bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024‒10‒20
29 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Tumor-Associated Macrophages as Major Immunosuppressive Cells in the Tumor Microenvironment.
  2. Immune Checkpoints and Cellular Landscape of the Tumor Microenvironment in Non-Melanoma Skin Cancer (NMSC).
  3. Crosstalk Between Macrophages and Breast Cancer Cells: Networking Within Tumors.
  4. Recent Progress on Nanomedicine-Mediated Repolarization of Tumor-Associated Macrophages for Cancer Immunotherapy.
  5. TRIP13: A promising cancer immunotherapy target.
  6. Advances in targeting tumor microenvironment for immunotherapy.
  7. Tumor microenvironment induced switch to mitochondrial metabolism promotes suppressive functions in immune cells.
  8. Mechanistic studies of tumor-associated macrophage immunotherapy.
  9. Targeted modulation of myeloid-derived suppressor cells in the tumor microenvironment: Implications for cancer therapy.
  10. The role of Tim-3 blockade in the tumor immune microenvironment beyond T cells.
  11. Beyond Cancer Cells: How the Tumor Microenvironment Drives Cancer Progression.
  12. The Zeb1-Cxcl1 axis impairs the antitumor immune response by inducing M2 macrophage polarization in breast cancer.
  13. Circadian rhythms of macrophages are altered by the acidic tumor microenvironment.
  14. Regulation of CD8+ T cells by lipid metabolism in cancer progression.
  15. Macrophages: Key Players in the Battle against Triple-Negative Breast Cancer.
  16. Dynamic reciprocal interactions between activated T cells and tumor associated macrophages drive macrophage reprogramming and proinflammatory T cell migration within prostate tumor models.
  17. Mesenchymal stromal cells as cancer promoters.
  18. Natural killer cell-based cancer immunotherapy: from basics to clinical trials.
  19. Exploring the role of EZH2 modulation in shaping the tumor microenvironment.
  20. The key role of matrix stiffness in colorectal cancer immunotherapy: mechanisms and therapeutic strategies.
  21. Hippo pathway in cancer cells induces NCAM1+αSMA+ fibroblasts to modulate tumor microenvironment.
  22. Substrate stiffness-dependent activation of Hippo pathway in cancer associated fibroblasts.
  23. Reshaping the tumor microenvironment by degrading glycoimmune checkpoints Siglec-7 and -9.
  24. Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer.
  25. The crosstalk between primary MSCs and cancer cells in 2D and 3D cultures: potential therapeutic strategies and impact on drug resistance.
  26. The MCIB Model: A Novel Theory for Describing the Spatial Heterogeneity of the Tumor Microenvironment.
  27. Impact of opioids and mu-opioid receptors on oncologic metastasis.
  28. Direct visualization of emergent metastatic features within an ex vivo model of the tumor microenvironment.
  29. The pH-sensitive chondroitin sulphate-based nanoparticles for co-delivery of doxorubicin and berberine enhance the treatment of breast cancer.
  1. Cancers (Basel). 2024 Oct 08. pii: 3410. [Epub ahead of print]16(19):
    Tumor-Associated Macrophages as Major Immunosuppressive Cells in the Tumor Microenvironment.
    Anghesom Ghebremedhin, Dipti Athavale, Yanting Zhang, Xiaodan Yao, Curt Balch, Shumei Song.
      Within the tumor microenvironment, myeloid cells constitute a dynamic immune population characterized by a heterogeneous phenotype and diverse functional activities. In this review, we consider recent literature shedding light on the increasingly complex biology of M2-like immunosuppressive tumor-associated macrophages (TAMs), including their contribution to tumor cell invasion and metastasis, stromal remodeling (fibrosis and matrix degradation), and immune suppressive functions, in the tumor microenvironment (TME). This review also delves into the intricate signaling mechanisms underlying the polarization of diverse macrophage phenotypes, and their plasticity. We also review the development of promising therapeutic approaches to target these populations in cancers. The expanding knowledge of distinct subsets of immunosuppressive TAMs, and their contributions to tumorigenesis and metastasis, has sparked significant interest among researchers regarding the therapeutic potential of TAM depletion or phenotypic modulation.
    Keywords:  cancers; immunosuppression; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3390/cancers16193410
  2. Cells. 2024 Sep 26. pii: 1615. [Epub ahead of print]13(19):
    Immune Checkpoints and Cellular Landscape of the Tumor Microenvironment in Non-Melanoma Skin Cancer (NMSC).
    Ahmed M Mousa, Alexander H Enk, Jessica C Hassel, Robin Reschke.
      Non-melanoma skin cancer (NMSC) is primarily categorized into basal cell carcinoma (BCC), the most prevalent form of skin cancer, and cutaneous squamous cell carcinoma (cSCC), the second most common type. Both BCC and cSCC represent a significant health burden, particularly in immunocompromised individuals and the elderly. The immune system plays a pivotal role in the development and progression of NMSC, making it a critical focus for therapeutic interventions. This review highlights key immunological targets in BCC and cSCC, with a focus on immune checkpoint molecules such as PD-1/PD-L1 and CTLA-4, which regulate T cell activity and contribute to immune evasion. This review also highlights anti-tumor immune cell subsets within the tumor microenvironment (TME), such as tumor-infiltrating lymphocytes (TILs) and dendritic cells. Additionally, it examines the immunosuppressive elements of the TME, including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs), as well as their roles in NMSC progression and resistance to therapy. Emerging strategies targeting these immune elements, such as monoclonal antibodies, are also discussed for their potential to enhance anti-tumor immune responses and improve clinical outcomes. By elucidating the immunological landscape of BCC and cSCC and drawing comparisons to melanoma, this review highlights the transformative potential of immunotherapy in treating these malignancies.
    Keywords:  BCC; ICI; NMSC; TME; cSCC; immune cells
    DOI:  https://doi.org/10.3390/cells13191615
  3. Results Probl Cell Differ. 2024 ;74 213-238
    Crosstalk Between Macrophages and Breast Cancer Cells: Networking Within Tumors.
    Pooja Kamal Melwani, Rahul Checker, Murali Mohan Sagar Balla, Badri Narain Pandey.
      Tumor associated macrophages (TAMs) are one of the most prominent immune cells in the breast tumor microenvironment (TME). TAMs are categorised into classically activated anti-tumorigenic M1 and alternatively activated pro-tumorigenic M2 macrophages. TAMs are known to promote cancer pathogenesis by facilitating cancer cell and cancer stem cell growth, angiogenesis, immune evasion, invasion, and migration. Consequently, TAMs drive cancer progression towards metastasis. This chapter describes the role of TME in driving monocyte recruitment and polarization toward the M2 phenotype. We also illustrate the modalities of intercellular networking such as paracrine signaling, exosomes, and tunneling nanotubes (TNTs) that TAMs and cancer cells employ within TME to communicate with each other and with other cells of TME to facilitate the dynamic process of cancer progression. Finally, we discuss the clinical implications of TAMs in breast cancer and potential therapeutic strategies targeting TAM recruitment, polarization, and TAM-mediated immune evasion for effective cancer therapy.
    Keywords:  Breast cancer; Intercellular communication; Metastasis; Tumor associated macrophages; Tumor microenvironment; Tunneling nanotubes
    DOI:  https://doi.org/10.1007/978-3-031-65944-7_8
  4. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2024 Sep-Oct;16(5):16(5): e2001
    Recent Progress on Nanomedicine-Mediated Repolarization of Tumor-Associated Macrophages for Cancer Immunotherapy.
    Jing-Yang Zhang, Yun-He Su, Xu Wang, Xueqing Yao, Jin-Zhi Du.
      Tumor-associated macrophages (TAMs) constitute the largest number of immune cells in the tumor microenvironment (TME). They play an essential role in promoting tumor progression and metastasis, which makes them a potential therapeutic target for cancer treatment. TAMs are usually divided into two categories: pro-tumoral M2-like TAMs and antitumoral M1 phenotypes at either extreme. The reprogramming of M2-like TAMs toward a tumoricidal M1 phenotype is of particular interest for the restoration of antitumor immunity in cancer immunotherapy. Notably, nanomedicines have shown great potential for cancer therapy due to their unique structures and properties. This review will briefly describe the biological features and roles of TAMs in tumor, and then discuss recent advances in nanomedicine-mediated repolarization of TAMs for cancer immunotherapy. Finally, perspectives on nanomedicine-mediated repolarization of TAMs for effective cancer immunotherapy are also presented.
    Keywords:  cancer immunotherapy; drug delivery; nanomedicine; repolarization; tumor‐associated macrophages
    DOI:  https://doi.org/10.1002/wnan.2001
  5. Cancer Innov. 2024 Dec;3(6): e147
    TRIP13: A promising cancer immunotherapy target.
    Shengnan Jing, Liya Zhao, Liwen Zhao, Yong-Jing Gao, Tianzhen He.
      The tumor microenvironment (TME) facilitates tumor development through intricate intercellular signaling, thereby supporting tumor growth and suppressing the immune response. Thyroid hormone receptor interactor 13 (TRIP13), an AAA+ ATPase, modulates the conformation of client macromolecules, consequently influencing cellular signaling pathways. TRIP13 has been implicated in processes such as proliferation, invasion, migration, and metastasis during tumor progression. Recent studies have revealed that TRIP13 also plays a role in immune response suppression within the TME. Thus, inhibiting these functions of TRIP13 could potentially enhance immune responses and improve the efficacy of immune checkpoint inhibition. This review summarizes the recent research progress of TRIP13 and discusses the potential of targeting TRIP13 to improve immune-based therapies for patients with cancer.
    Keywords:  immune responses; immune‐based therapies; thyroid hormone receptor interactor 13; tumor microenvironment
    DOI:  https://doi.org/10.1002/cai2.147
  6. Front Immunol. 2024 ;15 1472772
    Advances in targeting tumor microenvironment for immunotherapy.
    Lugang Wang, Liubo Zhang, Zhen Zhang, Peng Wu, Yi Zhang, Xinfeng Chen.
      The tumor microenvironment (TME) provides essential conditions for the occurrence, invasion, and spread of cancer cells. Initial research has uncovered immunosuppressive properties of the TME, which include low oxygen levels (hypoxia), acidic conditions (low pH), increased interstitial pressure, heightened permeability of tumor vasculature, and an inflammatory microenvironment. The presence of various immunosuppressive components leads to immune evasion and affects immunotherapy efficacy. This indicates the potential value of targeting the TME in cancer immunotherapy. Therefore, TME remodeling has become an effective method for enhancing host immune responses against tumors. In this study, we elaborate on the characteristics and composition of the TME and how it weakens immune surveillance and summarize targeted therapeutic strategies for regulating the TME.
    Keywords:  cancer; immunosuppression; immunotherapy; targeted; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1472772
  7. Int Rev Cell Mol Biol. 2024 ;pii: S1937-6448(24)00103-5. [Epub ahead of print]389 67-103
    Tumor microenvironment induced switch to mitochondrial metabolism promotes suppressive functions in immune cells.
    Sanjay Pandey, Vandana Anang, Michelle M Schumacher.
      Understanding the intricacies of the metabolic phenotype in immune cells and its plasticity within the tumor microenvironment is pivotal in understanding the pathology and prognosis of cancer. Unfavorable conditions and cellular stress in the tumor microenvironment (TME) exert a profound impact on cellular functions in immune cells, thereby influencing both tumor progression and immune responses. Elevated AMP:ATP ratio, a consequence of limited glucose levels, activate AMP-activated protein kinase (AMPK) while concurrently repressing the activity of mechanistic target of rapamycin (mTOR) and hypoxia-inducible factor 1-alpha (HIF-1α). The intricate balance between AMPK, mTOR, and HIF-1α activities defines the metabolic phenotype of immune cells in the TME. These Changes in metabolic phenotype are strongly associated with immune cell functions and play a crucial role in creating a milieu conducive to tumor progression. Insufficiency of nutrient and oxygen supply leads to a metabolic shift in immune cells characterized by a decrease in glycolysis and an increase in oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) rates. In most cases, this shift in metabolism is accompanied by a compromise in the effector functions of these immune cells. This metabolic adaptation prompts immune cells to turn down their effector functions, entering a quiescent or immunosuppressive state that may support tumor growth. This article discusses how tumor microenvironment alters the metabolism in immune cells leading to their tolerance and tumor progression, with emphasis on mitochondrial metabolism (OXPHOS and FAO).
    Keywords:  AMPK; CAR-T; Fatty acid oxidation; Glycolysis; HIF1α; MTOR; Metabolism; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion; Mitochondrial metabolism; OXPHOS; T cell exhaustion; T cell metabolism
    DOI:  https://doi.org/10.1016/bs.ircmb.2024.07.003
  8. Front Immunol. 2024 ;15 1476565
    Mechanistic studies of tumor-associated macrophage immunotherapy.
    Jiandong Cao, Chengsen Liu.
      Tumor-associated macrophages (TAMs) are present in the tumor microenvironment and can polarize into subtypes with different functions and characteristics in response to different stimuli, classifying them into anti-tumorigenic M1-type and pro-tumorigenic M2-type. The M1-type macrophages inhibit tumor growth through the release of pro-inflammatory cytokines, whereas the M2-type macrophages contribute to tumor progression through the promotion of tumor proliferation, angiogenesis and metastasis. Due to the duality of macrophage effects on tumors, TAMs have been a hot topic in tumor research. In this paper, the heterogeneity and plasticity of TAMs, the interactions between TAMs and other immune cells, and the effects of TAMs on tumors are reviewed, and the therapeutic strategies for TAMs are summarized and discussed. These therapeutic strategies encompass methods and approaches to inhibit the recruitment of TAMs, deplete TAMs, and modulate the polarization of TAMs. These studies help to deeply understand the mechanism of TAMs-tumor interaction and provide reference for combination therapy of tumors.
    Keywords:  TAMs; cancer; immunotherapy; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fimmu.2024.1476565
  9. Biomed Pharmacother. 2024 Oct 17. pii: S0753-3322(24)01476-8. [Epub ahead of print]180 117590
    Targeted modulation of myeloid-derived suppressor cells in the tumor microenvironment: Implications for cancer therapy.
    Yafeng Qi, Liying Zhang, Yeyuan Liu, Yangyang Li, Yongqi Liu, Zhiming Zhang.
      Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature myeloid cells originating from the bone marrow, known for their potent immunosuppressive functions that contribute to tumor immune evasion and progression. This paper provides a comprehensive analysis of the multifaceted interactions between MDSCs and tumors, exploring their distinct phenotypes and immunosuppressive mechanisms. Key roles of MDSCs in tumor biology are discussed, including their involvement in the formation of the pre-metastatic niche, facilitation of angiogenesis, enhancement of vascular permeability, suppression of tumor cell apoptosis, and promotion of resistance to cancer therapies. Additionally, the review highlights recent advances in the development of MDSC-targeting therapies, with a focus on their potential to enhance anti-tumor immunity. The therapeutic potential of Traditional Chinese Medicine (TCM) in modulating MDSC quantity and function is also explored, suggesting a novel approach to cancer treatment by integrating traditional and modern therapeutic strategies.
    Keywords:  Immunosuppression; Myeloid-derived suppressor cells; Traditional Chinese medicine; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.biopha.2024.117590
  10. Pharmacol Res. 2024 Oct 11. pii: S1043-6618(24)00403-1. [Epub ahead of print]209 107458
    The role of Tim-3 blockade in the tumor immune microenvironment beyond T cells.
    Jie Zhang, Longsheng Wang, Hongjie Guo, Shijia Kong, Wen Li, Qiaojun He, Ling Ding, Bo Yang.
      Numerous preclinical studies have demonstrated the inhibitory function of T cell immunoglobulin mucin domain-containing protein 3 (Tim-3) on T cells as an inhibitory receptor, leading to the clinical development of anti-Tim-3 blocking antibodies. However, recent studies have shown that Tim-3 is expressed not only on T cells but also on multiple cell types in the tumor microenvironment (TME), including dendritic cells (DCs), natural killer (NK) cells, macrophages, and tumor cells. Therefore, Tim-3 blockade in the immune microenvironment not only affect the function of T cells but also influence the functions of other cells. For example, Tim-3 blockade can enhance the ability of DCs to regulate innate and adaptive immunity. The role of Tim-3 blockade in NK cells function is controversial, as it can enhance the antitumor function of NK cells under certain conditions while having the opposite effect in other situations. Additionally, Tim-3 blockade can promote the reversal of macrophage polarization from the M2 phenotype to the M1 phenotype. Furthermore, Tim-3 blockade can inhibit tumor development by suppressing the proliferation and metastasis of tumor cells. In summary, increasing evidence has shown that Tim-3 in other cell types also plays a critical role in the efficacy of anti-Tim-3 therapy. Understanding the function of anti-Tim-3 therapy in non-T cells can help elucidate the diverse responses observed in clinical patients, leading to better development of relevant therapeutic strategies. This review aims to discuss the role of Tim-3 in the TME and emphasize the impact of Tim-3 blockade in the tumor immune microenvironment beyond T cells.
    Keywords:  Anti-Tim-3 antibodies; Dendritic cells; Immunotherapy; Tim-3; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.phrs.2024.107458
  11. Cells. 2024 Oct 09. pii: 1666. [Epub ahead of print]13(19):
    Beyond Cancer Cells: How the Tumor Microenvironment Drives Cancer Progression.
    Hussein Sabit, Borros Arneth, Shaimaa Abdel-Ghany, Engy F Madyan, Ashraf H Ghaleb, Periasamy Selvaraj, Dong M Shin, Ramireddy Bommireddy, Ahmed Elhashash.
      Liver cancer represents a substantial global health challenge, contributing significantly to worldwide morbidity and mortality. It has long been understood that tumors are not composed solely of cancerous cells, but also include a variety of normal cells within their structure. These tumor-associated normal cells encompass vascular endothelial cells, fibroblasts, and various inflammatory cells, including neutrophils, monocytes, macrophages, mast cells, eosinophils, and lymphocytes. Additionally, tumor cells engage in complex interactions with stromal cells and elements of the extracellular matrix (ECM). Initially, the components of what is now known as the tumor microenvironment (TME) were thought to be passive bystanders in the processes of tumor proliferation and local invasion. However, recent research has significantly advanced our understanding of the TME's active role in tumor growth and metastasis. Tumor progression is now known to be driven by an intricate imbalance of positive and negative regulatory signals, primarily influenced by specific growth factors produced by both inflammatory and neoplastic cells. This review article explores the latest developments and future directions in understanding how the TME modulates liver cancer, with the aim of informing the design of novel therapies that target critical components of the TME.
    Keywords:  ECM; TME; immunotherapy; liver cancer; targeted therapy; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells13191666
  12. Am J Cancer Res. 2024 ;14(9): 4378-4397
    The Zeb1-Cxcl1 axis impairs the antitumor immune response by inducing M2 macrophage polarization in breast cancer.
    Yang Ou, Hui-Min Jiang, Yan-Jing Wang, Qiu-Ying Shuai, Li-Xia Cao, Min Guo, Chun-Chun Qi, Zhao-Xian Li, Jie Shi, Hua-Yu Hu, Yu-Xin Liu, Si-Yu Zuo, Xiao Chen, Meng-Dan Feng, Yi Shi, Pei-Qing Sun, Hang Wang, Shuang Yang.
      Zeb1, a key epithelial-mesenchymal transition (EMT) regulator, has recently been found to be involved in M2 macrophage polarization in the tumor immune microenvironment, thereby promoting tumor development. However, the underlying mechanism of Zeb1-induced M2 macrophage polarization remains largely unexplored. To identify the potential role of Zeb1 in remodeling the tumor immune microenvironment in breast cancer, we crossed the floxed Zeb1 allele homozygously into PyMT mice to generate PyMT;Zeb1cKO (MMTV-Cre;PyMT;Zeb1fl/fl ) mice. We found that the recruitment of M2-type tumor-associated macrophages (TAMs) was significantly reduced in tumors from PyMT;Zeb1cKO mice, and their tumor suppressive effects were weakened. Mechanistically, Zeb1 played a crucial role in transcriptionally promoting the production of Cxcl1 in tumor cells. In turn, Cxcl1 activated the Cxcr2-Jak-Stat3 pathway to induce M2 polarization of TAMs in a paracrine manner, which eventually led to T-cell inactivation and impaired the antitumor immune response in breast cancer. Our results collectively revealed an important role of Zeb1 in remodeling the tumor microenvironment, suggesting a novel therapeutic intervention for the treatment of advanced breast cancer.
    Keywords:  Breast cancer; Cxcl1; M2 macrophage polarization; Zeb1; antitumor immune response; tumor immune microenvironment
    DOI:  https://doi.org/10.62347/UAIS7070
  13. EMBO Rep. 2024 Oct 16.
    Circadian rhythms of macrophages are altered by the acidic tumor microenvironment.
    Amelia M Knudsen-Clark, Daniel Mwangi, Juliana Cazarin, Kristina Morris, Cameron Baker, Lauren M Hablitz, Matthew N McCall, Minsoo Kim, Brian J Altman.
      Tumor-associated macrophages (TAMs) are prime therapeutic targets due to their pro-tumorigenic functions, but varying efficacy of macrophage-targeting therapies highlights our incomplete understanding of how macrophages are regulated within the tumor microenvironment (TME). The circadian clock is a key regulator of macrophage function, but how circadian rhythms of macrophages are influenced by the TME remains unknown. Here, we show that conditions associated with the TME such as polarizing stimuli, acidic pH, and lactate can alter circadian rhythms in macrophages. While cyclic AMP (cAMP) has been reported to play a role in macrophage response to acidic pH, our results indicate pH-driven changes in circadian rhythms are not mediated solely by cAMP signaling. Remarkably, circadian disorder of TAMs was revealed by clock correlation distance analysis. Our data suggest that heterogeneity in circadian rhythms within the TAM population level may underlie this circadian disorder. Finally, we report that circadian regulation of macrophages suppresses tumor growth in a murine model of pancreatic cancer. Our work demonstrates a novel mechanism by which the TME influences macrophage biology through modulation of circadian rhythms.
    Keywords:  Circadian Rhythms; Immuno-oncology; Immunology; Macrophage; Tumor Microenvironment
    DOI:  https://doi.org/10.1038/s44319-024-00288-2
  14. Cell Mol Immunol. 2024 Oct 14.
    Regulation of CD8+ T cells by lipid metabolism in cancer progression.
    Yong Tang, Ziqing Chen, Qianying Zuo, Yibin Kang.
      Dysregulation of lipid metabolism is a key characteristic of the tumor microenvironment, where tumor cells utilize lipids for proliferation, survival, metastasis, and evasion of immune surveillance. Lipid metabolism has become a critical regulator of CD8+ T-cell-mediated antitumor immunity, with excess lipids in the tumor microenvironment impeding CD8+ T-cell activities. Considering the limited efficacy of immunotherapy in many solid tumors, targeting lipid metabolism to enhance CD8+ T-cell effector functions could significantly improve immunotherapy outcomes. In this review, we examine recent findings on how lipid metabolic processes, including lipid uptake, synthesis, and oxidation, regulate CD8+ T cells within tumors. We also assessed the impact of different lipids on CD8+ T-cell-mediated antitumor immunity, with a particular focus on how lipid metabolism affects mitochondrial function in tumor-infiltrating CD8+ T cells. Furthermore, as cancer is a systemic disease, we examined systemic factors linking lipid metabolism to CD8+ T-cell effector function. Finally, we summarize current therapeutic approaches that target lipid metabolism to increase antitumor immunity and enhance immunotherapy. Understanding the molecular and functional interplay between lipid metabolism and CD8+ T cells offers promising therapeutic opportunities for cancer treatment.
    Keywords:  CD8+T cells; Immunotherapy; Lipid metabolism; Mitochondria; Oxidative phosphorylation
    DOI:  https://doi.org/10.1038/s41423-024-01224-z
  15. Int J Mol Sci. 2024 Oct 07. pii: 10781. [Epub ahead of print]25(19):
    Macrophages: Key Players in the Battle against Triple-Negative Breast Cancer.
    Irena Padzińska-Pruszyńska, Paulina Kucharzewska, Agata Matejuk, Małgorzata Górczak, Małgorzata Kubiak, Bartłomiej Taciak, Magdalena Król.
      Triple-negative breast cancer (TNBC) is a challenging subtype of breast cancer characterized by the absence of estrogen and progesterone receptors and HER2 expression, leading to limited treatment options and a poorer prognosis. TNBC is particularly prevalent in premenopausal African-descent women and is associated with aggressive tumor behavior and higher metastatic potential. Tumor-associated macrophages (TAMs) are abundantly present within the TNBC microenvironment and play pivotal roles in promoting tumor growth, progression, and metastasis through various mechanisms, including immune suppression and enhancement of angiogenesis. This review provides an in-depth overview of TNBC, focusing on its epidemiology, its molecular characteristics, and the critical influence of TAMs. It discusses the pathological and molecular aspects that define TNBC's aggressive nature and reviews current and emerging therapeutic strategies aimed at targeting these dynamics. Special attention is given to the role of TAMs, exploring their potential as therapeutic targets due to their significant impact on tumor behavior and patient outcomes. This review aims to highlight the complexities of the TNBC landscape and to present the innovative approaches that are currently being pursued to improve therapeutic efficacy and patient survival.
    Keywords:  targeted therapy; triple-negative breast cancer; tumor-associated macrophages
    DOI:  https://doi.org/10.3390/ijms251910781
  16. Sci Rep. 2024 10 16. 14(1): 24230
    Dynamic reciprocal interactions between activated T cells and tumor associated macrophages drive macrophage reprogramming and proinflammatory T cell migration within prostate tumor models.
    Erika Heninger, Matthew Thomas Breneman, Emma Elizabeth Recchia, Sheena Catherine Kerr, Reyna Elvan Dogru, Marina Nasrin Sharifi, Aaron Matthew LeBeau, David Kosoff.
      Tumor-associated macrophages (TAMs) have been implicated as a tumor microenvironment (TME) cell population, which may be playing a vital role in the inhibition of effective T cell responses in the prostate TME. In this manuscript, we leverage a novel microscale cell culture platform, known as Stacks, to investigate mono-, co-, and tri-culture TME models comprised of prostate tumor cell lines, primary macrophages, and autologous T cells from patients with prostate cancer. Through multiplexed analysis of these multi-cellular prostate tumor models, we capture a dynamic interaction between primary TAMs and activated T cells that resulted in reciprocal proinflammatory activation of both cell populations upon interaction. These findings suggest that activated T cells are capable of reprogramming immunosuppressive TAMs in the context of prostate tumor models and that TAM reprogramming may play a key supportive role in restoring proinflammatory T cell tumor responses in the prostate TME.
    Keywords:  Co-culture; Macrophage; T cells; TAM; Tumor microenvironment
    DOI:  https://doi.org/10.1038/s41598-024-75265-9
  17. Oncogene. 2024 Oct 16.
    Mesenchymal stromal cells as cancer promoters.
    Roula Antoon, Nina Overdevest, Amr H Saleh, Armand Keating.
      Mesenchymal stromal cells (MSCs) are important cellular constituents of tumor stroma that play an active role in tumor development. Complex interactions between MSCs and cancer promote tumor progression by creating a favorable milieu for tumor cell proliferation, angiogenesis, motility, invasion, and metastasis. The cellular heterogeneity, source of origin, diversity in isolation methods, culture techniques and model systems of MSCs, together with the different tumor subtypes, add to the complexity of MSC-tumor interactions. In this review, we discuss the mechanisms of MSC-mediated tumor promotion and evaluate cell-stromal interactions between cancer cells, MSCs, cells of the tumor microenvironment (TME), and the extracellular matrix (ECM). A more thorough understanding of tumor-MSC interactions is likely to lead to better cancer management.
    DOI:  https://doi.org/10.1038/s41388-024-03183-1
  18. Exp Hematol Oncol. 2024 Oct 16. 13(1): 101
    Natural killer cell-based cancer immunotherapy: from basics to clinical trials.
    Yinghong Shi, Donglin Hao, Hui Qian, Zhimin Tao.
      Cellular immunotherapy exploits the capacity of the human immune system in self-protection and surveillance to achieve the anti-tumor effects. Natural killer (NK) cells are lymphocytes of innate immune system and they display a unique inherent ability to identify and eliminate tumor cells. In this review, we first introduce the basic characteristics of NK cells in the physiological and pathological milieus, followed by a discussion of their effector function and immunosuppression in the tumor microenvironment. Clinical strategies and reports regarding NK cellular therapy are analyzed in the context of tumor treatment, especially against solid tumors. Given the widely studied T-cell therapy in the recent years, particularly the chimeric antigen receptor (CAR) T-cell therapy, we compare the technical features of NK- and T-cell based tumor therapies at the clinical front. Finally, the technical challenges and potential solutions for both T and NK cell-based immunotherapies in treating tumor malignancies are delineated. By overviewing its clinical applications, we envision the NK-cell based immunotherapy as an up-and-comer in cancer therapeutics.
    Keywords:  Chimeric antigen receptor; Clinical trial; Immunotherapy; Natural killer cells; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s40164-024-00561-z
  19. Epigenomics. 2024 Oct 10. 1-4
    Exploring the role of EZH2 modulation in shaping the tumor microenvironment.
    Irene Fischetti, Michele De Luca, Elena Jachetti.
      
    Keywords:  EZH2 inhibitors; cancer therapy; epigenetic modulation; immune system; tumor microenvironment
    DOI:  https://doi.org/10.1080/17501911.2024.2410693
  20. Biochim Biophys Acta Rev Cancer. 2024 Oct 15. pii: S0304-419X(24)00129-X. [Epub ahead of print]1879(6): 189198
    The key role of matrix stiffness in colorectal cancer immunotherapy: mechanisms and therapeutic strategies.
    Engeng Chen, Zhiru Zeng, Wei Zhou.
      Increased matrix stiffness within the colorectal cancer (CRC) tumor microenvironment (TME) has emerged as a pivotal determinant of immunotherapy outcomes. This review discusses the role of aberrant extracellular matrix (ECM) deposition and cross-linking in augmenting matrix stiffness, a phenomenon that not only scaffolds the tumor architecture but also contributes to tumorigenicity and immunologic evasion. Herein, we critically appraise the influence of matrix stiffness on the immunotherapeutic landscape of CRC, focusing on its capacity to impede therapeutic efficacy by modulating immune cell infiltration, activation, and functional performance. The review explores the molecular dynamics whereby matrix stiffness prompts tumor evolution, highlighting the integral role of integrin signaling, cancer-associated fibroblasts (CAFs), and the process of epithelial-mesenchymal transition (EMT). We bring to the fore the paradoxical impact of an indurated ECM on immune effector cells, chiefly T cells and macrophages, which are indispensable for immune surveillance and the execution of immunotherapeutic strategies, yet are markedly restrained by a fibrotic matrix. Furthermore, we examine how matrix stiffness modulates immune checkpoint molecule expression, thereby exacerbating the immunosuppressive milieu within the TME and attenuating immunotherapeutic potency. Emergent therapeutic regimens targeting matrix stiffness-including matrix modulators, inhibitors of mechanotransduction signaling pathways, and advanced biomaterials that mimic the ECM-proffer novel modalities to potentiate immunotherapy responsiveness. By refining the ECM's biomechanical attributes, the mechanical barriers posed by the tumor stroma can be improved, facilitating robust immune cell penetration and activity, and thereby bolstering the tumor's susceptibility to immunotherapy. Ongoing clinical trials are evaluating these innovative treatments, particularly in combination with immunotherapies, with the aim of enhancing clinical outcomes for CRC patients afflicted by pronounced matrix stiffness.
    Keywords:  Colorectal cancer immunotherapy; Matrix stiffness; Therapeutic strategies
    DOI:  https://doi.org/10.1016/j.bbcan.2024.189198
  21. Commun Biol. 2024 Oct 17. 7(1): 1343
    Hippo pathway in cancer cells induces NCAM1+αSMA+ fibroblasts to modulate tumor microenvironment.
    Chanida Thinyakul, Yasuhisa Sakamoto, Mayuko Shimoda, Yanliang Liu, Suyanee Thongchot, Omnia Reda, Akihiro Nita, Romgase Sakamula, Somponnat Sampattavanich, Ayato Maeda, Paweenapon Chunthaboon, David Nduru, Mayumi Niimura, Yohei Kanamori, Peti Thuwajit, Keiichi I Nakayama, Kun-Liang Guan, Yorifumi Satou, Chanitra Thuwajit, Toshiro Moroishi.
      Cancer cells adeptly manipulate the tumor microenvironment (TME) to evade host antitumor immunity. However, the role of cancer cell-intrinsic signaling in shaping the immunosuppressive TME remains unclear. Here, we found that the Hippo pathway in cancer cells orchestrates the TME by influencing the composition of cancer-associated fibroblasts (CAFs). In a 4T1 mouse breast cancer model, Hippo pathway kinases, large tumor suppressor 1 and 2 (LATS1/2), promoted the formation of neural cell adhesion molecule 1 (NCAM1)+alpha-smooth muscle actin (αSMA)+ CAFs expressing the transforming growth factor-β, which is associated with T cell inactivation and dysfunction. Depletion of LATS1/2 in cancer cells resulted in a less immunosuppressive TME, indicated by the reduced proportions of NCAM1+αSMA+ CAFs and dysfunctional T cells. Notably, similar Hippo pathway-induced NCAM1+αSMA+ CAFs were observed in human breast cancer, highlighting the potential of TME-manipulating strategies to reduce immunosuppression in cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s42003-024-07041-4
  22. Biomater Adv. 2024 Oct 09. pii: S2772-9508(24)00304-2. [Epub ahead of print]166 214061
    Substrate stiffness-dependent activation of Hippo pathway in cancer associated fibroblasts.
    Gerard Rubí-Sans, Agata Nyga, Miguel A Mateos-Timoneda, Elisabeth Engel.
      The tumor microenvironment (TME) comprises a heterogenous cell population within a complex three-dimensional (3D) extracellular matrix (ECM). Stromal cells within this TME are altered by signaling cues from cancer cells to support uncontrolled tumor growth and invasion events. Moreover, the ECM also plays a fundamental role in tumor development through pathological remodeling, stiffening and interaction with TME cells. In healthy tissues, Hippo signaling pathway actively contributes to tissue growth, cell proliferation and apoptosis. However, in cancer, the Hippo signaling pathway is highly dysregulated, leading to nuclear translocation of the YAP/TAZ complex, which directly contributes to uncontrolled cell proliferation and tissue growth, and ECM remodeling and stiffening processes. Here, we compare the effect of increasing cell culture substrate stiffness, derived from tumor progression, upon the dysregulation of the Hippo signaling pathway in colorectal cancer-associated fibroblasts (CAFs) and normal colorectal fibroblasts (NFs). We correlate the dysregulation of Hippo pathway with the magnitude of the traction forces exerted by healthy and malignant stromal cells. We found that ECM stiffening is crucial in Hippo pathway dysregulation in CAFs, but not in normal fibroblasts.
    Keywords:  Cancer-associated fibroblasts; Hippo pathway; Tumor microenvironment; YAP-TAZ
    DOI:  https://doi.org/10.1016/j.bioadv.2024.214061
  23. bioRxiv. 2024 Oct 12. pii: 2024.10.11.617879. [Epub ahead of print]
    Reshaping the tumor microenvironment by degrading glycoimmune checkpoints Siglec-7 and -9.
    Chao Wang, Yingqin Hou, Jaroslav Zak, Qinheng Zheng, Kelli A McCord, Mengyao Wu, Ding Zhang, Shereen Chung, Yujie Shi, Jinfeng Ye, Yunlong Zhao, Stephanie Hajjar, Ian A Wilson, James C Paulson, John R Teijaro, Xu Zhou, K Barry Sharpless, Matthew S Macauley, Peng Wu.
      Cancer treatment has been rapidly transformed by the development of immune checkpoint inhibitors targeting CTLA-4 and PD-1/PD-L1. However, many patients fail to respond, especially those with an immunosuppressive tumor microenvironment (TME), suggesting the existence of additional immune checkpoints that act through orthogonal mechanisms. Sialic acid-binding immunoglobulin-like lectin (Siglec)-7 and -9 are newly designated glycoimmune checkpoints that are abundantly expressed by tumor-infiltrating myeloid cells. We discovered that T cells express only basal levels of Siglec transcripts; instead, they acquire Siglec-7 and -9 from interacting myeloid cells in the TME via trogocytosis, which impairs their activation and effector function. Mechanistically, Siglec-7 and -9 suppress T cell activity by dephosphorylating T cell receptor (TCR)-related signaling cascades. Using sulfur fluoride exchange (SuFEx) click chemistry, we developed a ligand that binds to Siglec-7 and -9 with high-affinity and exclusive specificity. Using this ligand, we constructed a Siglec-7/9 degrader that targets membrane Siglec-7 and -9 to the lysosome for degradation. Administration of this degrader induced efficient Siglec degradation in both T cells and myeloid cells in the TME. We found that Siglec-7/9 degradation has a negligible effect on macrophage phagocytosis, but significantly enhances T cell anti-tumor immunity. The degrader, particularly when combined with anti-CTLA-4, enhanced macrophage antigen presentation, reshaped the TME, and resulted in long-lasting T cell memory and excellent tumor control in multiple murine tumor models. These findings underscore the need to consider exogenous checkpoints acquired by T cells in the TME when selecting specific checkpoint blockade therapy to enhance T cell immunity.
    DOI:  https://doi.org/10.1101/2024.10.11.617879
  24. Nat Commun. 2024 Oct 15. 15(1): 8895
    Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer.
    Bilal Unal, Omer Faruk Kuzu, Yang Jin, Daniel Osorio, Wanja Kildal, Manohar Pradhan, Sonia H Y Kung, Htoo Zarni Oo, Mads Daugaard, Mikkel Vendelbo, John B Patterson, Martin Kristian Thomsen, Marieke Lydia Kuijjer, Fahri Saatcioglu.
      Unfolded protein response (UPR) is a central stress response pathway that is hijacked by tumor cells for their survival. Here, we find that IRE1α signaling, one of the canonical UPR arms, is increased in prostate cancer (PCa) patient tumors. Genetic or small molecule inhibition of IRE1α in syngeneic mouse PCa models and an orthotopic model decreases tumor growth. IRE1α ablation in cancer cells potentiates interferon responses and activates immune system related pathways in the tumor microenvironment (TME). Single-cell RNA-sequencing analysis reveals that targeting IRE1α in cancer cells reduces tumor-associated macrophage abundance. Consistently, the small molecule IRE1α inhibitor MKC8866, currently in clinical trials, reprograms the TME and enhances anti-PD-1 therapy. Our findings show that IRE1α signaling not only promotes cancer cell growth and survival but also interferes with anti-tumor immunity in the TME. Thus, targeting IRE1α can be a promising approach for improving anti-PD-1 immunotherapy in PCa.
    DOI:  https://doi.org/10.1038/s41467-024-53039-1
  25. Stem Cells Transl Med. 2024 Oct 10. pii: szae077. [Epub ahead of print]
    The crosstalk between primary MSCs and cancer cells in 2D and 3D cultures: potential therapeutic strategies and impact on drug resistance.
    Ayesha Rehman, Sameer Kumar Panda, Martina Torsiello, Martina Marigliano, Camilla Carmela Tufano, Aditya Nigam, Zahida Parveen, Gianpaolo Papaccio, Marcella La Noce.
      The tumor microenvironment (TME) significantly influences cancer progression, and mesenchymal stem cells (MSCs) play a crucial role in interacting with tumor cells via paracrine signaling, affecting behaviors such as proliferation, migration, and epithelial-mesenchymal transition. While conventional 2D culture models have provided valuable insights, they cannot fully replicate the complexity and diversity of the TME. Therefore, developing 3D culture systems that better mimic in vivo conditions is essential. This review delves into the heterogeneous nature of the TME, spotlighting MSC-tumor cellular signaling and advancements in 3D culture technologies. Utilizing MSCs in cancer therapy presents opportunities to enhance treatment effectiveness and overcome resistance mechanisms. Understanding MSC interactions within the TME and leveraging 3D culture models can advance novel cancer therapies and improve clinical outcomes. Additionally, this review underscores the therapeutic potential of engineered MSCs, emphasizing their role in targeted anti-cancer treatments.
    Keywords:  MSCs; adipose stem cells; cancer stem cells; microenvironment; stem cell-microenvironment interaction
    DOI:  https://doi.org/10.1093/stcltm/szae077
  26. Int J Mol Sci. 2024 Sep 29. pii: 10486. [Epub ahead of print]25(19):
    The MCIB Model: A Novel Theory for Describing the Spatial Heterogeneity of the Tumor Microenvironment.
    Minghao Guo, Yinan Sun, Xiaohui Wang, Zikun Wang, Xun Yuan, Xinyi Chen, Xianglin Yuan, Lu Wang.
      The tumor microenvironment (TME) can be regarded as a complex and dynamic microecosystem generated by the interactions of tumor cells, interstitial cells, the extracellular matrix, and their products and plays an important role in the occurrence, progression and metastasis of tumors. In a previous study, we constructed an IEO model (prI-, prE-, and pOst-metastatic niche) according to the chronological sequence of TME development. In this paper, to fill the theoretical gap in spatial heterogeneity in the TME, we defined an MCIB model (Metabolic, Circulatory, Immune, and microBial microenvironment). The MCIB model divides the TME into four subtypes that interact with each other in terms of mechanism, corresponding to the four major links of metabolic reprogramming, vascular remodeling, immune response, and microbial action, providing a new way to assess the TME. The combination of the MCIB model and IEO model comprehensively depicts the spatiotemporal evolution of the TME and can provide a theoretical basis for the combination of clinical targeted therapy, immunotherapy, and other comprehensive treatment modalities for tumors according to the combination and crosstalk of different subtypes in the MCIB model and provide a powerful research paradigm for tumor drug-resistance mechanisms and tumor biological behavior.
    Keywords:  MCIB model; TME; spatial heterogeneity; tumor targeted therapy
    DOI:  https://doi.org/10.3390/ijms251910486
  27. Am J Cancer Res. 2024 ;14(9): 4236-4247
    Impact of opioids and mu-opioid receptors on oncologic metastasis.
    Runjia Wang, Shuai Li, Bomin Wang, Gongming Wang, Hui Zheng.
      Opioids are the most effective and widely used treatments for acute and chronic pain in patients with cancer. This review focuses on the impact of opioids and mu-opioid receptors (MORs) on the stages of oncologic metastasis. Studies have shown that opioids can facilitate tumor progression and are related to a poor prognosis in patients with cancer. As the primary receptor for opioids, MORs play a significant role in regulating malignant tumor transformation and are involved in processes, such as proliferation, angiogenesis, epithelial-mesenchymal transition (EMT), circulating tumor cells (CTCs) and the tumor microenvironment (TME). While clinical trials have investigated the relationship between opioids and patient prognosis, further research is needed to clarify the relationship between opioids, MORs and metastasis.
    Keywords:  Opioids; cancer; metastasis; mu-opioid receptor
    DOI:  https://doi.org/10.62347/SCLS3277
  28. Life Sci Alliance. 2025 Jan;pii: e202403053. [Epub ahead of print]8(1):
    Direct visualization of emergent metastatic features within an ex vivo model of the tumor microenvironment.
    Libi Anandi, Jeremy Garcia, Manon Ros, Libuše Janská, Josephine Liu, Carlos Carmona-Fontaine.
      Ischemic conditions such as hypoxia and nutrient starvation, together with interactions with stromal cells, are critical drivers of metastasis. These conditions arise deep within tumor tissues, and thus, observing nascent metastases is exceedingly challenging. We thus developed the 3MIC-an ex vivo model of the tumor microenvironment-to study the emergence of metastatic features in tumor cells in a 3-dimensional (3D) context. Here, tumor cells spontaneously create ischemic-like conditions, allowing us to study how tumor spheroids migrate, invade, and interact with stromal cells under different metabolic conditions. Consistent with previous data, we show that ischemia increases cell migration and invasion, but the 3MIC allowed us to directly observe and perturb cells while they acquire these pro-metastatic features. Interestingly, our results indicate that medium acidification is one of the strongest pro-metastatic cues and also illustrate using the 3MIC to test anti-metastatic drugs on cells experiencing different metabolic conditions. Overall, the 3MIC can help dissecting the complexity of the tumor microenvironment for the direct observation and perturbation of tumor cells during the early metastatic process.
    DOI:  https://doi.org/10.26508/lsa.202403053
  29. Int J Biol Macromol. 2024 Oct 14. pii: S0141-8130(24)07293-3. [Epub ahead of print] 136484
    The pH-sensitive chondroitin sulphate-based nanoparticles for co-delivery of doxorubicin and berberine enhance the treatment of breast cancer.
    Jingliang Wu, Yanying Li, Shujie Sun, Wenjun Li, Jingui Sun, Liping Zhu, Zhiqiang Wang, Fan Yang, Qing Wang, Huajie Ding, Xueying Ding, Zhentao Guo.
      In the tumor microenvironment (TME), cancer associated fibroblasts (CAFs) facilitate drug resistance and tumor metastasis. Therefore, more and more attention has been focused on the regulation of TME by preventing the cross-talk between tumor cells and CAFs in the treatment of breast cancer. In this study, we have combined the benefits of deep drug penetration, pH sensitivity, and tumor-targeting delivery to prepare chondroitin sulphate (CS)-based nanomicelles (BBR/CS-DOX) for the co-delivery of doxorubicin (DOX) and berberine (BBR). A unique MCF-7 + MRC-5 co-cultured cell model and 4 T1 + NIH3T3 co-implanted mice model, were established to simulate the TME of breast cancer (BC). As expected, BBR/CS-DOX could accumulate in tumor egion, be taken up by both tumor cells and CAFs, and improve drug absorption and retention. Compared with free drugs, BBR/CS-DOX demonstrated stonger pro-apoptotic and anti-metastatic effect in vitro and in vivo, respectively the histological studies showed that BBR/CS-DOX efficiently prevented the activation of fibroblasts, inhibited extracellular matrix (ECM) deposition, and decreased tumor angiogenesis, showing superior anti-tumor efficacy. In summary, BBR/CS-DOX has the potential to significantly enhance the therapeutic effect of breast cancer through inhibiting the "CAFs-tumor cells" crosstalk, and has promising clinical application prospects.
    Keywords:  Breast cancer; Combination therapy; Nanomicelle; cancer associated fibroblasts
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.136484
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