bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024–04–21
24 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Potential Therapeutic Targets in Myeloid Cell Therapy for Overcoming Chemoresistance and Immune Suppression in Gastrointestinal Tumors.
  2. Association between metabolic reprogramming and immune regulation in digestive tract tumors.
  3. METTL3: Melting the tumor microenvironment for improved immunotherapy.
  4. Targeting the Devil: Strategies Against Cancer-Associated Fibroblasts in Colorectal Cancer.
  5. Immune checkpoint inhibitors in the treatment of hepatocellular carcinoma.
  6. M2 Tumor-Associated Macrophages-Derived Exosomal MALAT1 Promotes Glycolysis and Gastric Cancer Progression.
  7. The essential link: How STAT3 connects tumor metabolism to immunity.
  8. Treatment Options for Hepatocellular Carcinoma Using Immunotherapy: Present and Future.
  9. Regulation of Tumor Dendritic Cells by Programmed Cell Death 1 Pathways.
  10. Cholesterol metabolism in tumor microenvironment: cancer hallmarks and therapeutic opportunities.
  11. Urolithin a inhibits breast cancer progression via activating TFEB-mediated mitophagy in tumor macrophages.
  12. Microglia and macrophage metabolism: a regulator of cerebral gliomas.
  13. Unraveling the Tumor Microenvironment: Insights into Cancer Metastasis and Therapeutic Strategies.
  14. Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma therapy: Challenges and opportunities.
  15. Traditional Chinese Medicine in Regulating Tumor Microenvironment.
  16. A Mathematical Model of TCR-T Cell Therapy for Cervical Cancer.
  17. Regulation of fatty acid delivery to metastases by tumor endothelium.
  18. Mesenchymal Stromal Cells Increase the Natural Killer Resistance of Circulating Tumor Cells via Intercellular Signaling of cGAS-STING-IFNβ-HLA.
  19. The Application of Nanoparticles Targeting Cancer-Associated Fibroblasts.
  20. Burning down the house: Pyroptosis in the tumor microenvironment of hepatocellular carcinoma.
  21. Advancements in Stimulus-Responsive Co-Delivery Nanocarriers for Enhanced Cancer Immunotherapy.
  22. D-mannose targets PD-1 to lysosomal degradation and enhances T cell-mediated anti-tumor immunity.
  23. Emerging paradigms in cancer cell plasticity.
  24. IL-7R Expression Correlates with Prognosis in Breast Cancer.
  1. Crit Rev Oncol Hematol. 2024 Apr 11. pii: S1040-8428(24)00105-7. [Epub ahead of print] 104362
    Potential Therapeutic Targets in Myeloid Cell Therapy for Overcoming Chemoresistance and Immune Suppression in Gastrointestinal Tumors.
    Jiawei Fan, Jianshu Zhu, He Zhu, Hong Xu.
      In the tumor microenvironment (TME), myeloid cells play a pivotal role. Myeloid-derived immunosuppressive cells, including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), are central components in shaping the immunosuppressive milieu of the tumor. Within the TME, a majority of TAMs assume an M2 phenotype, characterized by their pro-tumoral activity. These cells promote tumor cell growth, angiogenesis, invasion, and migration. In contrast, M1 macrophages, under appropriate activation conditions, exhibit cytotoxic capabilities against cancer cells. However, an excessive M1 response may lead to pro-tumoral inflammation. As a result, myeloid cells have emerged as crucial targets in cancer therapy. This review concentrates on gastrointestinal tumors, detailing methods for targeting macrophages to enhance tumor radiotherapy and immunotherapy sensitivity. We specifically delve into monocytes and tumor-associated macrophages' various functions, establishing an immunosuppressive microenvironment, promoting tumorigenic inflammation, and fostering neovascularization and stromal remodeling. Additionally, we examine combination therapeutic strategies.
    Keywords:  Drug resistance; Gastrointestinal Tumors; Immunotherapy; Macrophage; Myeloid Cell
    DOI:  https://doi.org/10.1016/j.critrevonc.2024.104362
  2. Oncol Res Treat. 2024 Apr 18.
    Association between metabolic reprogramming and immune regulation in digestive tract tumors.
    Jiafeng Liu, Tianxiao Wang, Wenxin Zhang, Yuxin Huang, Xinhai Wang, Qunyi Li.
       BACKGROUND: The cancers of the digestive tract, including colorectal cancer (CRC), gastric cancer (GC) and Esophageal cancer (ESCA), are part of the most common cancers as well as one of the most important leading causes of cancer death worldwide.
    SUMMARY: Despite the emergence of immune checkpoint inhibitors (e.g., anti-CTLA-4 and anti-PD-1/PD-L1) in the past decade, offering renewed optimism in cancer treatment, only a fraction of patients derive benefit from these therapies. This limited efficacy may stem from tumor heterogeneity and the impact of metabolic reprogramming on both tumor cells and immune cells within the tumor microenvironment (TME). The metabolic reprogramming of glucose, lipids, amino acids, and other nutrients represents a pivotal hallmark of cancer, serving to generate energy, reducing-equivalent and biological macromolecule, thereby fostering tumor proliferation and invasion. Significantly, the metabolic reprogramming of tumor cells can orchestrate changes within the TME, rendering patients unresponsive to immunotherapy.
    KEY MESSAGES: In this review, we predominantly encapsulate recent strides on metabolic reprogramming among digestive tract cancer, especially CRC, in the TME with a focus on how these alterations influence antitumor immunity. Additionally, we deliberate on potential strategies to address these abnormities in metabolic pathways and the viability of combined therapy within the realm of anticancer immunotherapy.
    DOI:  https://doi.org/10.1159/000538659
  3. Cell Chem Biol. 2024 Apr 18. pii: S2451-9456(24)00121-1. [Epub ahead of print]31(4): 629-631
    METTL3: Melting the tumor microenvironment for improved immunotherapy.
    Longfei Gao, Lei Ding.
      The tumor microenvironment (TME) dictates the outcome of cancer immunotherapy. In this issue of Cell Chemical Biology, Yu et al.1 report that targeting Mettl3 leads to a more inflamed, "hot" TME and effective anti-PD-1 therapy. This study points to a new target in remodeling the TME for improved immunotherapy.
    DOI:  https://doi.org/10.1016/j.chembiol.2024.03.005
  4. Transl Res. 2024 Apr 11. pii: S1931-5244(24)00080-X. [Epub ahead of print]
    Targeting the Devil: Strategies Against Cancer-Associated Fibroblasts in Colorectal Cancer.
    Yuting Chen, Zhiyong Liang, Maode Lai.
      Cancer-associated fibroblasts (CAFs), as significant constituents of the tumor microenvironment (TME), play a pivotal role in the progression of cancers, including colorectal cancer (CRC). In this comprehensive review, we presented the origin and activation mechanisms of CAFs in CRC, elaborating on how CAFs drive tumor advancement through their interactions with CRC cells, immune cells, vascular endothelial cells, and the extracellular matrix within the tumor microenvironment. We systematically outline the intricate web of interactions among CAFs, tumor cells, and other TME components, and based on this complex interplay, we summarize various therapeutic strategies designed to target CAFs in CRC. It is also essential to recognize that CAFs represent a highly heterogeneous group, encompassing various subtypes such as myofibroblastic CAF (myCAF), inflammatory CAF (iCAF), antigen-presenting CAF (apCAF), vessel-associated CAF (vCAF). Herein, we provide a summary of studies investigating the heterogeneity of CAFs in CRC and the characteristic expression patterns of each subtype. While the majority of CAFs contribute to the exacerbation of CRC malignancy, recent findings have revealed specific subtypes that exert inhibitory effects on CRC progression. Nevertheless, the comprehensive landscape of CAF heterogeneity still awaits exploration. We also highlight pivotal unanswered questions that need to be addressed before CAFs can be recognized as feasible targets for cancer treatment. In conclusion, the aim of our review is to elucidate the significance and challenges of advancing in-depth research on CAFs, while outlining the pathway to uncover the complex roles of CAFs in CRC and underscore their significant potential as therapeutic targets.
    Keywords:  Cancer-associated fibroblast; Colorectal cancer; Heterogeneity; Therapeutic target; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trsl.2024.04.003
  5. Front Immunol. 2024 ;15 1379622
    Immune checkpoint inhibitors in the treatment of hepatocellular carcinoma.
    Zeynep Akbulut, Başak Aru, Furkan Aydın, Gülderen Yanıkkaya Demirel.
      Despite advances in cancer treatment, hepatocellular carcinoma (HCC), the most common form of liver cancer, remains a major public health problem worldwide. The immune microenvironment plays a critical role in regulating tumor progression and resistance to therapy, and in HCC, the tumor microenvironment (TME) is characterized by an abundance of immunosuppressive cells and signals that facilitate immune evasion and metastasis. Recently, anti-cancer immunotherapies, therapeutic interventions designed to modulate the immune system to recognize and eliminate cancer, have become an important cornerstone of cancer therapy. Immunotherapy has demonstrated the ability to improve survival and provide durable cancer control in certain groups of HCC patients, while reducing adverse side effects. These findings represent a significant step toward improving cancer treatment outcomes. As demonstrated in clinical trials, the administration of immune checkpoint inhibitors (ICIs), particularly in combination with anti-angiogenic agents and tyrosine kinase inhibitors, has prolonged survival in a subset of patients with HCC, providing an alternative for patients who progress on first-line therapy. In this review, we aimed to provide an overview of HCC and the role of the immune system in its development, and to summarize the findings of clinical trials involving ICIs, either as monotherapies or in combination with other agents in the treatment of the disease. Challenges and considerations regarding the administration of ICIs in the treatment of HCC are also outlined.
    Keywords:  anticancer immunity; hepatocellular carcinoma; immune checkpoint inhibition; immune checkpoint proteins; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1379622
  6. Adv Sci (Weinh). 2024 Apr 19. e2309298
    M2 Tumor-Associated Macrophages-Derived Exosomal MALAT1 Promotes Glycolysis and Gastric Cancer Progression.
    Yanzheng Wang, Jiahui Zhang, Hui Shi, Maoye Wang, Dan Yu, Min Fu, Yu Qian, Xiaoxin Zhang, Runbi Ji, Shouyu Wang, Jianmei Gu, Xu Zhang.
      M2-polarized tumor-associated macrophages (M2 TAMs) promote cancer progression. Exosomes mediate cellular communication in the tumor microenvironment (TME). However, the roles of exosomes from M2 TAMs in gastric cancer progression are unclear. Herein, it is reported that M2 TAMs-derived exosomes induced aerobic glycolysis in gastric cancer cells and enhanced their proliferation, metastasis, and chemoresistance in a glycolysis-dependent manner. It is identified that MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) is enriched in M2 TAM exosomes and confirmed that MALAT1 transfer from M2 TAMs to gastric cancer cells via exosomes mediates this effect. Mechanistically, MALAT1 interacted with the δ-catenin protein and suppressed its ubiquitination and degradation by β-TRCP. In addition, MALAT1 upregulated HIF-1α expression by acting as a sponge for miR-217-5p. The activation of β-catenin and HIF-1α signaling pathways by M2 TAM exosomes collectively led to enhanced aerobic glycolysis in gastric cancer cells. Finally, a dual-targeted inhibition of MALAT1 in both gastric cancer cells and macrophages by exosome-mediated delivery of siRNA remarkably suppressed gastric cancer growth and improved chemosensitivity in mouse tumor models. Taken together, these results suggest that M2 TAMs-derived exosomes promote gastric cancer progression via MALAT1-mediated regulation of glycolysis. The findings offer a potential target for gastric cancer therapy.
    Keywords:  MALAT1; exosomes; gastric cancer; glycolysis; tumor‐associated macrophages
    DOI:  https://doi.org/10.1002/advs.202309298
  7. Biochim Biophys Acta Gene Regul Mech. 2024 Apr 16. pii: S1874-9399(24)00024-5. [Epub ahead of print] 195028
    The essential link: How STAT3 connects tumor metabolism to immunity.
    Shu Zhong, Jingjing Tong.
      Immunotherapy is a promising and long-lasting tumor treatment method, but it is challenged by the complex metabolism of tumors. To optimize immunotherapy, it is essential to further investigate the key proteins that regulate tumor metabolism and immune response. STAT3 plays a crucial role in regulating tumor dynamic metabolism and affecting immune cell function by responding to various cytokines and growth factors, which can be used as a potential target for immunotherapy. This review focuses on the crosstalk between STAT3 and tumor metabolism (including glucose, lipid, and amino acid metabolism) and its impact on the differentiation and function of immune cells such as T cells, tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs), and reveals potential treatment strategies.
    Keywords:  Immune cell; Immunotherapy; Metabolism; STAT3; Tumor
    DOI:  https://doi.org/10.1016/j.bbagrm.2024.195028
  8. J Clin Transl Hepatol. 2024 Apr 28. 12(4): 389-405
    Treatment Options for Hepatocellular Carcinoma Using Immunotherapy: Present and Future.
    Hongbin Wei, Chunlu Dong, Xun Li.
      Hepatocellular carcinoma (HCC) is a common cancer, and the body's immune responses greatly affect its progression and the prognosis of patients. Immunological suppression and the maintenance of self-tolerance in the tumor microenvironment are essential responses, and these form part of the theoretical foundations of immunotherapy. In this review, we first discuss the tumor microenvironment of HCC, describe immunosuppression in HCC, and review the major biomarkers used to track HCC progression and response to treatment. We then examine antibody-based therapies, with a focus on immune checkpoint inhibitors (ICIs), monoclonal antibodies that target key proteins in the immune response (programmed cell death protein 1, anti-cytotoxic T-lymphocyte associated protein 4, and programmed death-ligand 1) which have transformed the treatment of HCC and other cancers. ICIs may be used alone or in conjunction with various targeted therapies for patients with advanced HCC who are receiving first-line treatments or subsequent treatments. We also discuss the use of different cellular immunotherapies, including T cell receptor (TCR) T cell therapy and chimeric antigen receptor (CAR) T cell therapy. We then review the use of HCC vaccines, adjuvant immunotherapy, and oncolytic virotherapy, and describe the goals of future research in the development of treatments for HCC.
    Keywords:  Hepatocellular carcinoma; Immunotherapy; Liver cancer; Vaccines
    DOI:  https://doi.org/10.14218/JCTH.2023.00462
  9. J Immunol. 2024 May 01. 212(9): 1397-1405
    Regulation of Tumor Dendritic Cells by Programmed Cell Death 1 Pathways.
    Keith L Knutson.
      The advent of immune checkpoint blockade therapy has revolutionized cancer treatments and is partly responsible for the significant decline in cancer-related mortality observed during the last decade. Immune checkpoint inhibitors, such as anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1), have demonstrated remarkable clinical successes in a subset of cancer patients. However, a considerable proportion of patients remain refractory to immune checkpoint blockade, prompting the exploration of mechanisms of treatment resistance. Whereas much emphasis has been placed on the role of PD-L1 and PD-1 in regulating the activity of tumor-infiltrating T cells, recent studies have now shown that this immunoregulatory axis also directly regulates myeloid cell activity in the tumor microenvironment including tumor-infiltrating dendritic cells. In this review, I discuss the most recent advances in the understanding of how PD-1, PD-L1, and programmed cell death ligand 2 regulate the function of tumor-infiltrating dendritic cells, emphasizing the need for further mechanistic studies that could facilitate the development of novel combination immunotherapies for improved cancer patient benefit.
    DOI:  https://doi.org/10.4049/jimmunol.2300674
  10. Int J Biol Sci. 2024 ;20(6): 2044-2071
    Cholesterol metabolism in tumor microenvironment: cancer hallmarks and therapeutic opportunities.
    Wen Jiang, Wei-Lin Jin, A-Man Xu.
      Cholesterol is crucial for cell survival and growth, and dysregulation of cholesterol homeostasis has been linked to the development of cancer. The tumor microenvironment (TME) facilitates tumor cell survival and growth, and crosstalk between cholesterol metabolism and the TME contributes to tumorigenesis and tumor progression. Targeting cholesterol metabolism has demonstrated significant antitumor effects in preclinical and clinical studies. In this review, we discuss the regulatory mechanisms of cholesterol homeostasis and the impact of its dysregulation on the hallmarks of cancer. We also describe how cholesterol metabolism reprograms the TME across seven specialized microenvironments. Furthermore, we discuss the potential of targeting cholesterol metabolism as a therapeutic strategy for tumors. This approach not only exerts antitumor effects in monotherapy and combination therapy but also mitigates the adverse effects associated with conventional tumor therapy. Finally, we outline the unresolved questions and suggest potential avenues for future investigations on cholesterol metabolism in relation to cancer.
    Keywords:  antitumor immunity; cholesterol homeostasis; drug repurposing; metastasis; statin; tumor microenvironment
    DOI:  https://doi.org/10.7150/ijbs.92274
  11. J Adv Res. 2024 Apr 12. pii: S2090-1232(24)00153-X. [Epub ahead of print]
    Urolithin a inhibits breast cancer progression via activating TFEB-mediated mitophagy in tumor macrophages.
    Bowen Zheng, Yuying Wang, Baian Zhou, Fengyuan Qian, Diya Liu, Danrong Ye, Xiqian Zhou, Lin Fang.
       INTRODUCTION: Urolithin A (UA) is a naturally occurring compound that is converted from ellagitannin-like precursors in pomegranates and nuts by intestinal flora. Previous studies have found that UA exerts tumor-suppressive effects through antitumor cell proliferation and promotion of memory T-cell expansion, but its role in tumor-associated macrophages remains unknown.
    OBJECTIVES: Our study aims to reveal how UA affects tumor macrophages and tumor cells to inhibit breast cancer progression.
    METHODS: Observe the effect of UA treatment on breast cancer progression though in vivo and in vitro experiments. Western blot and PCR assays were performed to discover that UA affects tumor macrophage autophagy and inflammation. Co-ip and Molecular docking were used to explore specific molecular mechanisms.
    RESULTS: We observed that UA treatment could simultaneously inhibit harmful inflammatory factors, especially for InterleuKin-6 (IL-6) and tumor necrosis factor α (TNF-α), in both breast cancer cells and tumor-associated macrophages, thereby improving the tumor microenvironment and delaying tumor progression. Mechanistically, UA induced the key regulator of autophagy, transcription factor EB (TFEB), into the nucleus in a partially mTOR-dependent manner and inhibited the ubiquitination degradation of TFEB, which facilitated the clearance of damaged mitochondria via the mitophagy-lysosomal pathway in macrophages under tumor supernatant stress, and reduced the deleterious inflammatory factors induced by the release of nucleic acid from damaged mitochondria. Molecular docking and experimental studies suggest that UA block the recognition of TFEB by 1433 and induce TFEB nuclear localization. Notably, UA treatment demonstrated inhibitory effects on tumor progression in multiple breast cancer models.
    CONCLUSION: Our study elucidated the anti-breast cancer effect of UA from the perspective of tumor-associated macrophages. Specifically, TFEB is a crucial downstream target in macrophages.
    Keywords:  Breast cancer; Mitophagy; TFEB; Tumor-associated macrophages; Urolithin A
    DOI:  https://doi.org/10.1016/j.jare.2024.04.010
  12. Cell Biosci. 2024 Apr 17. 14(1): 49
    Microglia and macrophage metabolism: a regulator of cerebral gliomas.
    Yue Deng, Qinyan Chen, Chao Wan, Yajie Sun, Fang Huang, Yan Hu, Kunyu Yang.
      Reciprocal interactions between the tumor microenvironment (TME) and cancer cells play important roles in tumorigenesis and progression of glioma. Glioma-associated macrophages (GAMs), either of peripheral origin or representing brain-intrinsic microglia, are the majority population of infiltrating immune cells in glioma. GAMs, usually classified into M1 and M2 phenotypes, have remarkable plasticity and regulate tumor progression through different metabolic pathways. Recently, research efforts have increasingly focused on GAMs metabolism as potential targets for glioma therapy. This review aims to delineate the metabolic characteristics of GAMs within the TME and provide a summary of current therapeutic strategies targeting GAMs metabolism in glioma. The goal is to provide novel insights and therapeutic pathways for glioma by highlighting the significance of GAMs metabolism.
    Keywords:  Glioma; Glioma-associated macrophages; Metabolism; Targeted therapy
    DOI:  https://doi.org/10.1186/s13578-024-01231-7
  13. Cancer Lett. 2024 Apr 14. pii: S0304-3835(24)00287-8. [Epub ahead of print] 216894
    Unraveling the Tumor Microenvironment: Insights into Cancer Metastasis and Therapeutic Strategies.
    Mohamed El-Tanani, Syed Arman Rabbani, Rasha Babiker, Imran Rangraze, Sumedha Kapre, Sushesh Srivastsa Palakurthi, Abdullah M Alnuqaydan, Alaa A Aljabali, Manfredi Rizzo, Yahia El-Tanani, Murtaza M Tambuwala.
      This comprehensive review delves into the pivotal role of the tumor microenvironment (TME) in cancer metastasis and therapeutic response, offering fresh insights into the intricate interplay between cancer cells and their surrounding milieu. The TME, a dynamic ecosystem comprising diverse cellular and acellular elements, not only fosters tumor progression but also profoundly affects the efficacy of conventional and emerging cancer therapies. Through nuanced exploration, this review illuminates the multifaceted nature of the TME, elucidating its capacity to engender drug resistance via mechanisms such as hypoxia, immune evasion, and the establishment of physical barriers to drug delivery. Moreover, it investigates innovative therapeutic approaches aimed at targeting the TME, including stromal reprogramming, immune microenvironment modulation, extracellular matrix (ECM)-targeting agents, and personalized medicine strategies, highlighting their potential to augment treatment outcomes. Furthermore, this review critically evaluates the challenges posed by the complexity and heterogeneity of the TME, which contribute to variable therapeutic responses and potentially unintended consequences. This underscores the need to identify robust biomarkers and advance predictive models to anticipate treatment outcomes, as well as advocate for combination therapies that address multiple facets of the TME. Finally, the review emphasizes the necessity of an interdisciplinary approach and the integration of cutting-edge technologies to unravel the intricacies of the TME, thereby facilitating the development of more effective, adaptable, and personalized cancer treatments. By providing critical insights into the current state of TME research and its implications for the future of oncology, this review highlights the dynamic and evolving landscape of this field.
    DOI:  https://doi.org/10.1016/j.canlet.2024.216894
  14. Cancer Lett. 2024 Apr 13. pii: S0304-3835(24)00252-0. [Epub ahead of print]591 216859
    Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma therapy: Challenges and opportunities.
    Qin Qin, Rong Yu, John E Eriksson, Hsiang-I Tsai, Haitao Zhu.
      Pancreatic ductal adenocarcinoma (PDAC) is a solid organ malignancy with a high mortality rate. Statistics indicate that its incidence has been increasing as well as the associated deaths. Most patients with PDAC show poor response to therapies making the clinical management of this cancer difficult. Stromal cells in the tumor microenvironment (TME) contribute to the development of resistance to therapy in PDAC cancer cells. Cancer-associated fibroblasts (CAFs), the most prevalent stromal cells in the TME, promote a desmoplastic response, produce extracellular matrix proteins and cytokines, and directly influence the biological behavior of cancer cells. These multifaceted effects make it difficult to eradicate tumor cells from the body. As a result, CAF-targeting synergistic therapeutic strategies have gained increasing attention in recent years. However, due to the substantial heterogeneity in CAF origin, definition, and function, as well as high plasticity, majority of the available CAF-targeting therapeutic approaches are not effective, and in some cases, they exacerbate disease progression. This review primarily elucidates on the effect of CAFs on therapeutic efficiency of various treatment modalities, including chemotherapy, radiotherapy, immunotherapy, and targeted therapy. Strategies for CAF targeting therapies are also discussed.
    Keywords:  Cancer-associated fibroblasts; Heterogeneity; Pancreatic ductal adenocarcinoma; Therapy resistance; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2024.216859
  15. Onco Targets Ther. 2024 ;17 313-325
    Traditional Chinese Medicine in Regulating Tumor Microenvironment.
    Ziwei Wang, Mengyao Li, Ling Bi, Xueqing Hu, Yan Wang.
      Tumor microenvironment (TME) is a complex and integrated system containing a variety of tumor-infiltrating immune cells and stromal cells. They are closely connected with cancer cells and influence the development and progression of cancer. Traditional Chinese medicine (TCM) is an important complementary therapy for cancer treatment in China. It mainly eliminates cancer cells by regulating TME. The aim of this review is to systematically summarize the crosstalk between tumor cells and TME, and to summarize the research progress of TCM in regulating TME. The review is of great significance in revealing the therapeutic mechanism of action of TCM, and provides an opportunity for the combined application of TCM and immunotherapy in cancer treatment.
    Keywords:  anti-tumor effects; cancer; traditional Chinese medicine; tumor microenvironment
    DOI:  https://doi.org/10.2147/OTT.S444214
  16. Bull Math Biol. 2024 Apr 16. 86(5): 57
    A Mathematical Model of TCR-T Cell Therapy for Cervical Cancer.
    Zuping Wang, Heyrim Cho, Peter Choyke, Doron Levy, Noriko Sato.
      Engineered T cell receptor (TCR)-expressing T (TCR-T) cells are intended to drive strong anti-tumor responses upon recognition of the specific cancer antigen, resulting in rapid expansion in the number of TCR-T cells and enhanced cytotoxic functions, causing cancer cell death. However, although TCR-T cell therapy against cancers has shown promising results, it remains difficult to predict which patients will benefit from such therapy. We develop a mathematical model to identify mechanisms associated with an insufficient response in a mouse cancer model. We consider a dynamical system that follows the population of cancer cells, effector TCR-T cells, regulatory T cells (Tregs), and "non-cancer-killing" TCR-T cells. We demonstrate that the majority of TCR-T cells within the tumor are "non-cancer-killing" TCR-T cells, such as exhausted cells, which contribute little or no direct cytotoxicity in the tumor microenvironment (TME). We also establish two important factors influencing tumor regression: the reversal of the immunosuppressive TME following depletion of Tregs, and the increased number of effector TCR-T cells with antitumor activity. Using mathematical modeling, we show that certain parameters, such as increasing the cytotoxicity of effector TCR-T cells and modifying the number of TCR-T cells, play important roles in determining outcomes.
    Keywords:  Cervical cancer; Immunotherapy; Mathematical modeling; TCR-T cells; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s11538-024-01261-9
  17. bioRxiv. 2024 Apr 03. pii: 2024.04.02.587724. [Epub ahead of print]
    Regulation of fatty acid delivery to metastases by tumor endothelium.
    Deanna N Edwards, Shan Wang, Wenqiang Song, Laura C Kim, Verra M Ngwa, Yoonha Hwang, Kevin C Ess, Mark R Boothby, Jin Chen.
      Tumor metastasis, the main cause of death in cancer patients, requires outgrowth of tumor cells after their dissemination and residence in microscopic niches. Nutrient sufficiency is a determinant of such outgrowth 1 . Fatty acids (FA) can be metabolized by cancer cells for their energetic and anabolic needs but impair the cytotoxicity of T cells in the tumor microenvironment (TME) 2, 3 , thereby supporting metastatic progression. However, despite the important role of FA in metastatic outgrowth, the regulation of intratumoral FA is poorly understood. In this report, we show that tumor endothelium actively promotes tumor growth and restricts anti-tumor cytolysis by transferring FA into developing metastatic tumors. This process uses transendothelial fatty acid transport via endosome cargo trafficking in a mechanism that requires mTORC1 activity. Thus, tumor burden was significantly reduced upon endothelial-specific targeted deletion of Raptor, a unique component of the mTORC1 complex (Rptor ECKO ). In vivo trafficking of a fluorescent palmitic acid analog to tumor cells and T cells was reduced in Rptor ECKO lung metastatic tumors, which correlated with improved markers of T cell cytotoxicity. Combination of anti-PD1 with RAD001/everolimus, at a low dose that selectively inhibits mTORC1 in endothelial cells 4 , impaired FA uptake in T cells and reduced metastatic disease, corresponding to improved anti-tumor immunity. These findings describe a novel mechanism of transendothelial fatty acid transfer into the TME during metastatic outgrowth and highlight a target for future development of therapeutic strategies.
    DOI:  https://doi.org/10.1101/2024.04.02.587724
  18. Adv Sci (Weinh). 2024 Apr 18. e2400888
    Mesenchymal Stromal Cells Increase the Natural Killer Resistance of Circulating Tumor Cells via Intercellular Signaling of cGAS-STING-IFNβ-HLA.
    Ye Yi, Guihui Qin, Hongmei Yang, Hao Jia, Qibing Zeng, Dejin Zheng, Sen Ye, Zhiming Zhang, Tzu-Ming Liu, Kathy Qian Luo, Chu-Xia Deng, Ren-He Xu.
      Circulating tumor cells (CTCs) shed from primary tumors must overcome the cytotoxicity of immune cells, particularly natural killer (NK) cells, to cause metastasis. The tumor microenvironment (TME) protects tumor cells from the cytotoxicity of immune cells, which is partially executed by cancer-associated mesenchymal stromal cells (MSCs). However, the mechanisms by which MSCs influence the NK resistance of CTCs remain poorly understood. This study demonstrates that MSCs enhance the NK resistance of cancer cells in a gap junction-dependent manner, thereby promoting the survival and metastatic seeding of CTCs in immunocompromised mice. Tumor cells crosstalk with MSCs through an intercellular cGAS-cGAMP-STING signaling loop, leading to increased production of interferon-β (IFNβ) by MSCs. IFNβ reversely enhances the type I IFN (IFN-I) signaling in tumor cells and hence the expression of human leukocyte antigen class I (HLA-I) on the cell surface, protecting the tumor cells from NK cytotoxicity. Disruption of this loop reverses NK sensitivity in tumor cells and decreases tumor metastasis. Moreover, there are positive correlations between IFN-I signaling, HLA-I expression, and NK tolerance in human tumor samples. Thus, the NK-resistant signaling loop between tumor cells and MSCs may serve as a novel therapeutic target.
    Keywords:  cGAS‐STING‐IFNβ‐HLA pathway; circulating tumor cells; mesenchymal stromal cells; natural killer cells
    DOI:  https://doi.org/10.1002/advs.202400888
  19. Int J Nanomedicine. 2024 ;19 3333-3365
    The Application of Nanoparticles Targeting Cancer-Associated Fibroblasts.
    Qiu Huang, Yue Ge, Yu He, Jian Wu, Yonghua Tong, Haojie Shang, Xiao Liu, Xiaozhuo Ba, Ding Xia, Ejun Peng, Zhiqiang Chen, Kun Tang.
      Cancer-associated fibroblasts (CAF) are the most abundant stromal cells in the tumor microenvironment (TME), especially in solid tumors. It has been confirmed that it can not only interact with tumor cells to promote cancer progression and metastasis, but also affect the infiltration and function of immune cells to induce chemotherapy and immunotherapy resistance. So, targeting CAF has been considered an important method in cancer treatment. The rapid development of nanotechnology provides a good perspective to improve the efficiency of targeting CAF. At present, more and more researches have focused on the application of nanoparticles (NPs) in targeting CAF. These studies explored the effects of different types of NPs on CAF and the multifunctional nanomedicines that can eliminate CAF are able to enhance the EPR effect which facilitate the anti-tumor effect of themselves. There also exist amounts of studies focusing on using NPs to inhibit the activation and function of CAF to improve the therapeutic efficacy. The application of NPs targeting CAF needs to be based on an understanding of CAF biology. Therefore, in this review, we first summarized the latest progress of CAF biology, then discussed the types of CAF-targeting NPs and the main strategies in the current. The aim is to elucidate the application of NPs in targeting CAF and provide new insights for engineering nanomedicine to enhance immune response in cancer treatment.
    Keywords:  cancer; cancer therapy; cancer-associated fibroblasts; drug delivery; nanomedicine; nanoparticles
    DOI:  https://doi.org/10.2147/IJN.S447350
  20. Life Sci. 2024 Apr 11. pii: S0024-3205(24)00217-0. [Epub ahead of print] 122627
    Burning down the house: Pyroptosis in the tumor microenvironment of hepatocellular carcinoma.
    Chi Cheng, Sheng-Kai Hsu, Yen-Chun Chen, Wangta Liu, En-De Shu, Ching-Ming Chien, Chien-Chih Chiu, Wen-Tsan Chang.
      A high mortality rate makes hepatocellular carcinoma (HCC) a difficult cancer to treat. When surgery is not possible, liver cancer patients are treated with chemotherapy. However, HCC management and treatment are difficult. Sorafenib, which is a first-line treatment for hepatocellular carcinoma, initially slows disease progression. However, sorafenib resistance limits patient survival. Recent studies have linked HCC to programmed cell death, which has increased researcher interest in therapies targeting cell death. Pyroptosis, which is an inflammatory mode of programmed cell death, may be targeted to treat HCC. Pyroptosis pathways, executors, and effects are examined in this paper. This review summarizes how pyroptosis affects the tumor microenvironment (TME) in HCC, including the role of cytokines such as IL-1β and IL-18 in regulating immune responses. The use of chemotherapies and their ability to induce cancer cell pyroptosis as alternative treatments and combining them with other drugs to reduce side effects is also discussed. In conclusion, we highlight the potential of inducing pyroptosis to treat HCC and suggest ways to improve patient outcomes. Studies on cancer cell pyroptosis may lead to new HCC treatments.
    Keywords:  Hepatocellular carcinoma (HCC); Pyroptosis; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.lfs.2024.122627
  21. Int J Nanomedicine. 2024 ;19 3387-3404
    Advancements in Stimulus-Responsive Co-Delivery Nanocarriers for Enhanced Cancer Immunotherapy.
    Meng-Ru Zhang, Lin-Lin Fang, Yang Guo, Qin Wang, You-Jie Li, Hong-Fang Sun, Shu-Yang Xie, Yan Liang.
      Cancer immunotherapy has emerged as a novel therapeutic approach against tumors, with immune checkpoint inhibitors (ICIs) making significant clinical practice. The traditional ICIs, PD-1 and PD-L1, augment the cytotoxic function of T cells through the inhibition of tumor immune evasion pathways, ultimately leading to the initiation of an antitumor immune response. However, the clinical implementation of ICIs encounters obstacles stemming from the existence of an immunosuppressive tumor microenvironment and inadequate infiltration of CD8+T cells. Considerable attention has been directed towards advancing immunogenic cell death (ICD) as a potential solution to counteract tumor cell infiltration and the immunosuppressive tumor microenvironment. This approach holds promise in transforming "cold" tumors into "hot" tumors that exhibit responsiveness to antitumor. By combining ICD with ICIs, a synergistic immune response against tumors can be achieved. However, the combination of ICD inducers and PD-1/PD-L1 inhibitors is hindered by issues such as poor targeting and uncontrolled drug release. An advantageous solution presented by stimulus-responsive nanocarrier is integrating the physicochemical properties of ICD inducers and PD-1/PD-L1 inhibitors, facilitating precise delivery to specific tissues for optimal combination therapy. Moreover, these nanocarriers leverage the distinct features of the tumor microenvironment to accomplish controlled drug release and regulate the kinetics of drug delivery. This article aims to investigate the advancement of stimulus-responsive co-delivery nanocarriers utilizing ICD and PD-1/PD-L1 inhibitors. Special focus is dedicated to exploring the advantages and recent advancements of this system in enabling the combination of ICIs and ICD inducers. The molecular mechanisms of ICD and ICIs are concisely summarized. In conclusion, we examine the potential research prospects and challenges that could greatly enhance immunotherapeutic approaches for cancer treatment.
    Keywords:  antitumor therapy; co-delivery; immune-checkpoint inhibitors; immunogenic cell death; stimulus-responsive nanocarriers
    DOI:  https://doi.org/10.2147/IJN.S454004
  22. Cancer Lett. 2024 Apr 12. pii: S0304-3835(24)00276-3. [Epub ahead of print] 216883
    D-mannose targets PD-1 to lysosomal degradation and enhances T cell-mediated anti-tumor immunity.
    Wenjing Dong, Mingen Lin, Ruonan Zhang, Xue Sun, Hongchen Li, Tianshu Liu, Yanping Xu, Lei Lv.
      High expression of programmed cell death protein 1 (PD-1), a typical immune checkpoint, results in dysfunction of T cells in tumor microenvironment. Antibodies and inhibitors against PD-1 or its ligand (PD-L1) have been widely used in various malignant tumors. However, the mechanisms by which PD-1 is regulated are not fully understood. Here, we report a mechanism of PD-1 degradation triggered by D-mannose and the universality of this mechanism in anti-tumor immunity. We show that D-mannose inactivates GSK3β via promoting phosphorylation of GSK3β at Ser9, thereby leading to TFE3 translocation to nucleus and subsequent PD-1 proteolysis induced by enhanced lysosome biogenesis. Notably, combination of D-mannose and PD-1 blockade exhibits remarkable tumor growth suppression attributed to elevated cytotoxicity activity of T cells in vivo. Furthermore, D-mannose treatment dramatically improves the therapeutic efficacy of MEK inhibitor (MEKi) trametinib in vivo. Our findings unveil a universally unrecognized anti-tumor mechanism of D-mannose by destabilizing PD-1 and provide strategies to enhance the efficacy of both immune checkpoint blockade (ICB) and MEKi -based therapies.
    Keywords:  D-mannose; MEKi; PD-1; TFE3; lysosomal degradation; tumor immunity
    DOI:  https://doi.org/10.1016/j.canlet.2024.216883
  23. BMB Rep. 2024 Apr 17. pii: 6190. [Epub ahead of print]
    Emerging paradigms in cancer cell plasticity.
    Hyunbin D Huh, Hyun Woo Park.
      Cancer cells metastasize to distant organs by altering their characteristics within the tumor microenvironment (TME) to effectively overcome challenges during the multistep tumorigenesis. Plasticity endows cancer cell with the capacity to shift between different states to invade, disseminate, and seed metastasis. The epithelial-to-mesenchymal transition (EMT) is a cellular program that abrogates cell-cell adhesions by EMT transcription factors (TF) and acquires mesenchymal features during cancer progression. On the other hand, adherent-to-suspension transition (AST) is an emerging theory that describes the acquisition of hematopoietic features by AST-TFs that can induce the reprogramming of anchorage dependency and promote cancer cell dissemination. The induction and plasticity of EMT and AST dynamically reprogram cell-cell and cell-matrix interaction during cancer dissemination and colonization. Here, we review the mechanisms governing cellular plasticity of AST and EMT during the metastatic cascade and discuss therapeutic challenges posed by these two morphological adaptations to provide insights for establishing new therapeutic interventions.
  24. Comb Chem High Throughput Screen. 2024 Apr 17.
    IL-7R Expression Correlates with Prognosis in Breast Cancer.
    Xiaojie Yu, Hao Zhang, Jing Liu, Changran Hou, Haojie Zhang, Zhenlin Yang.
       BACKGROUND: The tumor microenvironment (TME) exerts a significant influence on the development, invasion, metastasis, and drug resistance of breast cancer. Therefore, this study sought to investigate potential prognostic factors and markers indicative of TME remodeling in breast cancer, utilizing data from the TCGA database.
    METHODS: In this study, transcriptome RNA-seq data from 1222 breast cancer samples were processed using CIBERSORT and ESTIMATE algorithms. We conducted a differential gene expression analysis utilizing COX regression analysis and constructed protein-protein interaction (PPI) networks for enhanced visualization. Through univariate COX analysis and cross-analysis within PPI networks, the Interleukin-7 receptor (IL-7R) emerged as a potential predictor. Subsequently, we performed a comprehensive investigation encompassing single-gene survival analysis, clinical correlation assessment, and GSEA enrichment analysis targeting IL-7R as a core gene associated with prognosis. We examined the expression of IL-7R in human breast cancer and normal breast tissue through clinical studies and cytology experiments, followed by an indepth analysis of the relationship between IL-7R and breast cancer.
    RESULTS: The survival analysis revealed that breast cancer patients with elevated IL-7R expression experienced prolonged survival compared to those with lower IL-7R levels. Results obtained from the Wilcoxon rank-sum test, along with clinical and cellular experiments, indicated higher IL-7R expression in tumor samples compared to normal samples. Correlation tests conducted between IL-7R expression and clinicopathological stage characteristics highlighted statistically significant associations between IL-7R expression and the T and M stages. Additionally, cell classification analysis of tumor-infiltrating immune cells (TIC) proportion showed that activated CD4+ T cells and CD8 T cells of memory B cells were positively correlated with IL-7R expression. These findings further underscored the impact of IL-7R levels on the tumor microenvironment (TME).
    CONCLUSION: IL-7R emerges as a potential prognostic indicator for breast cancer patients, particularly in sustaining the immunoactive status of the tumor microenvironment (TME) and contributing to immune reconstitution. These findings offer novel insights into breast cancer treatment strategies.
    Keywords:  IL-7R; Tumor microenvironment; breast cancer; prognostic indicator
    DOI:  https://doi.org/10.2174/0113862073293963240409040110
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