bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024–12–29
25 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. The effect of cancer cell-derived exosomal proteins on macrophage polarization: An in-depth review.
  2. Armoring chimeric antigen receptor (CAR) T cells as micropharmacies for cancer therapy.
  3. Cellular components of tumor microenvironment: understanding their role in lymphatic metastasis of tumors.
  4. Exploring the synergy between tumor microenvironment modulation and STING agonists in cancer immunotherapy.
  5. From nature to clinic: Quercetin's role in breast cancer immunomodulation.
  6. Regulation of Oxygen in the Tumor Microenvironment Synergizes with Immunotherapy to Suppress Tumor Progression.
  7. Development of anti-cancer drugs for tumor-associated macrophages: a comprehensive review and mechanistic insights.
  8. Ubiquitin-Conjugating Enzyme Ubc13 in Macrophages Suppresses Lung Tumor Progression Through Inhibiting PD-L1 Expression.
  9. FSTL1 Sustains Glioma Stem Cell Stemness and Promotes Immunosuppressive Macrophage Polarization in Glioblastoma.
  10. Turning cold into hot: emerging strategies to fire up the tumor microenvironment.
  11. Long non-coding RNAs are involved in the crosstalk between cancer-associated fibroblasts and tumor cells.
  12. A mechanistic, functional, and clinical perspective on targeting CD70 in cancer.
  13. Can interventions targeting MDSCs improve the outcome of vaccination in vulnerable populations?
  14. CD8+ T cell exhaustion in the tumor microenvironment of breast cancer.
  15. Protocol for generating a co-culture of macrophages with breast cancer tumoroids.
  16. Targeting caspase-8: a new strategy for combating hepatocellular carcinoma.
  17. Oncometabolites in pancreatic cancer: Strategies and its implications.
  18. Induction of cell death in malignant cells and regulatory T cells in the tumor microenvironment by targeting CD137.
  19. Neutrophils in cancer drug resistance: Roles and therapeutic opportunities.
  20. IGF2BP2 Shapes the Tumor Microenvironment by Regulating Monocyte and Macrophage Recruitment in Bladder Cancer.
  21. Single-cell transcriptomes of dissecting the intra-tumoral heterogeneity of breast cancer microenvironment.
  22. Nanozyme-mediated glutathione depletion for enhanced ROS-based cancer therapies: a comprehensive review.
  23. Current state and future prospects of spatial biology in colorectal cancer.
  24. Macrophages make "sense" of obesity-driven acidity in the TME.
  25. NGF-mediated crosstalk: unraveling the influence of metabolic deregulation on the interplay between neural and pancreatic cancer cells and its impact on patient outcomes.
  1. Exp Cell Res. 2024 Dec 20. pii: S0014-4827(24)00484-1. [Epub ahead of print]444(2): 114393
    The effect of cancer cell-derived exosomal proteins on macrophage polarization: An in-depth review.
    Khandu Wadhonkar, Soumalya Das, Ramachandran Subramanian, Mobbassar Hassan Sk, Yashi Singh, Mirza S Baig.
      Cancer is characterized by unregulated cell proliferation, enabling it to invade and spread to different organs and tissues in the body. Cancer progression is intricately influenced by the complex dynamics within the tumor microenvironment (TME). The TME is a composite and dynamic network comprising cancer cells and various immune cells, including tumor-associated macrophages. Exosomes facilitate the communication between different cancer cells as well as other types of cells. This review particularly focuses on exosomal proteins derived from different cancer cells in mounting the complex crosstalk between cells of cancer and macrophages within the TME. Most cancer-derived exosomal proteins polarize macrophages towards M2 phenotype, promoting cancer aggressiveness, while a few have role switching towards the M1 phenotype, inhibiting cancer proliferation, respectively. In this review, we summarize, for the first time, the dual impact of cancer cell-derived exosomal proteins on macrophage polarization and the associated signaling pathways, offering valuable insights for developing innovative therapeutic strategies against diverse cancer types.
    Keywords:  Cancer; Cell signaling; Exosomal proteins; Macrophage polarization; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.yexcr.2024.114393
  2. Immunooncol Technol. 2024 Dec;24 100739
    Armoring chimeric antigen receptor (CAR) T cells as micropharmacies for cancer therapy.
    C Carcopino, E Erdogan, M Henrich, S Kobold.
      Chimeric antigen receptor (CAR)-T-cell therapy has emerged as a powerful weapon in the fight against cancer. However, its efficacy is often hindered by challenges such as limited tumor penetration, antigen escape, and immune suppression within the tumor microenvironment. This review explores the potential of armored CAR-T cells, or 'micropharmacies', in overcoming these obstacles and enhancing the therapeutic outcomes of adoptive T-cell (ATC) therapy. We delve into the engineering strategies behind these advanced therapies and the mechanisms through which they improve CAR-T-cell efficacy. Additionally, we discuss the latest advancements and research findings in the field, providing a comprehensive understanding of the role of armored CAR-T cells in cancer treatment. Ultimately, this review highlights the promising future of integrating micropharmacies into ATC therapy, paving the way for more effective and targeted cancer treatments.
    Keywords:  BiTEs; CAR-T-cell therapy; TRUCKs; immuno-oncology; micropharmacies; next-generation CARs
    DOI:  https://doi.org/10.1016/j.iotech.2024.100739
  3. Front Pharmacol. 2024 ;15 1463538
    Cellular components of tumor microenvironment: understanding their role in lymphatic metastasis of tumors.
    Ziyi Wang, Zehui Li, Xiangyu Sun, Wanfu Men, Yan Xu.
      Metastasis is the leading cause of cancer-related death in cancer patients. Tumor cells primarily spread through the hematogenous and lymphatic system. The underlying mechanisms of hematogenous metastasis have been well described over the past few decades. However, the understanding of the molecular mechanisms involved in lymphatic metastasis is still at an early stage. Tumor microenvironment (TME), primarily consisting of T cells, B cells, tumor-associated macrophages, neutrophils, and cancer-associated fibroblasts, has been implicated in the development of lymphatic metastasis. Recent studies have been reported that the dynamic and complex interplay between these cellular components of TME has great effects on lymphatic metastasis. Here, we discussed the paradoxical roles of these cellular component within the TME during lymphatic metastasis, as well as potential therapeutic opportunities to re-educate these cells within the TME to have anti-tumorigenic effects.
    Keywords:  cancer; immune cell; lymph node; lymphatic metastasis; tumor microenvironment
    DOI:  https://doi.org/10.3389/fphar.2024.1463538
  4. Front Immunol. 2024 ;15 1488345
    Exploring the synergy between tumor microenvironment modulation and STING agonists in cancer immunotherapy.
    Xiaoyan Qi, Cheng Cheng, Dawei Zhang, Zongjiang Yu, Xiangwei Meng.
      
    Keywords:  STING agonists; cancer immunotherapy; immune suppression; macrophage polarization; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fimmu.2024.1488345
  5. Front Immunol. 2024 ;15 1483459
    From nature to clinic: Quercetin's role in breast cancer immunomodulation.
    Liguang Fang, Dandan Gao, Tong Wang, Haijun Zhao, Yanan Zhang, Shijun Wang.
      Immunotherapy has brought hope to many breast cancer patients, but not all patients benefit from it. Quercetin (Qu), a natural product found in various sources, has anti-inflammatory and anti-tumor properties. We conducted a review of the pharmacological research of Qu in regulating anti-tumor immunity in vivo and in vitro. Qu can directly regulate the local tumor microenvironment (TME) by enhancing the activity of immune cells which includes promoting the infiltration of T cells and natural killer (NK) cells, inhibiting the recruitment of myeloid-derived suppressor cells and tumor-associated macrophages. Additionally, Qu inhibits anaerobic glycolysis in tumor cells, thereby reducing the production and transport of lactic acid. It also suppresses tumor angiogenesis by targeting the vascular endothelial growth factor (VEGF) pathway and the vitamin D pathway. Furthermore, Qu can enhance the efficacy of immunotherapy for breast cancer by modulating the systemic microenvironment. This includes inhibiting obesity-related chronic inflammation to decrease the production of inflammatory factors, regulating the composition of intestinal microbiota, and intervening in the metabolism of intestinal flora. At the same time, we also address challenges in the clinical application of Qu, such as low absorption rates and unknown effective doses. In conclusion, we highlight Qu as a natural immunomodulator that enhances immune cell activity and has the potential to be developed as an adjunct for breast cancer.
    Keywords:  Quercetin; breast cancer; immunotherapy; natural immunomodulator; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1483459
  6. J Funct Biomater. 2024 Nov 25. pii: 357. [Epub ahead of print]15(12):
    Regulation of Oxygen in the Tumor Microenvironment Synergizes with Immunotherapy to Suppress Tumor Progression.
    Shoucheng Wang, Yongjie Chi, Danyang Wang, Kai Zhao, Lianyan Wang.
      Hypoxia represents a crucial characteristic of the tumor microenvironment, which is closely related to cell proliferation, angiogenesis, and metabolic responses. These factors will further promote tumor progression, increase tumor invasion, and enhance tumor metastasis potential. A hypoxic microenvironment will also inhibit the activity of infiltrated immune cells in the tumor microenvironment, leading to the failure of cancer immunotherapy. Additionally, the hypoxic tumor microenvironment contributes to resistance to conventional therapies and leads to unfavorable prognoses. This review discusses advancements in strategies aimed at ameliorating tumor hypoxia within the microenvironment and modulating immune cell responses against tumors.
    Keywords:  hypoxia; immunosuppression; tumor microenvironment
    DOI:  https://doi.org/10.3390/jfb15120357
  7. Front Mol Biosci. 2024 ;11 1463061
    Development of anti-cancer drugs for tumor-associated macrophages: a comprehensive review and mechanistic insights.
    Bingjun Bai, Shangzhi Xie, Ya Wang, Fei Wu, Yao Chen, Jia Bian, Xing Gao.
      This review provides an in-depth summary of the development of anti-cancer drugs for tumor-associated macrophages (TAMs), with a particular focus on the development and tissue specialization of macrophages, and factors influencing the polarization of M1 and M2 macrophages, and mechanistic insights underlying the targeting therapeutic approaches. TAMs, pivotal in the tumor microenvironment, exhibit notable plasticity and diverse functional roles. Influenced by the complex milieu, TAMs polarize into M1-type, which suppresses tumors, and M2-type, which promotes metastasis. Notably, targeting M2-TAMs is a promising strategy for tumor therapy. By emphasizing the importance of macrophages as a therapeutic target of anti-cancer drugs, this review aims to provide valuable insights and research directions for clinicians and researchers.
    Keywords:  M1 and M2 macrophages; TAMs-targeted therapies; macrophage polarization; tumor microenvironment (TME); tumor-associated macrophages (TAMs)
    DOI:  https://doi.org/10.3389/fmolb.2024.1463061
  8. Eur J Immunol. 2024 Dec 23. e202451118
    Ubiquitin-Conjugating Enzyme Ubc13 in Macrophages Suppresses Lung Tumor Progression Through Inhibiting PD-L1 Expression.
    Siying Sun, Jun Ni, Jiamin Liu, Juofang Tan, Runsen Jin, Hecheng Li, Xuefeng Wu.
      Tumor cell-intrinsic ubiquitin-conjugating enzyme Ubc13 promotes tumorigenesis, yet how Ubc13 in immune cell compartments regulates tumor progression remains elusive. Here, we show that myeloid-specific deletion of Ubc13 (Ubc13fl/flLyz2Cre) leads to accelerated transplanted lung tumor growth in mice. Compared with their littermate controls, tumor-bearing Ubc13fl/flLyz2Cre mice had lower proliferation and effector function of CD8+ T lymphocytes, accompanied by increased infiltration of myeloid-derived suppressor cells within the tumor microenvironment. Mechanistically, Ubc13 deficiency leads to upregulation of Arg1 and PD-L1, the latter is modulated by reduced Ubc13-mediated K63-linked polyubiquitination and increasing activation of Akt, thereby inducing skewness to protumoral polarization and immunosuppressive manifestation. Taken together, we reveal that macrophage-intrinsic Ubc13 restrains lung tumor progression, indicating that activating Ubc13 in macrophages could be an effective immunotherapeutic regimen for lung cancer.
    Keywords:  Lung cancer; PD‐L1; Ubc13; immunotherapy; macrophage
    DOI:  https://doi.org/10.1002/eji.202451118
  9. Cancer Lett. 2024 Dec 23. pii: S0304-3835(24)00795-X. [Epub ahead of print] 217400
    FSTL1 Sustains Glioma Stem Cell Stemness and Promotes Immunosuppressive Macrophage Polarization in Glioblastoma.
    Fengqi Zhou, Jincheng Tao, Huiqing Gou, Shuheng Liu, Dong Yu, Junxia Zhang, Jianxiong Ji, Ning Lin, Yingyi Wang.
      Tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) play a crucial role in glioblastoma (GBM) progression by interacting with glioma stem cells (GSCs). These interactions lead to the polarization of TAMs toward an M2 phenotype, which, in turn, enhances the stem-like traits and malignant progression of GSCs. Our study shows that FSTL1, a protein released by GSCs, is significantly elevated in gliomas and linked to the progression of the disease. By suppressing FSTL1 in a mouse model, we observed reduced tumor growth and a decrease in M2 macrophages. In vitro studies show that FSTL1 from GSCs promotes M2 polarization and infiltration. Importantly, GSCs utilize autocrine FSTL1 to interact with TLR2, which inhibits the endocytosis-lysosomal degradation pathway mediated by EGFR, resulting in the activation of the PI3K-AKT signaling pathway that is critical for maintaining their self-renewal. These findings underscore the importance of FSTL1 in GSC maintenance and M2 macrophage polarization, suggesting that interventions targeting the FSTL1/TLR2 pathway could provide a novel therapeutic approach for GBM patients.
    Keywords:  FSTL1; Glioma; Glioma Stem Cells; Immune Microenvironment; Macrophage Polarization
    DOI:  https://doi.org/10.1016/j.canlet.2024.217400
  10. Trends Cancer. 2024 Dec 26. pii: S2405-8033(24)00278-4. [Epub ahead of print]
    Turning cold into hot: emerging strategies to fire up the tumor microenvironment.
    Kaili Ma, Lin Wang, Wenhui Li, Tingting Tang, Bo Ma, Liyuan Zhang, Lianjun Zhang.
      The tumor microenvironment (TME) is a complex, highly structured, and dynamic ecosystem that plays a pivotal role in the progression of both primary and metastatic tumors. Precise assessment of the dynamic spatiotemporal features of the TME is crucial for understanding cancer evolution and designing effective therapeutic strategies. Cancer is increasingly recognized as a systemic disease, influenced not only by the TME, but also by a multitude of systemic factors, including whole-body metabolism, gut microbiome, endocrine signaling, and circadian rhythm. In this review, we summarize the intrinsic, extrinsic, and systemic factors contributing to the formation of 'cold' tumors within the framework of the cancer-immunity cycle. Correspondingly, we discuss potential strategies for converting 'cold' tumors into 'hot' ones to enhance therapeutic efficacy.
    Keywords:  cancer immunotherapy; cold tumor; hot tumor; systemic regulation; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2024.11.011
  11. Front Immunol. 2024 ;15 1469918
    Long non-coding RNAs are involved in the crosstalk between cancer-associated fibroblasts and tumor cells.
    Chenbo Yang, Jiao Shu, Yiwei Li, Na Zhao, Xiaonan Liu, Xiangyu Tian, Zexin Sun, Muhammad Saud Tabish, Yichen Hong, Kuisheng Chen, Miaomiao Sun.
      The proliferation of tumors is not merely self-regulated by the cancer cells but is also intrinsically connected to the tumor microenvironment (TME). Within this complex TME, cancer-associated fibroblasts (CAFs) are pivotal in the modulation of tumor onset and progression. Rich signaling interactions exist between CAFs and tumor cells, which are crucial for tumor regulation. Long non-coding RNAs (LncRNAs) emerge from cellular transcription as a class of functionally diverse RNA molecules. Recent studies have revealed that LncRNAs are integral to the crosstalk between CAFs and tumor cells, with the capacity to modify cellular transcriptional activity and secretion profiles, thus facilitating CAFs activation, tumor proliferation, metastasis, drug resistance, and other related functionalities. This comprehensive review revisits the latest research on LncRNA-mediated interactions between CAFs and tumor cells, encapsulates the biological roles of LncRNAs, and delves into the molecular pathways from a broader perspective, aspiring to offer novel perspectives for a deeper comprehension of the etiology of tumors and the enhancement of therapeutic approaches.
    Keywords:  cancer-associated fibroblasts; long non-coding RNAs; signaling pathway; tumor growth; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1469918
  12. Cancer Lett. 2024 Dec 24. pii: S0304-3835(24)00823-1. [Epub ahead of print] 217428
    A mechanistic, functional, and clinical perspective on targeting CD70 in cancer.
    Sandeep Kumar, Sowdhamini Mahendiran, Rakesh Sathish Nair, Harsh Vyas, Sunil Kumar Singh, Piush Srivastava, Saket Jha, Basabi Rana, Ajay Rana.
      The oncoimmunology research has witnessed notable advancements in recent years. Reshaping the tumor microenvironment (TME) approach is an effective method to improve antitumor immune response. The T cell-mediated antitumor response is crucial for favorable therapeutic outcomes in several cancers. The United States Food and Drug Administration (FDA) has approved immune checkpoint inhibitors (ICIs) for targeting the immune checkpoint proteins (ICPs) expressed in various hematological and solid malignancies. The ICPs are T cell co-inhibitory molecules that block T cell activation and, thus, antitumor response. Currently, most of the FDA-approved ICIs are antagonistic antibodies of programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). In contrast to ICPs, the T cell costimulatory molecules are required for T cell activation, expansion, and effector function. However, the abrupt expression of these costimulatory molecules in tumors presents a concern for T cell-mediated antitumor response. One of the T cell costimulatory molecules, the cluster of differentiation 70 (CD70), has emerged as a druggable target in various hematological and solid malignancies due to its role in T cell effector function and immune evasion. The present review describes the expression of CD70, factors affecting the CD70 expression, the physiological and clinical relevance of CD70, and the current approaches to target CD70 in hematological and solid malignancies.
    Keywords:  CAR T cells; CD70; Cancer; Clinical trials; Immune evasion
    DOI:  https://doi.org/10.1016/j.canlet.2024.217428
  13. Int Rev Immunol. 2024 Dec 21. 1-17
    Can interventions targeting MDSCs improve the outcome of vaccination in vulnerable populations?
    Yuliya V Perfilyeva, Arthur D Aquino, Maxim A Borodin, Aikyn Kali, Nurshat Abdolla, Yekaterina O Ostapchuk, Raikhan Tleulieva, Anastassiya V Perfilyeva, Nurlan T Jainakbayev, Kamalidin O Sharipov, Nikolai N Belyaev.
      Preventive vaccination is a crucial strategy for controlling and preventing infectious diseases, offering both effectiveness and cost-efficiency. However, despite the widespread success of vaccination programs, there are still certain population groups who struggle to mount adequate responses to immunization. These at-risk groups include but are not restricted to the elderly, overweight individuals, individuals with chronic infections and cancer patients. All of these groups are characterized by persistent chronic inflammation. Recent studies have demonstrated that one of the key players in immune regulation and the promotion of chronic inflammation are myeloid-derived suppressor cells (MDSCs). These cells possess a wide range of immunosuppressive mechanisms and are able to dampen immune responses in both antigen-specific and antigen-nonspecific manner, thus contributing to the establishment and maintenance of an inflammatory environment. Given their pivotal role in immune modulation, there is growing interest in understanding how MDSCs may influence the efficacy of vaccines, particularly in vulnerable populations. In this narrative review, we discuss whether MDSCs are able to regulate vaccine-induced immunity and whether their suppression can potentially enhance vaccine efficacy in vulnerable populations.
    Keywords:  Aging; cancer; chronic infection; myeloid-derived suppressor cell; obesity; vaccination
    DOI:  https://doi.org/10.1080/08830185.2024.2443423
  14. Front Immunol. 2024 ;15 1507283
    CD8+ T cell exhaustion in the tumor microenvironment of breast cancer.
    Hanghang Xie, Xiaowei Xi, Ting Lei, Hongli Liu, Zhijia Xia.
      CD8+ T cells are crucial cytotoxic components of the tumor immune system. In chronic inflammation, they become low-responsive, a state known as T cell exhaustion (TEX). The aim of immune checkpoint blockade is to counteract TEX, yet its dynamics in breast cancer remain poorly understood. This review defines CD8+ TEX and outlines its features and underlying mechanisms. It also discusses the primary mechanisms of CD8+ TEX in breast cancer, covering inhibitory receptors, immunosuppressive cells, cytokines, transcriptomic and epigenetic alterations, metabolic reprogramming, and exosome pathways, offering insights into potential immunotherapy strategies for breast cancer.
    Keywords:  CD8; T cell exhaustion; breast cancer; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1507283
  15. STAR Protoc. 2024 Dec 20. pii: S2666-1667(24)00701-9. [Epub ahead of print]6(1): 103536
    Protocol for generating a co-culture of macrophages with breast cancer tumoroids.
    Antonella Raffo-Romero, Lydia Ziane-Chaouche, Nawale Hajjaji, Michel Salzet, Marie Duhamel.
      Cancer progression and treatment outcomes are heavily influenced by the tumor microenvironment (TME), especially through immune cell interactions. Here, we present a protocol for generating co-cultures of tumoroids with macrophages, either semi-liquid or Matrigel-embedded. We describe steps for macrophage preparation, co-culture establishment, and medium adjustments to support cell viability and function. While optimized for breast cancer models, this protocol can be adapted to other tumor types with appropriate medium adjustments. For complete details on the use and execution of this protocol, please refer to Raffo-Romero et al.1.
    Keywords:  cancer; cell culture; cell isolation; immunology; organoids
    DOI:  https://doi.org/10.1016/j.xpro.2024.103536
  16. Front Immunol. 2024 ;15 1501659
    Targeting caspase-8: a new strategy for combating hepatocellular carcinoma.
    Haoran Chen, Yumeng Lin, Jie Chen, Xuemei Luo, Yubo Kan, Yuqi He, Renhe Zhu, Jiahui Jin, Dongxuan Li, Yi Wang, Zhongyu Han.
      Hepatocellular carcinoma (HCC) represents the most prevalent form of primary liver cancer and has a high mortality rate. Caspase-8 plays a pivotal role in an array of cellular signaling pathways and is essential for the governance of programmed cell death mechanisms, inflammatory responses, and the dynamics of the tumor microenvironment. Dysregulation of caspase-8 is intricately linked to the complex biological underpinnings of HCC. In this manuscript, we provide a comprehensive review of the regulatory roles of caspase-8 in apoptosis, necroptosis, pyroptosis, and PANoptosis, as well as its impact on inflammatory reactions and the intricate interplay with critical immune cells within the tumor microenvironment, such as tumor-associated macrophages, T cells, natural killer cells, and dendritic cells. Furthermore, we emphasize how caspase-8 plays pivotal roles in the development, progression, and drug resistance observed in HCC, and explore the potential of targeting caspase-8 as a promising strategy for HCC treatment.
    Keywords:  PANoptosis; apoptosis; caspase-8; hepatocellular carcinoma; necroptosis; pyroptosis; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1501659
  17. World J Exp Med. 2024 Dec 20. 14(4): 96005
    Oncometabolites in pancreatic cancer: Strategies and its implications.
    Arunima Maiti, Susmita Mondal, Sounetra Choudhury, Arnab Bandopadhyay, Sanghamitra Mukherjee, Nilabja Sikdar.
      Pancreatic cancer (PanCa) is a catastrophic disease, being third lethal in both the genders around the globe. The possible reasons are extreme disease invasiveness, highly fibrotic and desmoplastic stroma, dearth of confirmatory diagnostic approaches and resistance to chemotherapeutics. This inimitable tumor microenvironment (TME) or desmoplasia with excessive extracellular matrix accumulation, create an extremely hypovascular, hypoxic and nutrient-deficient zone inside the tumor. To survive, grow and proliferate in such tough TME, pancreatic tumor and stromal cells transform their metabolism. Transformed glucose, glutamine, fat, nucleotide metabolism and inter-metabolite communication between tumor and TME in synergism, impart therapy resistance, and immunosuppression in PanCa. Thus, a finer knowledge of altered metabolism would uncover its metabolic susceptibilities. These unique metabolic targets may help to device novel diagnostic/prognostic markers and therapeutic strategies for better management of PanCa. In this review, we sum up reshaped metabolic pathways in PanCa to formulate detection and remedial strategies of this devastating disease.
    Keywords:  Anti-pancreatic cancer therapy; Metabolic reprogramming; Metabolic symbiosis; Pancreatic cancer; Therapy resistance
    DOI:  https://doi.org/10.5493/wjem.v14.i4.96005
  18. Oncoimmunology. 2025 Dec;14(1): 2443265
    Induction of cell death in malignant cells and regulatory T cells in the tumor microenvironment by targeting CD137.
    Rui Sun, Kang Yi Lee, Yu Mei, Emily Nickles, Jia Le Lin, Runze Xia, Haiyan Liu, Herbert Schwarz.
      Regulatory T cells (Tregs) contribute significantly to the immunosuppressive nature of the tumor microenvironment which is a main barrier for immunotherapies of solid cancers. Reducing Treg numbers enhances anti-tumor immune responses but current depletion strategies also impair effector T cells (Teffs), potentially leading to reduced anti-tumor immunity and/or autoimmune diseases. CD137 has been identified as the most differentially expressed gene between peripheral Tregs and intratumoral Tregs in virtually all solid cancers. Further, CD137 is expressed by malignant cells of certain cancers, making it a potential target for tumor immunotherapy. Here, we report the development of a fully human anti-human CD137 antibody of the IgG1 isotype, clone P1A1, that induces antibody-dependent cell-mediated cytotoxicity (ADCC) in CD137+ Tregs and cancer cells. P1A1 cross-reacts with murine CD137 which allowed testing murine chimeric P1A1 in syngeneic murine tumor models where P1A1 significantly reduced the number of CD137+ Tregs and inhibited tumor growth in a murine hepatocellular carcinoma (HCC) and a melanoma lung metastasis model. P1A1 can also be internalized thus enabling it as a carrier for drugs to target CD137+ Tregs and cancer cells. These anti-cancer properties suggest a translation of P1A1 to human immunotherapy.
    Keywords:  Antibody; CD137; depletion; regulatory T cell; tumor microenvironment
    DOI:  https://doi.org/10.1080/2162402X.2024.2443265
  19. Cancer Lett. 2024 Dec 23. pii: S0304-3835(24)00812-7. [Epub ahead of print] 217417
    Neutrophils in cancer drug resistance: Roles and therapeutic opportunities.
    Hao Liu, Hongyu Zhao, Mingzhen Zhou, Xiaodi Zhao, Yuanyuan Lu.
      The tumor microenvironment (TME) is closely associated with the therapeutic response and clinical outcome of cancer drug therapies, which mainly include immunotherapy, chemotherapy and targeted therapy. Neutrophils that infiltrate tumors, also known as tumor-associated neutrophils (TANs), constitute a primary part of the TME. However, the functional importance of TANs in cancer drug therapy has long been overlooked because of their relatively short life span. Recent studies have shown that TANs play crucial protumoral or antitumoral roles in cancer drug treatment, largely because of their diversity and plasticity. This review describes the development, heterogeneity and recruitment of neutrophils in the context of cancer and emphasizes the role and mechanisms of TANs in cancer drug resistance. Additionally, several potential neutrophil-targeted strategies are discussed.
    Keywords:  cancer; drug resistance; neutrophil; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2024.217417
  20. Cancer Med. 2024 Dec;13(24): e70506
    IGF2BP2 Shapes the Tumor Microenvironment by Regulating Monocyte and Macrophage Recruitment in Bladder Cancer.
    Jianpeng Li, Yunzhong Jiang, Minghai Ma, Lu Wang, Minxuan Jing, Zezhong Yang, Lizhao Wang, Quanpeng Qiu, Rundong Song, Yuanchun Pu, Yuanquan Zhang, Nan Mei, Mengzhao Zhang, Jinhai Fan.
       BACKGROUND: Immunotherapy has shown promise for bladder cancer (BC) treatment but is effective only in a subset of patients. Understanding the tumor microenvironment (TME) and its regulators, such as the expression of N6-methyladenosine (m6A) regulators, may improve therapeutic outcomes. This study focuses on the role of IGF2BP2, an m6A reader, in modulating the BC TME.
    METHODS: Transcriptomic and single-cell RNA-seq data from public databases were analyzed to identify BC subgroups and investigate IGF2BP2's role in the TME. Clustering and PCA identified key m6A regulators. NicheNet and SCENIC analyses were used to predict cell-cell interactions and transcriptional regulators, respectively. IGF2BP2's role in macrophage recruitment was validated via co-culture experiments and RNA sequencing.
    RESULTS: Unsupervised clustering identified BC subgroups with distinct TME characteristics, with IGF2BP2 emerging as a key regulator associated with poor prognosis and reduced response to immunotherapy. Single-cell analysis revealed IGF2BP2's high expression in the GE-9 epithelial subpopulation, characterized by immune evasion features and cytokine-mediated macrophage recruitment. NicheNet analysis showed that GE-9 cells interact with monocyte/macrophage populations through cytokine signaling. Co-culture experiments confirmed IGF2BP2's role in recruiting macrophages, partially mediated by CCL2. Furthermore, IGF2BP2 expression was linked to immunosuppressive M2-like and SPP1+ macrophages, contributing to an angiogenesis-promoting and immunosuppressive TME.
    CONCLUSION: IGF2BP2 shapes the BC TME by modulating macrophage infiltration and polarization, leading to an immunosuppressive microenvironment that hinders immunotherapy. Targeting IGF2BP2 could enhance the efficacy of current therapies and improve patient outcomes.
    Keywords:  IGF2BP2; bladder cancer; epithelial cell; m6A; macrophage; tumor infiltration immune cells
    DOI:  https://doi.org/10.1002/cam4.70506
  21. J Cancer Res Clin Oncol. 2024 Dec 26. 151(1): 17
    Single-cell transcriptomes of dissecting the intra-tumoral heterogeneity of breast cancer microenvironment.
    Peixian Chen, Kaifeng Liang, Xiaofan Mao, Qiuyuan Wu, Zhiyan Chen, Yabin Jin, Kairong Lin, Tiancheng He, Shuqing Yang, Huiqi Huang, Guolin Ye, Juntao Gao, Dan Zhou, Zhihao Zeng.
       OBJECTIVE: To investigate the mechanism by which heterogeneity in breast cancer developed and acted in single-cell transcriptomes.
    METHODS: The composition of breast cancer based on the single-cell transcriptomes of 54,055 high-quality cells from clinical specimens of 4 malignant and 4 non-malignant patients were investigated.
    RESULTS: We identified six common expression programs and six subtype-specific expression programs form malignant epithelial cells. The expression program of malignant epithelial cells exhibited activated EMT (Epithelial Mesenchymal Transition) in TME, which might indicate EMT intervention have a general therapeutic effect on various subtypes. Gene set enrichment analysis (GSEA) based on the top 50 highly NMF (non-negative matrix factorization) score genes in each program depicted the distinct function of each program in breast cancer progression. Moreover, we revealed the profound cellular heterogeneity of myeloid cell lineages in breast cancer. In macrophages, two mainly tumor associated macrophages (TAMs), TAM1 and TAM2, were also detected and the highly variable genes in TAM2 were strongly enriched in IFN-α and IFN-γ. The changes of lipid metabolism pathways in macrophages are closely related to the microenvironment of breast cancer.
    CONCLUSION: We constructed a comprehensive single-cell transcriptome atlas of 54,055 cells from 4 malignant and 4 nonmalignant patients, providing insights into the mechanisms underlying breast cancer progression and the development of potential therapeutic strategies in breast cancer.
    Keywords:  Breast cancer; EMT; Single-cell RNA-Seq; Tumor associated macrophages (TAM); Tumor heterogeneity
    DOI:  https://doi.org/10.1007/s00432-024-06015-7
  22. Nanomedicine (Lond). 2024 Dec 27. 1-12
    Nanozyme-mediated glutathione depletion for enhanced ROS-based cancer therapies: a comprehensive review.
    Xinyu Wang, Nan Wei, Yang Zhang, Yuan Fang, Yijun Li, Songguo Li, Zhanggui Wang, Chenglong Sun.
      Nanozymes can improve reactive oxygen species (ROS)-based cancer therapies by targeting cancer cells' antioxidant defense mechanisms, particularly glutathione (GSH) depletion, to overcome ROS-resistant cancer cells. Nanozymes, innovative enzyme-mimetic nanomaterials, can generate ROS, alter the tumor microenvironment (TME), and synergize with photodynamic therapy (PDT), chemodynamic therapy (CDT), radiotherapy, and immunotherapy. This review shows how nanozymes catalyze ROS generation, selectively deplete GSH, and target cancer elimination, offering clear advantages over standard therapies. Nanozymes selectively target cancer cells' antioxidant defenses to improve PDT, CDT, and radiation therapies. To maximize nanozyme-based cancer treatment efficacy, biodistribution, biocompatibility, and tumor heterogeneity must be assessed. To improve cancer treatment, multifunctional, stimuli-responsive nanozymes and synergistic combination drugs should be developed.
    Keywords:  Nanozymes; multimodal cancer therapies; nanozymes glutathione depletion; reactive oxygen species (ROS); tumor microenvironment (TME)
    DOI:  https://doi.org/10.1080/17435889.2024.2446138
  23. Front Oncol. 2024 ;14 1513821
    Current state and future prospects of spatial biology in colorectal cancer.
    Francisco G Carranza, Fernando C Diaz, Maria Ninova, Enrique Velazquez-Villarreal.
      Over the past century, colorectal cancer (CRC) has become one of the most devastating cancers impacting the human population. To gain a deeper understanding of the molecular mechanisms driving this solid tumor, researchers have increasingly turned their attention to the tumor microenvironment (TME). Spatial transcriptomics and proteomics have emerged as a particularly powerful technology for deciphering the complexity of CRC tumors, given that the TME and its spatial organization are critical determinants of disease progression and treatment response. Spatial transcriptomics enables high-resolution mapping of the whole transcriptome. While spatial proteomics maps protein expression and function across tissue sections. Together, they provide a detailed view of the molecular landscape and cellular interactions within the TME. In this review, we delve into recent advances in spatial biology technologies applied to CRC research, highlighting both the methodologies and the challenges associated with their use, such as the substantial tissue heterogeneity characteristic of CRC. We also discuss the limitations of current approaches and the need for novel computational tools to manage and interpret these complex datasets. To conclude, we emphasize the importance of further developing and integrating spatial transcriptomics into CRC precision medicine strategies to enhance therapeutic targeting and improve patient outcomes.
    Keywords:  bioinformatics; colorectal cancer; genomics; personalized medicine; spatial biology; spatial proteomics; spatial transcriptomics; translational research
    DOI:  https://doi.org/10.3389/fonc.2024.1513821
  24. Cell Chem Biol. 2024 Dec 19. pii: S2451-9456(24)00488-4. [Epub ahead of print]31(12): 2021-2023
    Macrophages make "sense" of obesity-driven acidity in the TME.
    Spenser H Stone, Jeffrey C Rathmell, Jackie E Bader.
      Obesity is a leading risk factor and a negative prognostic indicator for many cancers. In a recent issue of Science Immunology, Bagchi et al. identified that tumor-associated macrophages upregulate GPR65 in response to obesity-driven intratumor acidity resulting in reduced effector function to promote tumor growth.1.
    DOI:  https://doi.org/10.1016/j.chembiol.2024.11.008
  25. Front Pharmacol. 2024 ;15 1499414
    NGF-mediated crosstalk: unraveling the influence of metabolic deregulation on the interplay between neural and pancreatic cancer cells and its impact on patient outcomes.
    Francesca Trentini, Virginia Agnetti, Martina Manini, Elisa Giovannetti, Ingrid Garajová.
      Neural invasion is one of the most common routes of invasion in pancreatic cancer and it is responsible for the high rate of tumor recurrence after surgery and the pain generation associated with pancreatic cancer. Several molecules implicated in neural invasion are also responsible for pain onset including NGF belonging to the family of neutrophins. NGF released by cancer cells can sensitize sensory nerves which in turn results in severe pain. NGF receptors, TrkA and P75NTR, are expressed on both PDAC cells and nerves, strongly suggesting their role in neural invasion. The crosstalk between the nervous system and cancer cells has emerged as an important regulator of pancreatic cancer and its microenvironment. Nerve cells influence the pancreatic tumor microenvironment and these interactions are important for cancer metabolism reprogramming and tumor progression. In this review, we summarized the current knowledge on the interaction between nerves and pancreatic cancer cells and its impact on cancer metabolism.
    Keywords:  NGF; metabolism; neural invasion; pain; pancreatic cancer
    DOI:  https://doi.org/10.3389/fphar.2024.1499414
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