencing; cancer-associated fibroblasts; gastric cancer; ligand-receptor pairs; myeloid cells; tumor microenvironment
    DOI:  https://doi.org/10.2174/0113892029300608240531111743
  18. Cancer Lett. 2024 Sep 24. pii: S0304-3835(24)00667-0. [Epub ahead of print] 217272
    Cellular Dynamics of Tumor Microenvironment Driving Immunotherapy Resistance in Non-Small-Cell Lung Carcinoma.
    Shujie Huang, Jeff Yat-Fai Chung, Chunjie Li, Yi Wu, Guibin Qiao, Ka-Fai To, Patrick Ming-Kuen Tang.
      Immune checkpoint inhibitors (ICIs) have profoundly reshaped the treatment paradigm for non-small cell lung cancer (NSCLC). Despite these advancements, primary and secondary resistance to ICIs remain prevalent challenges in managing advanced NSCLC. Recent studies have highlighted the significant role of the tumor microenvironment (TME) in modulating treatment responses. This review aims to comprehensively examine the interactive roles of immune/stromal cells-such as T cells, B cells, neutrophils, macrophages, and CAFs within the TME, elucidating how these diverse cellular interactions contribute to immunotherapy resistance. It focuses on the dynamic interactions among diverse cell types such as the varying states of T cells under the influence of TME constituents like immune cells and cancer-associated fibroblasts (CAFs). By exploring the mechanisms involved in the complex cellular interactions, we highlight novel therapeutic targets and strategies aimed at overcoming resistance, thereby enhancing the efficacy of ICIs in NSCLC. Our synthesis of recent research provides critical insights into the multifaceted mechanisms of resistance and paves the way for the development of more effective, personalized treatment approaches.
    Keywords:  Clinical trials; Immunotherapy resistance; Lung cancer; T cells; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2024.217272
  19. Clin Exp Med. 2024 Sep 26. 24(1): 227
    The crossroad between tumor and endothelial cells.
    Domenico Ribatti.
      Endothelial cells are critical in tumor development, and the specific targeting of endothelial cells offers a potent means to effectively impede angiogenesis and suppress the growth of tumors. Tumor endothelial cells are responsible for the loss of anticancer immunity, the so-called endothelial anergy, i.e., the unresponsiveness of tumor endothelial cells to pro-inflammatory stimulation, not allowing adhesion of immune cells to the endothelium. Endothelial cells downregulate antigen presentation and recruitment of immune cells, contributing to immunosuppression. Targeting endothelial cells may assist in improving the immune effect of immune cells in tumor microenvironment.
    Keywords:  Endothelial anergy; Endothelium; Inflammation; Metastasis; Tumor growth
    DOI:  https://doi.org/10.1007/s10238-024-01490-1
  20. Zhongguo Fei Ai Za Zhi. 2024 Aug 20. 27(8): 613-621
    [Research Progresses on the Effects of CCL4 on Immune Escape 
in Tumor Microenvironment].
    Ran Chen, Xinyue Yang, Qian Liu, Shucai Zhang, Li Ma.
      Immunotherapy has become the cornerstone of current malignant tumor treatment. However, the response of different patients to immunotherapy is highly heterogeneous, and not all patients can benefit from it. There is an urgent need to find biomarkers that can effectively predict the efficacy of immunotherapy. C-C chemokine ligand 4 (CCL4) is a cytokine, belonging to the inflammatory CCL subfamily. It is mainly secreted by immune cells and tumor cells and shows low or no expression in normal tissues but abnormally high expression in various malignant tumor tissues. After binding to CCL4 and its receptor C-C chemokine receptor type 5 (CCR5), it can recruit and mediate immune cell migration, destroy the stability of the tumor microenvironment (TME), participate in carcinogenesis and promote the development of tumors. In the tumor immune microenvironment, CCL4 can mediate and recruit the directed migration of key immune cells such as monocytes, macrophages, natural killer (NK) cells, and T cells, which makes it a potentially important element affecting the efficacy of immunotherapy and has specific value. This paper reviews the research progresses of CCL4's effects on immune escape in TME, in order to provide clues and references for basic research and clinical diagnosis and treatment.
.
    Keywords:  CCL4; Immune escape; Immune response; Immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.3779/j.issn.1009-3419.2024.106.23
  21. MedComm (2020). 2024 Oct;5(10): e710
    Intricate relationship between cancer stemness, metastasis, and drug resistance.
    Tikam Chand Dakal, Ravi Bhushan, Caiming Xu, Bhana Ram Gadi, Swaranjit Singh Cameotra, Vikas Yadav, Jarek Maciaczyk, Ingo G H Schmidt-Wolf, Abhishek Kumar, Amit Sharma.
      Cancer stem cells (CSCs) are widely acknowledged as the drivers of tumor initiation, epithelial-mesenchymal transition (EMT) progression, and metastasis. Originating from both hematologic and solid malignancies, CSCs exhibit quiescence, pluripotency, and self-renewal akin to normal stem cells, thus orchestrating tumor heterogeneity and growth. Through a dynamic interplay with the tumor microenvironment (TME) and intricate signaling cascades, CSCs undergo transitions from differentiated cancer cells, culminating in therapy resistance and disease recurrence. This review undertakes an in-depth analysis of the multifaceted mechanisms underlying cancer stemness and CSC-mediated resistance to therapy. Intrinsic factors encompassing the TME, hypoxic conditions, and oxidative stress, alongside extrinsic processes such as drug efflux mechanisms, collectively contribute to therapeutic resistance. An exploration into key signaling pathways, including JAK/STAT, WNT, NOTCH, and HEDGEHOG, sheds light on their pivotal roles in sustaining CSCs phenotypes. Insights gleaned from preclinical and clinical studies hold promise in refining drug discovery efforts and optimizing therapeutic interventions, especially chimeric antigen receptor (CAR)-T cell therapy, cytokine-induced killer (CIK) cell therapy, natural killer (NK) cell-mediated CSC-targeting and others. Ultimately use of cell sorting and single cell sequencing approaches for elucidating the fundamental characteristics and resistance mechanisms inherent in CSCs will enhance our comprehension of CSC and intratumor heterogeneity, which ultimately would inform about tailored and personalized interventions.
    Keywords:  EMT; cancer stem cells; cancer stemness; drug resistance; metastasis; signaling pathways; tumor microenvironment
    DOI:  https://doi.org/10.1002/mco2.710
  22. Curr Med Res Opin. 2024 Sep 24. 1-35
    The missing link between cancer stem cells and immunotherapy.
    Lobna Safwat Ali, Youssef A M Attia, Sohaila Mourad, Esraa M Halawa, Noreen H AbdElghaffar, Seham Shokry, Omar M Attia, Maha Makram, Al-Hassan Soliman Wadan, Walaa A Negm, Engy Elekhnawy.
      Cancer stem cells (CSCs) are cancer cells that can self-renew and give rise to tumors. The multipotency of CSCs enables the generation of diverse cancer cell types and their potential for differentiation and resilience against chemotherapy and radiation. Additionally, specific biomarkers have been identified for them, such as CD24, CD34, CD44, CD47, CD90, and CD133. The CSC model suggests that a subset of CSCs within tumors is responsible for tumor growth. The tumor microenvironment (TME), including Fibroblasts, immune cells, adipocytes, endothelial cells, neuroendocrine (NE) cells, extracellular matrix (ECM), and extracellular vesicles, has a part in shielding CSCs from the host immune response as well as protecting them against anticancer drugs. The regulation of cancer stem cell plasticity by cancer-associated fibroblasts (CAFs) occurs through specific signaling pathways that differ among various types of cancer, utilizing the IGF-II/IGF1R, FAK, and c-Met/FRA1/HEY1 signaling pathways. Due to the intricate dynamics of CSC proliferation, controlling their growth necessitates innovative approaches and much more research. Our current review speculates an outline of how the TME safeguards stem cells, their interaction with CSCs, and the involvement of the immune and inflammatory systems in CSC differentiation and maintenance. Several technologies have the ability to identify CSCs; however, each approach has limitations. We discuss how these methods can aid in recognizing CSCs in several cancer types, comprising brain, breast, liver, stomach, and colon cancer. Furthermore, we explore different immunotherapeutic strategies targeting CSCs, including stimulating cancer-specific T cells, modifying immunosuppressive TMEs, and antibody-mediated therapy targeting CSC markers.
    Keywords:  CSCS; Immune cells; TME; immunotherapy
    DOI:  https://doi.org/10.1080/03007995.2024.2407963
  23. bioRxiv. 2024 Sep 10. pii: 2024.09.08.611922. [Epub ahead of print]
    CD200 depletion in glioma enhances antitumor immunity and induces tumor rejection.
    Itay Raphael, Anzar A Mujeeb, Elisabet Ampudia-Mesias, ReidAnn E Sever, Brandon McClellan, Stephen C Frederico, Chaim T Sneiderman, Apoorva Mirji, Ali Daba, Francisco Puerta-Martinez, Michal Nisnboym, Wilson B Edwards, Michael Graner, Christopher L Moertel, Maria G Castro, Gary Kohanbash, Michael R Olin.
      High-grade gliomas are a major health challenge with poor prognosis and high morbidity. Immune-checkpoint inhibitors (ICI) have emerged as promising therapeutic options for several malignancies yet show little efficacy against central nervous system (CNS) tumors. CD200 is a newly recognized immune checkpoint that modulates immune homeostasis. CD200 protein is expressed by a variety of cells, including immune cells and stromal cells, and is overexpressed by many tumors. The shedding of CD200 from tumor cells can create an immunosuppressive environment that dampens anti-tumor immunity by modulating cytolytic activity and cytokine expression both within and outside the tumor microenvironment (TME). While it is well-accepted that CD200 induces a pro-tumorigenic environment through its ability to suppress the immune response, we sought to determine the role of glioma-specific expression of CD200. We show that CD200 is expressed across glioma types, is shed from tumor cells, and increases over time in the serum of patients undergoing immunotherapy. Using CD200 knockout (KO) glioma models, we demonstrated that glioma cell-derived CD200 promotes tumor growth in vivo and in vitro. Notably, CD200 KO gliomas are spontaneously rejected by their host, a process that required a fully functional immune system, including NK and T-cells. Moreover, we report that glioma-derived or brain-injected soluble CD200 contributes to the suppression of antigen-specific CD8 T-cells in the draining lymph nodes (dLNs). Our work provides new mechanistic insights regarding CD200-mediated immunosuppression by gliomas.
    Statement of significance: We demonstrate mechanisms of the druggable glioma-derived CD200 checkpoint on tumor growth and immune suppression.
    DOI:  https://doi.org/10.1101/2024.09.08.611922
  24. Oncol Res. 2024 ;32(10): 1613-1621
    The role of cholesterol metabolism in lung cancer.
    Weigang Xiu, Xingyu Liu, Kaixin Hu, Qin Zhang, Huashan Shi.
      Elevated serum cholesterol metabolism is associated with a reduced risk of lung cancer. Disrupted cholesterol metabolism is evident in both lung cancer patients and tumor cells. Inhibiting tumor cell cholesterol uptake or biosynthesis pathways, through the modulation of receptors and enzymes such as liver X receptor and sterol-regulatory element binding protein 2, effectively restrains lung tumor growth. Similarly, promoting cholesterol excretion yields comparable effects. Cholesterol metabolites, including oxysterols and isoprenoids, play a crucial role in regulating cholesterol metabolism within tumor cells, consequently impacting cancer progression. In lung cancer patients, both the cholesterol levels in the tumor microenvironment and within tumor cells significantly influence cell growth, proliferation, and metastasis. The effects of cholesterol metabolism are further mediated by the reprogramming of immune cells such as T cells, B cells, macrophages, myeloid-derived suppressor cells, among others. Ongoing research is investigating drugs targeting cholesterol metabolism for clinical treatments. Statins, targeting the cholesterol biosynthesis pathway, are widely employed in lung cancer treatment, either as standalone agents or in combination with other drugs. Additionally, drugs focusing on cholesterol transportation have shown promise as effective therapies for lung cancer. In this review, we summarized current research regarding the rule of cholesterol metabolism and therapeutic advances in lung cancer.
    Keywords:  Cholesterol metabolism; Immune cells; Lung cancer; Targeted strategies
    DOI:  https://doi.org/10.32604/or.2024.047933
  25. Cancer Sci. 2024 Sep 25.
    Host ANGPTL2 establishes an immunosuppressive tumor microenvironment and resistance to immune checkpoint therapy.
    Shinsei Yumoto, Haruki Horiguchi, Tsuyoshi Kadomatsu, Taichi Horino, Michio Sato, Kazutoyo Terada, Keishi Miyata, Toshiro Moroishi, Hideo Baba, Yuichi Oike.
      Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy has advanced rapidly in the clinic; however, mechanisms underlying resistance to ICI therapy, including impaired T cell infiltration, low immunogenicity, and tumor "immunophenotypes" governed by the host, remain unclear. We previously reported that in some cancer contexts, tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) has tumor-promoting functions. Here, we asked whether ANGPTL2 deficiency could enhance antitumor ICI activity in two inflammatory contexts: a murine syngeneic model of colorectal cancer and a mouse model of high-fat diet (HFD)-induced obesity. Systemic ANGPTL2 deficiency potentiated ICI efficacy in the syngeneic model, supporting an immunosuppressive role for host ANGPTL2. Relevant to the mechanism, we found that ANGPTL2 induces pro-inflammatory cytokine production in adipose tissues, driving generation of myeloid-derived suppressor cells (MDSCs) in bone marrow and contributing to an immunosuppressive tumor microenvironment and resistance to ICI therapy. Moreover, HFD-induced obese mice showed impaired responsiveness to ICI treatment, suggesting that obesity-induced chronic inflammation facilitated by high ANGPTL2 expression blocks ICI antitumor effects. Our findings overall provide novel insight into protumor ANGPTL2 functions and illustrate the essential role of the host system in ICI responsiveness.
    Keywords:  ANGPTL2; MDSC; cancer immunity; chronic inflammation; immune checkpoint inhibitor
    DOI:  https://doi.org/10.1111/cas.16348
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