bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024–01–28
27 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Macrophage barrier in the tumor microenvironment and potential clinical applications.
  2. Targeted Mevalonate Pathway and Autophagy in Antitumor Immunotherapy.
  3. Glioma-Immune Cell Crosstalk in Tumor Progression.
  4. Metastasis and cancer associated fibroblasts: taking it up a NOTCH.
  5. The immune regulatory function of B7-H3 in malignancy: spotlight on the IFN-STAT1 axis and regulation of tumor-associated macrophages.
  6. Analyzing the impact of metabolism on immune cells in tumor microenvironment to promote the development of immunotherapy.
  7. Targeting the macrophage immunocheckpoint: a novel insight into solid tumor immunotherapy.
  8. Polyamine Signal through HCC Microenvironment: A Key Regulator of Mitochondrial Preservation and Turnover in TAMs.
  9. Novel immunotherapies for breast cancer: Focus on 2023 findings.
  10. The Tumor Microenvironment and Immune Response in Breast Cancer.
  11. Antigen presenting cells in cancer immunity and mediation of immune checkpoint blockade.
  12. The role of miRNAs in T helper cell development, activation, fate decisions and tumor immunity.
  13. Tumor-Microenvironment-Activatable Nanoparticle Mediating Immunogene Therapy and M2 Macrophage-Targeted Inhibitor for Synergistic Cancer Immunotherapy.
  14. Unlocking antitumor immunity with adenosine receptor blockers.
  15. Combined use of NK cells and radiotherapy in the treatment of solid tumors.
  16. Tumor-Associated Macrophage Targeting of Nanomedicines in Cancer Therapy.
  17. CXCR2 inhibition in G-MDSCs enhances CD47 blockade for melanoma tumor cell clearance.
  18. The Potential of Siglecs and Sialic Acids as Biomarkers and Therapeutic Targets in Tumor Immunotherapy.
  19. Anti-stromal nanotherapeutics for hepatocellular carcinoma.
  20. Lipid peroxidation of immune cells in cancer.
  21. TP53 to mediate immune escape in tumor microenvironment: an overview of the research progress.
  22. Immune cells in the B-cell lymphoma microenvironment: From basic research to clinical applications.
  23. Interleukin-4 induced 1-mediated resistance to an immune checkpoint inhibitor through suppression of CD8+ T cell infiltration in melanoma.
  24. Beyond Viral Infections: The Multifaceted Roles of Human Papillomavirus and Epstein-Barr Virus in Shaping the Tumor Microenvironment.
  25. Nano-medicine therapy reprogramming metabolic network of tumor microenvironment: new opportunity for cancer therapies.
  26. The role of dendritic cells in cancer immunity and therapeutic strategies.
  27. CD36: The Bridge between Lipids and Tumors.
  1. Cell Commun Signal. 2024 Jan 26. 22(1): 74
    Macrophage barrier in the tumor microenvironment and potential clinical applications.
    Shuai Ji, Yuqing Shi, Bo Yin.
      The tumor microenvironment (TME) constitutes a complex microenvironment comprising a diverse array of immune cells and stromal components. Within this intricate context, tumor-associated macrophages (TAMs) exhibit notable spatial heterogeneity. This heterogeneity contributes to various facets of tumor behavior, including immune response modulation, angiogenesis, tissue remodeling, and metastatic potential. This review summarizes the spatial distribution of macrophages in both the physiological environment and the TME. Moreover, this paper explores the intricate interactions between TAMs and diverse immune cell populations (T cells, dendritic cells, neutrophils, natural killer cells, and other immune cells) within the TME. These bidirectional exchanges form a complex network of immune interactions that influence tumor immune surveillance and evasion strategies. Investigating TAM heterogeneity and its intricate interactions with different immune cell populations offers potential avenues for therapeutic interventions. Additionally, this paper discusses therapeutic strategies targeting macrophages, aiming to uncover novel approaches for immunotherapy. Video Abstract.
    Keywords:  Macrophage; Tumor immunology; Tumor microenvironment; Tumor-associated macrophages (TAMs)
    DOI:  https://doi.org/10.1186/s12964-023-01424-6
  2. Curr Cancer Drug Targets. 2024 Jan 24.
    Targeted Mevalonate Pathway and Autophagy in Antitumor Immunotherapy.
    Zongrui Xing, Xiangyan Jiang, Yuxia Wu, Zeyuan Yu.
      Tumors of the digestive system are currently one of the leading causes of cancer-related death worldwide. Despite considerable progress in tumor immunotherapy, the prognosis for most patients remains poor. In the tumor microenvironment (TME), tumor cells attain immune escape through immune editing and acquire immune tolerance. The mevalonate pathway and autophagy play important roles in cancer biology, antitumor immunity, and regulation of the TME. In addition, there is metabolic crosstalk between the two pathways. However, their role in promoting immune tolerance in digestive system tumors has not previously been summarized. Therefore, this review focuses on the cancer biology of the mevalonate pathway and autophagy, the regulation of the TME, metabolic crosstalk between the pathways, and the evaluation of their efficacy as targeted inhibitors in clinical tumor immunotherapy.
    Keywords:  Mevalonate pathway; antitumor immunotherapy; autophagy; metabolic crosstalk; tumor microenvironment.
    DOI:  https://doi.org/10.2174/0115680096273730231206054104
  3. Cancers (Basel). 2024 Jan 11. pii: 308. [Epub ahead of print]16(2):
    Glioma-Immune Cell Crosstalk in Tumor Progression.
    Mahmoud Elguindy, Jacob S Young, Isha Mondal, Rongze O Lu, Winson S Ho.
      Glioma progression is a complex process controlled by molecular factors that coordinate the crosstalk between tumor cells and components of the tumor microenvironment (TME). Among these, immune cells play a critical role in cancer survival and progression. The complex interplay between cancer cells and the immune TME influences the outcome of immunotherapy and other anti-cancer therapies. Here, we present an updated view of the pro- and anti-tumor activities of the main myeloid and lymphocyte cell populations in the glioma TME. We review the underlying mechanisms involved in crosstalk between cancer cells and immune cells that enable gliomas to evade the immune system and co-opt these cells for tumor growth. Lastly, we discuss the current and experimental therapeutic options being developed to revert the immunosuppressive activity of the glioma TME. Knowledge of the complex interplay that elapses between tumor and immune cells may help develop new combination treatments able to overcome tumor immune evasion mechanisms and enhance response to immunotherapies.
    Keywords:  glioma; immune; immune evasion; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers16020308
  4. Front Cell Dev Biol. 2023 ;11 1277076
    Metastasis and cancer associated fibroblasts: taking it up a NOTCH.
    Argha Ghosh, Anirban K Mitra.
      Metastasis is the least understood aspect of cancer biology. 90% of cancer related deaths occur due extensive metastatic burden in patients. Apart from metastasizing cancer cells, the pro-tumorigenic and pro-metastatic role of the tumor stroma plays a crucial part in this complex process often leading to disease relapse and therapy resistance. Cellular signaling processes play a crucial role in the process of tumorigenesis and metastasis when aberrantly turned on, not just in the cancer cells, but also in the cells of the tumor microenvironment (TME). One of the most conserved pathways includes the Notch signaling pathway that plays a crucial role in the development and progression of many cancers. In addition to its well documented role in cancer cells, recent evidence suggests crucial involvement of Notch signaling in the stroma as well. This review aims to highlight the current findings focusing on the oncogenic role of notch signaling in cancer cells and the TME, with a specific focus on cancer associated fibroblasts (CAFs), which constitute a major part of the tumor stroma and are important for tumor progression. Recent efforts have focused on the development of anti-cancer and anti-metastatic therapies targeting TME. Understanding the importance of Notch signaling in the TME would help identify important drivers for stromal reprogramming, metastasis and importantly, drive future research in the effort to develop TME-targeted therapies utilizing Notch.
    Keywords:  Notch signaling; cancer associated fibroblasts; cancer metastasis; ovarian cancer; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2023.1277076
  5. Immunol Res. 2024 Jan 24.
    The immune regulatory function of B7-H3 in malignancy: spotlight on the IFN-STAT1 axis and regulation of tumor-associated macrophages.
    Robin Park, James Yu, Moazzam Shazad, Sunggon Lee, Jong Dae Ji.
      B7-H3 is a member of the B7 superfamily and a putative inhibitory immune checkpoint molecule. Several early-phase clinical trials have reported promising anti-tumor activity and safety of anti-cancer drugs targeting B7-H3, suggesting that it may be a promising target for a potential next-generation immune checkpoint inhibitor. Despite ongoing clinical studies, most B7-H3-targeted drugs being currently investigated rely on direct cytotoxicity as their mechanisms of action rather than modulating its function as an immune checkpoint, at least in part due to its incompletely understood immune regulatory function. Recent studies have begun to elucidate the role of B7-H3 in regulating the tumor microenvironment (TME). Emerging evidence suggests that B7-H3 may regulate the interferon-STAT1 axis in the TME and promote immune suppression. Similarly, increasing evidence shows B7-H3 may be implicated in promoting M1 to M2 polarization of tumor-associated macrophages (TAMs). There is also accumulating evidence suggesting that B7-H3 may play a role in the heterotypic fusion of cancer stem cells and macrophages, thereby promoting tumor invasion and metastasis. Here, we review the recent advances in the understanding of B7-H3 cancer immunobiology with a focus on highlighting its potential role in the interferon priming of TAMs and the heterotypic fusion of TAMs with cancer stem cells and suggest future direction in elucidating its immune checkpoint function.
    Keywords:  B7-H3; IFN-STAT1 axis; Immune checkpoint inhibitors; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1007/s12026-024-09458-9
  6. Front Immunol. 2023 ;14 1307228
    Analyzing the impact of metabolism on immune cells in tumor microenvironment to promote the development of immunotherapy.
    Yanru Long, Houhui Shi, Yuedong He, Xiaorong Qi.
      Tumor metabolism and tumor immunity are inextricably linked. Targeting the metabolism of tumors is a point worth studying in tumor immunotherapy. Recently, the influence of the metabolism of tumors and immune cells on the occurrence, proliferation, metastasis, and prognosis of tumors has attracted more attention. Tumor tissue forms a specific tumor microenvironment (TME). In addition to tumor cells, there are also immune cells, stromal cells, and other cells in TME. To adapt to the environment, tumor cells go through the metabolism reprogramming of various substances. The metabolism reprogramming of tumor cells may further affect the formation of the tumor microenvironment and the function of a variety of cells, especially immune cells, eventually promoting tumor development. Therefore, it is necessary to study the metabolism of tumor cells and its effects on immune cells to guide tumor immunotherapy. Inhibiting tumor metabolism may restore immune balance and promote the immune response in tumors. This article will describe glucose metabolism, lipid metabolism, amino acid metabolism, and immune cells in tumors. Besides, the impact of metabolism on the immune cells in TME is also discussed for analyzing and exploring tumor immunotherapy.
    Keywords:  amino acid metabolism; glucose metabolism; immunotherapy; lipid metabolism; metabolism reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1307228
  7. Cell Commun Signal. 2024 Jan 25. 22(1): 66
    Targeting the macrophage immunocheckpoint: a novel insight into solid tumor immunotherapy.
    Bei Zhou, Yan Yang, Yan Kang, Jingjing Hou, Yun Yang.
      Tumor immunotherapy, which targets immune checkpoints, presents a promising strategy for the treatment of various cancer types. However, current clinical data indicate challenges in its application to solid tumors. Recent studies have revealed a significant correlation between the degree of immune response in immunotherapy and the tumor microenvironment, particularly with regard to tumor-infiltrating immune cells. Among these immune cells, macrophages, a critical component, are playing an increasingly vital role in tumor immunotherapy. This review focuses on elucidating the role of macrophages within solid tumors and provides an overview of the progress in immunotherapy approaches centered around modulating macrophage responses through various immune factors. Video Abstract.
    Keywords:  Immune factors; Immunotherapy; Macrophage; Solid tumor
    DOI:  https://doi.org/10.1186/s12964-023-01384-x
  8. Int J Mol Sci. 2024 Jan 13. pii: 996. [Epub ahead of print]25(2):
    Polyamine Signal through HCC Microenvironment: A Key Regulator of Mitochondrial Preservation and Turnover in TAMs.
    Qingqing Liu, Xiaoyu Yan, Runyuan Li, Yuan Yuan, Jian Wang, Yuanxin Zhao, Jiaying Fu, Jing Su.
      Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and, with increasing research on the tumor immune microenvironment (TIME), the immunosuppressive micro-environment of HCC hampers further application of immunotherapy, even though immunotherapy can provide survival benefits to patients with advanced liver cancer. Current studies suggest that polyamine metabolism is not only a key metabolic pathway for the formation of immunosuppressive phenotypes in tumor-associated macrophages (TAMs), but it is also profoundly involved in mitochondrial quality control signaling and the energy metabolism regulation process, so it is particularly important to further investigate the role of polyamine metabolism in the tumor microenvironment (TME). In this review, by summarizing the current research progress of key enzymes and substrates of the polyamine metabolic pathway in regulating TAMs and T cells, we propose that polyamine biosynthesis can intervene in the process of mitochondrial energy metabolism by affecting mitochondrial autophagy, which, in turn, regulates macrophage polarization and T cell differentiation. Polyamine metabolism may be a key target for the interactive dialog between HCC cells and immune cells such as TAMs, so interfering with polyamine metabolism may become an important entry point to break intercellular communication, providing new research space for developing polyamine metabolism-based therapy for HCC.
    Keywords:  EVs; TME; mitochondria; polyamine; spermidine
    DOI:  https://doi.org/10.3390/ijms25020996
  9. Int Immunopharmacol. 2024 Jan 23. pii: S1567-5769(24)00067-5. [Epub ahead of print]128 111549
    Novel immunotherapies for breast cancer: Focus on 2023 findings.
    Huan-Rong Lan, Min Chen, Shi-Ya Yao, Jun-Xia Chen, Ke-Tao Jin.
      Immunotherapy has emerged as a revolutionary approach in cancer therapy, and recent advancements hold significant promise for breast cancer (BCa) management. Employing the patient's immune system to combat BCa has become a focal point in immunotherapeutic investigations. Strategies such as immune checkpoint inhibitors (ICIs), adoptive cell transfer (ACT), and targeting the tumor microenvironment (TME) have disclosed encouraging clinical outcomes. ICIs, particularly programmed cell death protein 1 (PD-1)/PD-L1 inhibitors, exhibit efficacy in specific BCa subtypes, including triple-negative BCa (TNBC) and human epidermal growth factor receptor 2 (HER2)-positive cancers. ACT approaches, including tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T-cell therapy, showed promising clinical outcomes in enhancing tumor recognition and elimination. Targeting the TME through immune agonists and oncolytic viruses signifies a burgeoning field of research. While challenges persist in patient selection, resistance mechanisms, and combination therapy optimization, these novel immunotherapies hold transformative potential for BCa treatment. Continued research and clinical trials are imperative to refine and implement these innovative approaches, paving the way for improved outcomes and revolutionizing the management of BCa. This review provides a concise overview of the latest immunotherapies (2023 studies) in BCa, highlighting their potential and current status.
    Keywords:  Breast cancer; Clinical trials; Combination therapy; Immunotherapy; Treatment
    DOI:  https://doi.org/10.1016/j.intimp.2024.111549
  10. Int J Mol Sci. 2024 Jan 11. pii: 914. [Epub ahead of print]25(2):
    The Tumor Microenvironment and Immune Response in Breast Cancer.
    Behjatolah Monzavi-Karbassi, Thomas Kelly, Steven R Post.
      The complex interactions between cancer cells and their surrounding microenvironment are fundamental in determining tumor progression, response to therapy, and, ultimately, patient prognosis [...].
    DOI:  https://doi.org/10.3390/ijms25020914
  11. Clin Exp Metastasis. 2024 Jan 23.
    Antigen presenting cells in cancer immunity and mediation of immune checkpoint blockade.
    Cassia Wang, Lee Chen, Doris Fu, Wendi Liu, Anusha Puri, Manolis Kellis, Jiekun Yang.
      Antigen-presenting cells (APCs) are pivotal mediators of immune responses. Their role has increasingly been spotlighted in the realm of cancer immunology, particularly as our understanding of immunotherapy continues to evolve and improve. There is growing evidence that these cells play a non-trivial role in cancer immunity and have roles dependent on surface markers, growth factors, transcription factors, and their surrounding environment. The main dendritic cell (DC) subsets found in cancer are conventional DCs (cDC1 and cDC2), monocyte-derived DCs (moDC), plasmacytoid DCs (pDC), and mature and regulatory DCs (mregDC). The notable subsets of monocytes and macrophages include classical and non-classical monocytes, macrophages, which demonstrate a continuum from a pro-inflammatory (M1) phenotype to an anti-inflammatory (M2) phenotype, and tumor-associated macrophages (TAMs). Despite their classification in the same cell type, each subset may take on an immune-activating or immunosuppressive phenotype, shaped by factors in the tumor microenvironment (TME). In this review, we introduce the role of DCs, monocytes, and macrophages and recent studies investigating them in the cancer immunity context. Additionally, we review how certain characteristics such as abundance, surface markers, and indirect or direct signaling pathways of DCs and macrophages may influence tumor response to immune checkpoint blockade (ICB) therapy. We also highlight existing knowledge gaps regarding the precise contributions of different myeloid cell subsets in influencing the response to ICB therapy. These findings provide a summary of our current understanding of myeloid cells in mediating cancer immunity and ICB and offer insight into alternative or combination therapies that may enhance the success of ICB in cancers.
    Keywords:  Antigen presenting cells; Cancer immunity; Dendritic cell; Immune checkpoint blockade; Macrophage; Monocyte
    DOI:  https://doi.org/10.1007/s10585-023-10257-z
  12. Front Immunol. 2023 ;14 1320305
    The role of miRNAs in T helper cell development, activation, fate decisions and tumor immunity.
    Shi-Jun Xu, Jin-Hua Chen, Suhwan Chang, Hai-Liang Li.
      T helper (Th) cells are central members of adaptive immunity and comprise the last line of defense against pathogen infection and malignant cell invasion by secreting specific cytokines. These cytokines then attract or induce the activation and differentiation of other immune cells, including antibody-producing B cells and cytotoxic CD8+ T cells. Therefore, the bidirectional communication between Th cells and tumor cells and their positioning within the tumor microenvironment (TME), especially the tumor immune microenvironment (TIME), sculpt the tumor immune landscape, which affects disease initiation and progression. The type, number, and condition of Th cells in the TME and TIME strongly affect tumor immunity, which is precisely regulated by key effectors, such as granzymes, perforins, cytokines, and chemokines. Moreover, microRNAs (miRNAs) have emerged as important regulators of Th cells. In this review, we discuss the role of miRNAs in regulating Th cell mediated adaptive immunity, focusing on the development, activation, fate decisions, and tumor immunity.
    Keywords:  activation; development; fate decisions; miRNAs; T helper cell; tumor immunity; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1320305
  13. ACS Nano. 2024 Jan 22.
    Tumor-Microenvironment-Activatable Nanoparticle Mediating Immunogene Therapy and M2 Macrophage-Targeted Inhibitor for Synergistic Cancer Immunotherapy.
    Yuzhu Hu, Wen Nie, Liang Lyu, Xifeng Zhang, Wanyu Wang, Yunchu Zhang, Shi He, Anjie Guo, Fei Liu, Bilan Wang, Zhiyong Qian, Xiang Gao.
      Immunotherapy has achieved prominent clinical efficacy in combating cancer and has recently become a mainstream treatment strategy. However, achieving broad efficacy with a single modality is challenging, and the heterogeneity of the tumor microenvironment (TME) restricts the accuracy and effectiveness of immunotherapy strategies for tumors. Herein, a TME-responsive targeted nanoparticle to enhance antitumor immunity and reverse immune escape by codelivering interleukin-12 (IL-12) expressing gene and colony-stimulating factor-1 receptor (CSF-1R) inhibitor PLX3397 (PLX) is presented. The introduction of disulfide bonds and cyclo(Arg-Gly-Asp-d-Phe-Lys) (cRGD) peptides conferred reduction reactivity and tumor targeting to the nanoparticles, respectively. It is hypothesized that activating host immunity by the local expression of IL-12, while modulating the tumor-associated macrophages (TAM) function through blocking CSF-1/CSF-1R signaling, could constitute a feasible approach for cancer immunotherapy. The fabricated functional nanoparticle successfully ameliorated the TME by stimulating the proliferation and activation of T lymphocytes, promoting the repolarization of TAMs, reducing myeloid-derived suppressor cells (MDSCs), and promoting the maturation of dendritic cells (DC) as well as the secretion of antitumor cytokines, which efficiently suppressed tumor growth and metastasis. Finally, substantial changes in the TME were deciphered by single-cell analysis including infiltration of different cells, transcriptional states, secretory signaling and cell-cell communications. These findings provide a promising combinatorial immunotherapy strategy through immunomodulatory nanoparticles.
    Keywords:  IL-12; Immunotherapy; colony stimulating factor-1 receptor; gene therapy; microenvironment remodeling
    DOI:  https://doi.org/10.1021/acsnano.3c10037
  14. Cancer Drug Resist. 2023 ;6(4): 748-767
    Unlocking antitumor immunity with adenosine receptor blockers.
    Victoria A Remley, Joel Linden, Todd W Bauer, Julien Dimastromatteo.
      Tumors survive by creating a tumor microenvironment (TME) that suppresses antitumor immunity. The TME suppresses the immune system by limiting antigen presentation, inhibiting lymphocyte and natural killer (NK) cell activation, and facilitating T cell exhaustion. Checkpoint inhibitors like anti-PD-1 and anti-CTLA4 are immunostimulatory antibodies, and their blockade extends the survival of some but not all cancer patients. Extracellular adenosine triphosphate (ATP) is abundant in inflamed tumors, and its metabolite, adenosine (ADO), is a driver of immunosuppression mediated by adenosine A2A receptors (A2AR) and adenosine A2B receptors (A2BR) found on tumor-associated lymphoid and myeloid cells. This review will focus on adenosine as a key checkpoint inhibitor-like immunosuppressive player in the TME and how reducing adenosine production or blocking A2AR and A2BR enhances antitumor immunity.
    Keywords:  Immunotherapy; adenosine; adenosine A2A receptors (A2AR); adenosine A2B receptors (A2BR); adenosine receptors; immune cells; tumor cells; tumor microenvironment
    DOI:  https://doi.org/10.20517/cdr.2023.63
  15. Front Immunol. 2023 ;14 1306534
    Combined use of NK cells and radiotherapy in the treatment of solid tumors.
    Wang Zheng, Sunkai Ling, Yuandong Cao, Chunlin Shao, Xinchen Sun.
      Natural killer (NK) cells are innate lymphocytes possessing potent tumor surveillance and elimination activity. Increasing attention is being focused on the role of NK cells in integral antitumor strategies (especially immunotherapy). Of note, therapeutic efficacy is considerable dependent on two parameters: the infiltration and cytotoxicity of NK cells in tumor microenvironment (TME), both of which are impaired by several obstacles (e.g., chemokines, hypoxia). Strategies to overcome such barriers are needed. Radiotherapy is a conventional modality employed to cure solid tumors. Recent studies suggest that radiotherapy not only damages tumor cells directly, but also enhances tumor recognition by immune cells through altering molecular expression of tumor or immune cells via the in situ or abscopal effect. Thus, radiotherapy may rebuild a NK cells-favored TME, and thus provide a cost-effective approach to improve the infiltration of NK cells into solid tumors, as well as elevate immune-activity. Moreover, the radioresistance of tumor always hampers the response to radiotherapy. Noteworthy, the puissant cytotoxic activity of NK cells not only kills tumor cells directly, but also increases the response of tumors to radiation via activating several radiosensitization pathways. Herein, we review the mechanisms by which NK cells and radiotherapy mutually promote their killing function against solid malignancies. We also discuss potential strategies harnessing such features in combined anticancer care.
    Keywords:  CGAS/STING signaling; granzyme B; natural killer cell; radiotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1306534
  16. Pharmaceutics. 2023 Dec 29. pii: 61. [Epub ahead of print]16(1):
    Tumor-Associated Macrophage Targeting of Nanomedicines in Cancer Therapy.
    Xuejia Kang, Yongzhuo Huang, Huiyuan Wang, Sanika Jadhav, Zongliang Yue, Amit K Tiwari, R Jayachandra Babu.
      The tumor microenvironment (TME) is pivotal in tumor growth and metastasis, aligning with the "Seed and Soil" theory. Within the TME, tumor-associated macrophages (TAMs) play a central role, profoundly influencing tumor progression. Strategies targeting TAMs have surfaced as potential therapeutic avenues, encompassing interventions to block TAM recruitment, eliminate TAMs, reprogram M2 TAMs, or bolster their phagocytic capabilities via specific pathways. Nanomaterials including inorganic materials, organic materials for small molecules and large molecules stand at the forefront, presenting significant opportunities for precise targeting and modulation of TAMs to enhance therapeutic efficacy in cancer treatment. This review provides an overview of the progress in designing nanoparticles for interacting with and influencing the TAMs as a significant strategy in cancer therapy. This comprehensive review presents the role of TAMs in the TME and various targeting strategies as a promising frontier in the ever-evolving field of cancer therapy. The current trends and challenges associated with TAM-based therapy in cancer are presented.
    Keywords:  nanomedicine; suppressive immune environment; targeted delivery systems; tumor proliferation and metastasis; tumor-associated macrophage
    DOI:  https://doi.org/10.3390/pharmaceutics16010061
  17. Proc Natl Acad Sci U S A. 2024 Jan 30. 121(5): e2318534121
    CXCR2 inhibition in G-MDSCs enhances CD47 blockade for melanoma tumor cell clearance.
    Allison Banuelos, Allison Zhang, Hala Berouti, Michelle Baez, Leyla Yılmaz, Nardin Georgeos, Kristopher D Marjon, Masanori Miyanishi, Irving L Weissman.
      The use of colony-stimulating factor-1 receptor (CSF1R) inhibitors has been widely explored as a strategy for cancer immunotherapy due to their robust depletion of tumor-associated macrophages (TAMs). While CSF1R blockade effectively eliminates TAMs from the solid tumor microenvironment, its clinical efficacy is limited. Here, we use an inducible CSF1R knockout model to investigate the persistence of tumor progression in the absence of TAMs. We find increased frequencies of granulocytic myeloid-derived suppressor cells (G-MDSCs) in the bone marrow, throughout circulation, and in the tumor following CSF1R deletion and loss of TAMs. We find that G-MDSCs are capable of suppressing macrophage phagocytosis, and the elimination of G-MDSCs through CXCR2 inhibition increases macrophage capacity for tumor cell clearance. Further, we find that combination therapy of CXCR2 inhibition and CD47 blockade synergize to elicit a significant anti-tumor response. These findings reveal G-MDSCs as key drivers of tumor immunosuppression and demonstrate their inhibition as a potent strategy to increase macrophage phagocytosis and enhance the anti-tumor efficacy of CD47 blockade in B16-F10 melanoma.
    Keywords:  CD47 blockade; CXCR2; macrophages; myeloid-derived suppressor cells; tumor immunology
    DOI:  https://doi.org/10.1073/pnas.2318534121
  18. Cancers (Basel). 2024 Jan 10. pii: 289. [Epub ahead of print]16(2):
    The Potential of Siglecs and Sialic Acids as Biomarkers and Therapeutic Targets in Tumor Immunotherapy.
    Haokang Feng, Jiale Feng, Xu Han, Ying Ying, Wenhui Lou, Liang Liu, Lei Zhang.
      The dysregulation of sialic acid is closely associated with oncogenesis and tumor progression. Most tumor cells exhibit sialic acid upregulation. Sialic acid-binding immunoglobulin-like lectins (Siglecs) are receptors that recognize sialic acid and are expressed in various immune cells. The activity of Siglecs in the tumor microenvironment promotes immune escape, mirroring the mechanisms of the well-characterized PD-1/PD-L1 pathway in cancer. Cancer cells utilize sialic acid-linked glycans to evade immune surveillance. As Siglecs exhibit similar mechanisms as the established immune checkpoint inhibitors (ICIs), they are potential therapeutic targets for different forms of cancer, especially ICI-resistant malignancies. Additionally, the upregulation of sialic acid serves as a potential tumor biomarker. This review examines the feasibility of using sialic acid and Siglecs for early malignant tumor detection and discusses the potential of targeting Siglec-sialic acid interaction as a novel cancer therapeutic strategy.
    Keywords:  Siglecs; immune cells; immune checkpoint inhibitors; immune evasion; sialylation
    DOI:  https://doi.org/10.3390/cancers16020289
  19. J Control Release. 2024 Jan 24. pii: S0168-3659(24)00066-X. [Epub ahead of print]
    Anti-stromal nanotherapeutics for hepatocellular carcinoma.
    Zhuo Yu, Leaf Huang, Jianfeng Guo.
      Hepatocellular carcinoma (HCC), the most commonly diagnosed primary liver cancer, has become a leading cause of cancer-related death worldwide. Accumulating evidence confirms that the stromal constituents within the tumor microenvironment (TME) exacerbate HCC malignancy and set the barriers to current anti-HCC treatments. Recent developments of nano drug delivery system (NDDS) have facilitated the application of stroma-targeting therapeutics, disrupting the stromal TME in HCC. This review discusses the stromal activities in HCC development and therapy resistance. In addition, it addresses the delivery challenges of NDDS for stroma-targeting therapeutics (termed anti-stromal nanotherapeutics in this review), and provides recent advances in anti-stromal nanotherapeutics for safe, effective, and specific HCC therapy.
    Keywords:  Combination therapy; Drug delivery; Liver cancer; Nanoparticle; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.jconrel.2024.01.050
  20. Front Immunol. 2023 ;14 1322746
    Lipid peroxidation of immune cells in cancer.
    Liuling Xiao, Miao Xian, Chuanchao Zhang, Qi Guo, Qing Yi.
      Growing evidence indicates that cellular metabolism is a critical determinant of immune cell viability and function in antitumor immunity and lipid metabolism is important for immune cell activation and adaptation to the tumor microenvironment (TME). Lipid peroxidation is a process in which oxidants attack lipid-containing carbon-carbon double bonds and is an important part of lipid metabolism. In the past decades, studies have shown that lipid peroxidation participates in signal transduction to control cell proliferation, differentiation, and cell death, which is essential for cell function execution and human health. More importantly, recent studies have shown that lipid peroxidation affects immune cell function to modulate tumor immunity and antitumor ability. In this review, we briefly overview the effect of lipid peroxidation on the adaptive and innate immune cell activation and function in TME and discuss the effectiveness and sensitivity of the antitumor ability of immune cells by regulating lipid peroxidation.
    Keywords:  TME; adaptive immune cells; innate immune cells; lipid peroxidation; tumor immunity
    DOI:  https://doi.org/10.3389/fimmu.2023.1322746
  21. Mol Biol Rep. 2024 Jan 25. 51(1): 205
    TP53 to mediate immune escape in tumor microenvironment: an overview of the research progress.
    Kai-Li Zhu, Fei Su, Jing-Ru Yang, Ruo-Wen Xiao, Rui-Yue Wu, Meng-Yue Cao, Xiao-Ling Ling, Tao Zhang.
      Increasing evidence suggests that key cancer-causing driver genes continue to exert a sustained influence on the tumor microenvironment (TME), highlighting the importance of immunotherapeutic targeting of gene mutations in governing tumor progression. TP53 is a prominent tumor suppressor that encodes the p53 protein, which controls the initiation and progression of different tumor types. Wild-type p53 maintains cell homeostasis and genomic instability through complex pathways, and mutant p53 (Mut p53) promotes tumor occurrence and development by regulating the TME. To date, it has been wildly considered that TP53 is able to mediate tumor immune escape. Herein, we summarized the relationship between TP53 gene and tumors, discussed the mechanism of Mut p53 mediated tumor immune escape, and summarized the progress of applying p53 protein in immunotherapy. This study will provide a basic basis for further exploration of therapeutic strategies targeting p53 protein.
    Keywords:  Immune escape; Immunotherapy; TP53; Tumors
    DOI:  https://doi.org/10.1007/s11033-023-09097-7
  22. Chin Med J (Engl). 2024 Jan 25.
    Immune cells in the B-cell lymphoma microenvironment: From basic research to clinical applications.
    Wenli Zhang, Mengmeng Liu, Wei Li, Yongping Song.
       ABSTRACT: B-cell lymphoma is a group of hematological malignancies characterized by variable genetic and biological features and clinical behaviors. The tumor microenvironment (TME) is a complex network in tumors, which consists of surrounding blood vessels, extracellular matrix, immune and non-immune cells, and signaling molecules. Increasing evidence has shown that the TME, especially immune cells within, is a double-edged sword, acting either as a tumor killer or as a promoter of tumor progression. These pro-tumor activities are driven by subpopulations of immune cells that express typical markers but have unique transcriptional characteristics, making tumor-associated immune cells good targets for human anti-cancer therapy by ablating immunosuppressive cells or enhancing immune-activated cells. Thus, exploring the role of immune cells in the TME provides distinct insights for immunotherapy in B-cell lymphoma. In this review, we elucidated the interaction between immune cells and tumor cells and their function in the initiation, progression, and prognosis of B-cell lymphoma, from preclinical experiments to clinical trials. Furthermore, we outlined potential therapeutic approaches and discussed the potential clinical value and future perspectives of targeting immune cells in patients with B-cell lymphoma.
    DOI:  https://doi.org/10.1097/CM9.0000000000002919
  23. Cancer Sci. 2024 Jan 22.
    Interleukin-4 induced 1-mediated resistance to an immune checkpoint inhibitor through suppression of CD8+ T cell infiltration in melanoma.
    Shiho Hirose, Tetsuo Mashima, Xunmei Yuan, Makiko Yamashita, Shigehisa Kitano, Shinichi Torii, Toshiro Migita, Hiroyuki Seimiya.
      Cancer cells adopt multiple strategies to escape tumor surveillance by the host immune system and aberrant amino acid metabolism in the tumor microenvironment suppresses the immune system. Among the amino acid-metabolizing enzymes is an L-amino-acid oxidase called interleukin-4 induced 1 (IL4I1), which depletes essential amino acids in immune cells and is associated with a poor prognosis in various cancer types. Although IL4I1 is involved in immune metabolism abnormalities, its effect on the therapeutic efficacy of immune checkpoint inhibitors is unknown. In this study, we established murine melanoma cells overexpressing IL4I1 and investigated their effects on the intratumor immune microenvironment and the antitumor efficacy of anti-programmed death-ligand 1 (PD-L1) antibodies (Abs) in a syngeneic mouse model. As a result, we found that IL4I1-overexpressing B16-F10-derived tumors showed resistance to anti-PD-L1 Ab therapy. Transcriptome analysis revealed that immunosuppressive genes were globally upregulated in the IL4I1-overexpressing tumors. Consistently, we showed that IL4I1-overexpressing tumors exhibited an altered subset of lymphoid cells and particularly significant suppression of cytotoxic T cell infiltration compared to mock-infected B16-F10-derived tumors. After treatment with anti-PD-L1 Abs, we also found a more prominent elevation of tumor-associated macrophage (TAM) marker, CD68, in the IL4I1-overexpressing tumors than in the mock tumors. Consistently, we confirmed an enhanced TAM infiltration in the IL4I1-overexpressing tumors and a functional involvement of TAMs in the tumor growth. These observations indicate that IL4I1 reprograms the tumor microenvironment into an immunosuppressive state and thereby confers resistance to anti-PD-L1 Abs.
    Keywords:  IL4I1; immune checkpoint inhibitor; immune escape; melanoma; tumor microenvironment
    DOI:  https://doi.org/10.1111/cas.16073
  24. Discov Med. 2024 Jan;36(180): 1-15
    Beyond Viral Infections: The Multifaceted Roles of Human Papillomavirus and Epstein-Barr Virus in Shaping the Tumor Microenvironment.
    Queenie Fernandes, Gulab Sher, Kirti S Prabhu, Shilpa Kuttikrishnan, Maysaloun Merhi, Said Dermime, Kulsoom Junejo, Ajaz A Bhat, Shahab Uddin.
      The tumor microenvironment (TME) exerts a profound influence on the oncogenesis and progression of various cancers, notably those instigated by the human papillomavirus (HPV) and the Epstein-Barr virus (EBV). The etiology of HPV and EBV-associated malignancies is rooted in intricate interactions that intertwine viral infections, genetic predispositions, and distinct TME dynamics. These interactions foster a milieu that can either support or hinder tumorigenic progression. Gaining in-depth knowledge of the TME's unique features, including its cellular composition, cytokine profiles, and metabolic alterations specific to HPV and EBV-associated cancers, is fundamental to innovating more efficacious therapeutic strategies. This review delineates the intricate roles of HPV and EBV in shaping the TME and expounds upon the unique TME characteristics specific to HPV and EBV-driven cancers. Additionally, we spotlight innovative approaches to remodel the TME, aiming to augment therapeutic efficacy in combatting HPV and EBV-associated neoplasms.
    Keywords:  Epstein-Barr virus; human papillomavirus; immune cell infiltration; oncogenic interactions; therapeutic strategies; tumor microenvironment
    DOI:  https://doi.org/10.24976/Discov.Med.202436180.1
  25. J Drug Target. 2024 Jan 22. 1-47
    Nano-medicine therapy reprogramming metabolic network of tumor microenvironment: new opportunity for cancer therapies.
    Xiaojie Zhang, Min An, Juntao Zhang, Yumeng Zhao, Yanhua Liu.
      Metabolic heterogeneity is one of the characteristics of tumor cells. In order to adapt to the tumor microenvironment of hypoxia, acidity and nutritional deficiency, tumor cells have undergone extensive metabolic reprogramming. Metabolites involved in tumor cell metabolism are also very different from normal cells, such as a large number of lactate and adenosine. Metabolites play an important role in regulating the whole tumor microenvironment. Taking metabolites as the target, it aims to change the metabolic pattern of tumor cells again, destroy the energy balance it maintains, activate the immune system, and finally kill tumor cells. In this paper, the regulatory effects of metabolites such as lactate, glutamine, arginine, tryptophan, fatty acids and adenosine were reviewed, and the related targeting strategies of nano-medicines were summarized, and the future therapeutic strategies of nano-drugs were discussed. The abnormality of tumor metabolites caused by tumor metabolic remodeling not only changes the energy and material supply of tumor, but also participates in the regulation of tumor-related signal pathways, which plays an important role in the survival, proliferation, invasion and metastasis of tumor cells. Regulating the availability of local metabolites is a new aspect that affects tumor progress.
    Keywords:  immune cells; metabolite; nano-medicine; tumor microenvironment
    DOI:  https://doi.org/10.1080/1061186X.2024.2309565
  26. Int Immunopharmacol. 2024 Jan 19. pii: S1567-5769(24)00066-3. [Epub ahead of print]128 111548
    The role of dendritic cells in cancer immunity and therapeutic strategies.
    Yunze Tai, Man Chen, Fang Wang, Yu Fan, Junlong Zhang, Bei Cai, Lin Yan, Yao Luo, Yi Li.
      Dendritic cells (DCs) are asserted as the most potent antigen-presenting cells (APCs) that orchestrate both innate and adaptive immunity, being extremely effective in the induction of robust anti-cancer T cell responses. Hence, the modulation of DCs function represents an attractive target for improving cancer immunotherapy efficacy. A better understanding of the immunobiology of DCs, the interaction among DCs, immune effector cells and tumor cells in tumor microenvironment (TME) and the latest advances in biomedical engineering technology would be required for the design of optimal DC-based immunotherapy. In this review, we focus on elaborating the immunobiology of DCs in healthy and cancer environments, the recent advances in the development of enhancing endogenous DCs immunocompetence via immunomodulators as well as DC-based vaccines. The rapidly developing field of applying nanotechnology to improve DC-based immunotherapy is also highlighted.
    Keywords:  Cancer; Dendritic cells; Immunotherapy; Nanotherapy; Tumor microenvironment; Vaccines
    DOI:  https://doi.org/10.1016/j.intimp.2024.111548
  27. Molecules. 2024 Jan 21. pii: 531. [Epub ahead of print]29(2):
    CD36: The Bridge between Lipids and Tumors.
    Xuan Zhou, Manman Su, Jungu Lu, Deming Li, Xinhui Niu, Yi Wang.
      It has been found that the development of some cancers can be attributed to obesity, which is associated with the excessive intake of lipids. Cancer cells undergo metabolic reprogramming, shifting from utilizing glucose to fatty acids (FAs) for energy. CD36, a lipid transporter, is highly expressed in certain kinds of cancer cells. High expressions of CD36 in tumor cells triggers FA uptake and lipid accumulation, promoting rapid tumor growth and initiating metastasis. Meanwhile, immune cells in the tumor microenvironment overexpress CD36 and undergo metabolic reprogramming. CD36-mediated FA uptake leads to lipid accumulation and has immunosuppressive effects. This paper reviews the types of FAs associated with cancer, high expressions of CD36 that promote cancer development and progression, effects of CD36 on different immune cells in the tumor microenvironment, and the current status of CD36 as a therapeutic target for the treatment of tumors with high CD36 expression.
    Keywords:  CD36; fatty acid; immunosuppress; lipid; metastasis-initiating cells
    DOI:  https://doi.org/10.3390/molecules29020531
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