bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024–09–01
27 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Cracking the Codes behind Cancer Cells' Immune Evasion.
  2. Multifaceted metabolic role of infections in the tumor microenvironment.
  3. Reprogramming the immunosuppressive tumor microenvironment through nanomedicine: an immunometabolism perspective.
  4. Reshaping the tumor immune microenvironment to improve CAR-T cell-based cancer immunotherapy.
  5. MiRNAs as Regulators of Immune Cells in the Tumor Microenvironment of Ovarian Cancer.
  6. Precision Targeting Strategies in Pancreatic Cancer: The Role of Tumor Microenvironment.
  7. Unveiling the Dynamic Interplay between Cancer Stem Cells and the Tumor Microenvironment in Melanoma: Implications for Novel Therapeutic Strategies.
  8. Natural Killer cells at the frontline in the fight against cancer.
  9. The role of metabolic reprogramming in immune escape of triple-negative breast cancer.
  10. Metabolic and Aging Influence on Anticancer Immunity in Oral Cancer.
  11. Master regulator: p53's pivotal role in steering NK-cell tumor patrol.
  12. Focus on Pancreatic Cancer Microenvironment.
  13. Immunometabolism of ferroptosis in the tumor microenvironment.
  14. Tumour's Digest: Macrophage metabolism creates a barrier to T cells.
  15. Intratumoral Microbiota: Metabolic Influences and Biomarker Potential in Gastrointestinal Cancer.
  16. The complex role of macrophages in pancreatic cancer tumor microenvironment: a review on cancer progression and potential therapeutic targets.
  17. Role of Autophagy and AMPK in Cancer Stem Cells: Therapeutic Opportunities and Obstacles in Cancer.
  18. Tissue- and Temporal-Dependent Dynamics of Myeloablation in Response to Gemcitabine Chemotherapy.
  19. Chemotherapy-mediated lncRNA-induced immune cell plasticity in cancer immunopathogenesis.
  20. Mannan-Decorated Lipid Calcium Phosphate Nanoparticle Vaccine Increased the Antitumor Immune Response by Modulating the Tumor Microenvironment.
  21. Cancer Stem Cell markers: Symphonic masters of chemoresistance and immune evasion.
  22. Role of MicroRNA-204 in Regulating the Hallmarks of Breast Cancer: An Update.
  23. The role of cancer-associated fibroblasts and exosomal miRNAs-mediated intercellular communication in the tumor microenvironment and the biology of carcinogenesis: a systematic review.
  24. Dysregulation of Transposon Transcription Profiles in Cancer Cells Resembles That of Embryonic Stem Cells.
  25. Biomarkers Identification in the Microenvironment of Oral Squamous Cell Carcinoma: A Systematic Review of Proteomic Studies.
  26. Differential Regulation of Wingless-Wnt/c-Jun N-Terminal Kinase Crosstalk via Oxidative Eustress in Primary and Metastatic Colorectal Cancer Cells.
  27. LncRNA HAGLROS promotes breast cancer evolution through miR-135b-3p/COL10A1 axis and exosome-mediated macrophage M2 polarization.
  1. Int J Mol Sci. 2024 Aug 15. pii: 8899. [Epub ahead of print]25(16):
    Cracking the Codes behind Cancer Cells' Immune Evasion.
    Nikita Mundhara, Pritam Sadhukhan.
      Immune evasion is a key phenomenon in understanding tumor recurrence, metastasis, and other critical steps in tumor progression. The tumor microenvironment (TME) is in constant flux due to the tumor's ability to release signals that affect it, while immune cells within it can impact cancer cell behavior. Cancer cells undergo several changes, which can change the enrichment of different immune cells and modulate the activity of existing immune cells in the tumor microenvironment. Cancer cells can evade immune surveillance by downregulating antigen presentation or expressing immune checkpoint molecules. High levels of tumor-infiltrating lymphocytes (TILs) correlate with better outcomes, and robust immune responses can control tumor growth. On the contrary, increased enrichment of Tregs, myeloid-derived suppressor cells, and M2-like anti-inflammatory macrophages can hinder effective immune surveillance and predict poor prognosis. Overall, understanding these immune evasion mechanisms guides therapeutic strategies. Researchers aim to modulate the TME to enhance immune surveillance and improve patient outcomes. In this review article, we strive to summarize the composition of the tumor immune microenvironment, factors affecting the tumor immune microenvironment (TIME), and different therapeutic modalities targeting the immune cells. This review is a first-hand reference to understand the basics of immune surveillance and immune evasion.
    Keywords:  cancer biology; cancer immunology; immune evasion; immunotherapy; targeted therapy
    DOI:  https://doi.org/10.3390/ijms25168899
  2. Curr Opin Biotechnol. 2024 Aug 27. pii: S0958-1669(24)00119-8. [Epub ahead of print]89 103183
    Multifaceted metabolic role of infections in the tumor microenvironment.
    Hanna F Willenbockel, Birte Dowerg, Thekla Cordes.
      The impact of bacteria and viruses on tumor growth has long been recognized. In recent decades, interest in the role of microorganisms in the tumor microenvironment (TME) has expanded. Infections induce metabolic reprogramming and influence immune responses within the TME that may either support proliferation and metastasis or limit tumor growth. The natural ability to infect cells and alter the TME is also utilized for cancer detection and treatment. In this review, we discuss recent discoveries about the mechanisms of bacteria and viruses affecting TME, as well as strategies in cancer therapy focusing on metabolic alterations. Infections with engineered bacteria and viruses represent promising therapeutic approaches to develop novel and more effective therapies to constrain tumor growth.
    DOI:  https://doi.org/10.1016/j.copbio.2024.103183
  3. EBioMedicine. 2024 Aug 22. pii: S2352-3964(24)00337-2. [Epub ahead of print]107 105301
    Reprogramming the immunosuppressive tumor microenvironment through nanomedicine: an immunometabolism perspective.
    Jieyu Liu, Yinan Bai, Yinggang Li, Xiaoling Li, Kui Luo.
      Increasing evidence indicates that immunotherapy is hindered by a hostile tumor microenvironment (TME) featured with deprivation of critical nutrients and pooling of immunosuppressive metabolites. Tumor cells and immunosuppressive cells outcompete immune effector cells for essential nutrients. Meanwhile, a wide range of tumor cell-derived toxic metabolites exerts negative impacts on anti-tumor immune response, diminishing the efficacy of immunotherapy. Nanomedicine with excellent targetability offers a novel approach to improving cancer immunotherapy via metabolically reprogramming the immunosuppressive TME. Herein, we review recent strategies of enhancing immunotherapeutic effects through rewiring tumor metabolism via nanomedicine. Attention is drawn on immunometabolic tactics for immune cells and stromal cells in the TME via nanomedicine. Additionally, we discuss future directions of developing metabolism-regulating nanomedicine for precise and efficacious cancer immunotherapy.
    Keywords:  Anti-tumor immunity; Immunometabolism; Metabolic reprogramming; Nanomedicine; Tumor immune microenvironment
    DOI:  https://doi.org/10.1016/j.ebiom.2024.105301
  4. Mol Cancer. 2024 Aug 26. 23(1): 175
    Reshaping the tumor immune microenvironment to improve CAR-T cell-based cancer immunotherapy.
    Xueting Xia, Zongxin Yang, Qisi Lu, Zhenyun Liu, Lei Wang, Jinwen Du, Yuhua Li, Dong-Hua Yang, Shaojie Wu.
      In many hematologic malignancies, the adoptive transfer of chimeric antigen receptor (CAR) T cells has demonstrated notable success; nevertheless, further improvements are necessary to optimize treatment efficacy. Current CAR-T therapies are particularly discouraging for solid tumor treatment. The immunosuppressive microenvironment of tumors affects CAR-T cells, limiting the treatment's effectiveness and safety. Therefore, enhancing CAR-T cell infiltration capacity and resolving the immunosuppressive responses within the tumor microenvironment could boost the anti-tumor effect. Specific strategies include structurally altering CAR-T cells combined with targeted therapy, radiotherapy, or chemotherapy. Overall, monitoring the tumor microenvironment and the status of CAR-T cells is beneficial in further investigating the viability of such strategies and advancing CAR-T cell therapy.
    Keywords:  CAR-T; Solid tumor; Tumor immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12943-024-02079-8
  5. Cells. 2024 Aug 13. pii: 1343. [Epub ahead of print]13(16):
    MiRNAs as Regulators of Immune Cells in the Tumor Microenvironment of Ovarian Cancer.
    Miłosz Wilczyński, Jacek Wilczyński, Marek Nowak.
      Ovarian cancer is one of the leading causes of cancer deaths among women. There is an ongoing need to develop new biomarkers and targeted therapies to improve patient outcomes. One of the most critical research areas in ovarian cancer is identifying tumor microenvironment (TME) functions. TME consists of tumor-infiltrating immune cells, matrix, endothelial cells, pericytes, fibroblasts, and other stromal cells. Tumor invasion and growth depend on the multifactorial crosstalk between tumor cells and immune cells belonging to the TME. MiRNAs, which belong to non-coding RNAs that post-transcriptionally control the expression of target genes, regulate immune responses within the TME, shaping the landscape of the intrinsic environment of tumor cells. Aberrant expression of miRNAs may lead to the pathological dysfunction of signaling pathways or cancer cell-regulatory factors. Cell-to-cell communication between infiltrating immune cells and the tumor may depend on exosomes containing multiple miRNAs. MiRNAs may exert both immunosuppressive and immunoreactive responses, which may cause cancer cell elimination or survival. In this review, we highlighted recent advances in the field of miRNAs shaping the landscape of immune cells in the TME.
    Keywords:  miRNAs; ovarian cancer; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells13161343
  6. Cancers (Basel). 2024 Aug 19. pii: 2876. [Epub ahead of print]16(16):
    Precision Targeting Strategies in Pancreatic Cancer: The Role of Tumor Microenvironment.
    Nikolaos Vitorakis, Antonios N Gargalionis, Kostas A Papavassiliou, Christos Adamopoulos, Athanasios G Papavassiliou.
      Pancreatic cancer demonstrates an ever-increasing incidence over the last years and represents one of the top causes of cancer-associated mortality. Cells of the tumor microenvironment (TME) interact with cancer cells in pancreatic ductal adenocarcinoma (PDAC) tumors to preserve cancer cells' metabolism, inhibit drug delivery, enhance immune suppression mechanisms and finally develop resistance to chemotherapy and immunotherapy. New strategies target TME genetic alterations and specific pathways in cell populations of the TME. Complex molecular interactions develop between PDAC cells and TME cell populations including cancer-associated fibroblasts, myeloid-derived suppressor cells, pancreatic stellate cells, tumor-associated macrophages, tumor-associated neutrophils, and regulatory T cells. In the present review, we aim to fully explore the molecular landscape of the pancreatic cancer TME cell populations and discuss current TME targeting strategies to provide thoughts for further research and preclinical testing.
    Keywords:  cancer-associated fibroblasts (CAFs); immunotherapy; myeloid-derived suppressor cells (MDSCs); pancreatic cancer; pancreatic ductal adenocarcinoma (PDAC); tumor microenvironment (TME); tumor-associated macrophages (TAMs)
    DOI:  https://doi.org/10.3390/cancers16162876
  7. Cancers (Basel). 2024 Aug 16. pii: 2861. [Epub ahead of print]16(16):
    Unveiling the Dynamic Interplay between Cancer Stem Cells and the Tumor Microenvironment in Melanoma: Implications for Novel Therapeutic Strategies.
    Patrizia Limonta, Raffaella Chiaramonte, Lavinia Casati.
      Cutaneous melanoma still represents a significant health burden worldwide, being responsible for the majority of skin cancer deaths. Key advances in therapeutic strategies have significantly improved patient outcomes; however, most patients experience drug resistance and tumor relapse. Cancer stem cells (CSCs) are a small subpopulation of cells in different tumors, including melanoma, endowed with distinctive capacities of self-renewal and differentiation into bulk tumor cells. Melanoma CSCs are characterized by the expression of specific biomarkers and intracellular pathways; moreover, they play a pivotal role in tumor onset, progression and drug resistance. In recent years, great efforts have been made to dissect the molecular mechanisms underlying the protumor activities of melanoma CSCs to provide the basis for novel CSC-targeted therapies. Herein, we highlight the intricate crosstalk between melanoma CSCs and bystander cells in the tumor microenvironment (TME), including immune cells, endothelial cells and cancer-associated fibroblasts (CAFs), and its role in melanoma progression. Specifically, we discuss the peculiar capacities of melanoma CSCs to escape the host immune surveillance, to recruit immunosuppressive cells and to educate immune cells toward an immunosuppressive and protumor phenotype. We also address currently investigated CSC-targeted strategies that could pave the way for new promising therapeutic approaches for melanoma care.
    Keywords:  CSC markers; CSC-TME interplay; CSC-targeted therapies; bidirectional cell-to-cell communication; cancer stem cells (CSCs); melanoma; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3390/cancers16162861
  8. Cell Death Dis. 2024 Aug 23. 15(8): 614
    Natural Killer cells at the frontline in the fight against cancer.
    Loïs Coënon, Mannon Geindreau, François Ghiringhelli, Martin Villalba, Mélanie Bruchard.
      Natural Killer (NK) cells are innate immune cells that play a pivotal role as first line defenders in the anti-tumor response. To prevent tumor development, NK cells are searching for abnormal cells within the body and appear to be key players in immunosurveillance. Upon recognition of abnormal cells, NK cells will become activated to destroy them. In order to fulfill their anti-tumoral function, they rely on the secretion of lytic granules, expression of death receptors and production of cytokines. Additionally, NK cells interact with other cells in the tumor microenvironment. In this review, we will first focus on NK cells' activation and cytotoxicity mechanisms as well as NK cells behavior during serial killing. Lastly, we will review NK cells' crosstalk with the other immune cells present in the tumor microenvironment.
    DOI:  https://doi.org/10.1038/s41419-024-06976-0
  9. Front Immunol. 2024 ;15 1424237
    The role of metabolic reprogramming in immune escape of triple-negative breast cancer.
    Ruochen Bao, Hongtao Qu, Baifeng Li, Kai Cheng, Yandong Miao, Jiangtao Wang.
      Triple-negative breast cancer (TNBC) has become a thorny problem in the treatment of breast cancer because of its high invasiveness, metastasis and recurrence. Although immunotherapy has made important progress in TNBC, immune escape caused by many factors, especially metabolic reprogramming, is still the bottleneck of TNBC immunotherapy. Regrettably, the mechanisms responsible for immune escape remain poorly understood. Exploring the mechanism of TNBC immune escape at the metabolic level provides a target and direction for follow-up targeting or immunotherapy. In this review, we focus on the mechanism that TNBC affects immune cells and interstitial cells through hypoxia, glucose metabolism, lipid metabolism and amino acid metabolism, and changes tumor metabolism and tumor microenvironment. This will help to find new targets and strategies for TNBC immunotherapy.
    Keywords:  amino acid metabolism; glucose metabolism; hypoxia; immune escape; lipid metabolism; triple-negative breast cancer
    DOI:  https://doi.org/10.3389/fimmu.2024.1424237
  10. J Dent Res. 2024 Aug 26. 220345241264728
    Metabolic and Aging Influence on Anticancer Immunity in Oral Cancer.
    T P M D Santos, W L Hicks, W J Magner, A Al Afif, K L Kirkwood.
      The average age and obesity prevalence are increasing globally. Both aging and metabolic disease burden increase the risk of oral squamous cell carcinoma (OSCC) through profound effects on the immunological and metabolic characteristics within the OSCC tumor microenvironment. While the mechanisms that link aging and obesity to OSCC remain unclear, there is evidence that the antitumor responses are diminished in both conditions. Remarkably, however, immune checkpoint blockade, a form of cancer immunotherapy, remains intact despite the enhanced immunosuppressive tumor microenvironment in the context of either aging or obesity. Herein, we review the current knowledge of how aging and systemic metabolic changes affect antitumor immunity with an emphasis on the role of tumor-associated macrophages that greatly contribute to tumor immunosuppression. Key aspects discussed include the mechanisms of angiogenesis, cytokine release, phagocytosis attenuation, and immune cell recruitment during obesity and aging that create an immune-suppressive tumor microenvironment by recruitment and repolarization of tumor-associated macrophages. Through a deeper appreciation of these mechanisms, the development of novel therapeutic approaches to control OSCC will provide more refined management of the tumor microenvironment in the context of aging and obesity.
    Keywords:  biological aging; immune checkpoint molecules; obesity; oral squamous cell carcinoma; tumor microenvironment
    DOI:  https://doi.org/10.1177/00220345241264728
  11. Front Immunol. 2024 ;15 1428653
    Master regulator: p53's pivotal role in steering NK-cell tumor patrol.
    Haohao Wang, Qingjie Chen, Qinghua Liu, Changjiang Luo.
      The p53 protein, encoded by TP53, is a tumor suppressor that plays a critical role in regulating apoptosis, cell cycle regulation, and angiogenesis in tumor cells via controlling various downstream signals. Natural killer (NK) cell-mediated immune surveillance is a vital self-defense mechanism against cancer and other diseases, with NK cell activity regulated by various mechanisms. Among these, p53 plays a significant role in immune regulation by maintaining the homeostasis and functionality of NK cells. It enhances the transcriptional activity of NK cell-activating ligands and downregulates inhibitory ligands to boost NK cell activation and tumor-killing efficacy. Additionally, p53 influences NK cell cytotoxicity by promoting apoptosis, autophagy, and ferroptosis in different tumor cells. p53 is involved in the regulation of NK cell activity and effector functions through multiple pathways. p53 also plays a pivotal role in the tumor microenvironment (TME), regulating the activity of NK cells. NK cells are critical components of the TME and are capable of directly killing tumor cells. And p53 mutates in numerous cancers, with the most common alteration being a missense mutation. These mutations are commonly associated with poor survival rates in patients with cancer. This review details p53's role in NK cell tumor immunosurveillance, summarizing how p53 enhances NK cell recognition and tumor destruction. We also explore the potential applications of p53 in tumor immunotherapy, discussing strategies for modulating p53 to enhance NK cell function and improve the efficacy of tumor immunotherapy, along with the associated challenges. Understanding the interaction between p53 and NK cells within the TME is crucial for advancing NK cell-based immunotherapy and developing p53-related novel therapeutics.
    Keywords:  NK cells; immunotherapy; p53; tumor microenvironment; tumor surveillance
    DOI:  https://doi.org/10.3389/fimmu.2024.1428653
  12. Curr Oncol. 2024 Jul 26. 31(8): 4241-4260
    Focus on Pancreatic Cancer Microenvironment.
    Fabiana Pratticò, Ingrid Garajová.
      Pancreatic ductal adenocarcinoma remains one of the most lethal solid tumors due to its local aggressiveness and metastatic potential, with a 5-year survival rate of only 13%. A robust connection between pancreatic cancer microenvironment and tumor progression exists, as well as resistance to current anticancer treatments. Pancreatic cancer has a complex tumor microenvironment, characterized by an intricate crosstalk between cancer cells, cancer-associated fibroblasts and immune cells. The complex composition of the tumor microenvironment is also reflected in the diversity of its acellular components, such as the extracellular matrix, cytokines, growth factors and secreted ligands involved in signaling pathways. Desmoplasia, the hallmark of the pancreatic cancer microenvironment, contributes by creating a dense and hypoxic environment that promotes further tumorigenesis, provides innate systemic resistance and suppresses anti-tumor immune invasion. We discuss the complex crosstalk among tumor microenvironment components and explore therapeutic strategies and opportunities in pancreatic cancer research. Better understanding of the tumor microenvironment and its influence on pancreatic cancer progression could lead to potential novel therapeutic options, such as integration of immunotherapy and cytokine-targeted treatments.
    Keywords:  cancer therapy; cancer-associated fibroblasts; cytokines; desmoplasia; immune cells; immunotherapy; pancreatic ductal adenocarcinoma; tumor microenvironment
    DOI:  https://doi.org/10.3390/curroncol31080316
  13. Front Oncol. 2024 ;14 1441338
    Immunometabolism of ferroptosis in the tumor microenvironment.
    Gian Luca Lupica-Tondo, Emily N Arner, Denis A Mogilenko, Kelsey Voss.
      Ferroptosis is an iron-dependent form of cell death that results from excess lipid peroxidation in cellular membranes. Within the last decade, physiological and pathological roles for ferroptosis have been uncovered in autoimmune diseases, inflammatory conditions, infection, and cancer biology. Excitingly, cancer cell metabolism may be targeted to induce death by ferroptosis in cancers that are resistant to other forms of cell death. Ferroptosis sensitivity is regulated by oxidative stress, lipid metabolism, and iron metabolism, which are all influenced by the tumor microenvironment (TME). Whereas some cancer cell types have been shown to adapt to these stressors, it is not clear how immune cells regulate their sensitivities to ferroptosis. In this review, we discuss the mechanisms of ferroptosis sensitivity in different immune cell subsets, how ferroptosis influences which immune cells infiltrate the TME, and how these interactions can determine epithelial-to-mesenchymal transition (EMT) and metastasis. While much focus has been placed on inducing ferroptosis in cancer cells, these are important considerations for how ferroptosis-modulating strategies impact anti-tumor immunity. From this perspective, we also discuss some promising immunotherapies in the field of ferroptosis and the challenges associated with targeting ferroptosis in specific immune cell populations.
    Keywords:  TME; ferroptosis; immunometabolism; iron; metastasis
    DOI:  https://doi.org/10.3389/fonc.2024.1441338
  14. Cancer Res. 2024 Aug 26.
    Tumour's Digest: Macrophage metabolism creates a barrier to T cells.
    Eleanor Jane Tyler, Oliver M T Pearce.
      Changes in the composition and physical properties of the tumor extracellular matrix are linked to poor cytotoxic T-cell infiltration and therapy response, yet the underlying mechanisms remain unclear. Tharp and colleagues revealed a fascinating cascade where tumor fibrosis alters macrophage metabolism, restricting the nutrients available to infiltrating T-cells and resulting in their suppression and exclusion from the tumor microenvironment. This study suggests that targeting metabolic pathways could be a promising strategy to overcome the immune suppression induced by the tumor extracellular matrix.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-3039
  15. Biomolecules. 2024 Jul 27. pii: 917. [Epub ahead of print]14(8):
    Intratumoral Microbiota: Metabolic Influences and Biomarker Potential in Gastrointestinal Cancer.
    Xueyuan Bi, Jihan Wang, Cuicui Liu.
      Gastrointestinal (GI) cancers impose a substantial global health burden, highlighting the necessity for deeper understanding of their intricate pathogenesis and treatment strategies. This review explores the interplay between intratumoral microbiota, tumor metabolism, and major types of GI cancers (including esophageal, gastric, liver, pancreatic, and colorectal cancers), summarizing recent studies and elucidating their clinical implications and future directions. Recent research revealed altered microbial signatures within GI tumors, impacting tumor progression, immune responses, and treatment outcomes. Dysbiosis-induced alterations in tumor metabolism, including glycolysis, fatty acid metabolism, and amino acid metabolism, play critical roles in cancer progression and therapeutic resistance. The integration of molecular mechanisms and potential biomarkers into this understanding further enhances the prognostic significance of intratumoral microbiota composition and therapeutic opportunities targeting microbiota-mediated tumor metabolism. Despite advancements, challenges remain in understanding the dynamic interactions within the tumor microenvironment (TME). Future research directions, including advanced omics technologies and prospective clinical studies, offer promising avenues for precision oncology and personalized treatment interventions in GI cancer. Overall, integrating microbiota-based approaches and molecular biomarkers into GI cancer management holds promise for improving patient outcomes and survival.
    Keywords:  gastrointestinal cancer; intratumoral microbiota; microbial biomarkers; tumor metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3390/biom14080917
  16. Discov Oncol. 2024 Aug 26. 15(1): 369
    The complex role of macrophages in pancreatic cancer tumor microenvironment: a review on cancer progression and potential therapeutic targets.
    Parsa Lorestani, Mohsen Dashti, Negar Nejati, Mohammad Amin Habibi, Mandana Askari, Behruz Robat-Jazi, Sajjad Ahmadpour, Soheil Tavakolpour.
      Pancreatic cancer (PC) is one of the deadliest cancers worldwide with low survival rates and poor outcomes. The treatment landscape for PC is fraught with obstacles, including drug resistance, lack of effective targeted therapies and the immunosuppressive tumor microenvironment (TME). The resistance of PC to existing immunotherapies highlights the need for innovative approaches, with the TME emerging as a promising therapeutic target. The recent advancements in understanding the role of macrophages, this context highlight their significant impact on tumor development and progression. There are two important types of macrophages: M1 and M2, which play critical roles in the TME. Therapeutics strategies including, depletion of tumor-associated macrophages (TAMs), reprogramming TAMs to promote anti-tumor activity, and targeting macrophage recruitment can lead to promising outcomes. Targeting macrophage-related pathways may offer novel strategies for modulating immune responses, inhibiting angiogenesis, and overcoming resistance to chemotherapy in PC treatment.
    Keywords:  Immunotherapies; Macrophage-targeted therapy; Macrophages; Pancreatic cancer; Pancreatic ductal adenocarcinoma; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12672-024-01256-x
  17. Int J Mol Sci. 2024 Aug 08. pii: 8647. [Epub ahead of print]25(16):
    Role of Autophagy and AMPK in Cancer Stem Cells: Therapeutic Opportunities and Obstacles in Cancer.
    Lochana Kovale, Manish Kumar Singh, Joungmok Kim, Joohun Ha.
      Cancer stem cells represent a resilient subset within the tumor microenvironment capable of differentiation, regeneration, and resistance to chemotherapeutic agents, often using dormancy as a shield. Their unique properties, including drug resistance and metastatic potential, pose challenges for effective targeting. These cells exploit certain metabolic processes for their maintenance and survival. One of these processes is autophagy, which generally helps in energy homeostasis but when hijacked by CSCs can help maintain their stemness. Thus, it is often referred as an Achilles heel in CSCs, as certain cancers tend to depend on autophagy for survival. Autophagy, while crucial for maintaining stemness in cancer stem cells (CSCs), can also serve as a vulnerability in certain contexts, making it a complex target for therapy. Regulators of autophagy like AMPK (5' adenosine monophosphate-activated protein kinase) also play a crucial role in maintaining CSCs stemness by helping CSCs in metabolic reprogramming in harsh environments. The purpose of this review is to elucidate the interplay between autophagy and AMPK in CSCs, highlighting the challenges in targeting autophagy and discussing therapeutic strategies to overcome these limitations. This review focuses on previous research on autophagy and its regulators in cancer biology, particularly in CSCs, addresses the remaining unanswered questions, and potential targets for therapy are also brought to attention.
    Keywords:  AMPK; autophagy; cancer stem cells
    DOI:  https://doi.org/10.3390/ijms25168647
  18. Cells. 2024 Aug 07. pii: 1317. [Epub ahead of print]13(16):
    Tissue- and Temporal-Dependent Dynamics of Myeloablation in Response to Gemcitabine Chemotherapy.
    Lydia E Kitelinger, Eric A Thim, Sarah Y Zipkowitz, Richard J Price, Timothy N J Bullock.
      For triple-negative breast cancer (TNBC), the most aggressive subset of breast cancer, immune cell infiltrates have prognostic implications. The presence of myeloid-derived suppressor cells supports tumor progression, while tumor-infiltrating lymphocytes (TILs) correlate with improved survival and responsiveness to immunotherapy. Manipulating the abundance of these populations may enhance tumor immunity. Gemcitabine (GEM), a clinically employed chemotherapeutic, is reported to be systemically myeloablative, and thus it is a potentially useful adjunct therapy for promoting anti-tumor immunity. However, knowledge about the immunological effects of GEM intratumorally is limited. Thus, we directly compared the impact of systemic GEM on immune cell presence and functionality in the tumor microenvironment (TME) to its effects in the periphery. We found that GEM is not myeloablative in the TME; rather, we observed sustained, significant reductions in TILs and dendritic cells-crucial components in initiating an adaptive immune response. We also performed bulk-RNA sequencing to identify immunological alterations transcriptionally induced by GEM. While we found evidence of upregulation in the interferon-gamma (IFN-γ) response pathway, we determined that GEM-mediated growth control is not dependent on IFN-γ. Overall, our findings yield new insights into the tissue- and temporal-dependent immune ablative effects of GEM, contrasting the paradigm that this therapy is specifically myeloablative.
    Keywords:  chemotherapy; gemcitabine; triple-negative breast cancer; tumor immunology; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells13161317
  19. Int Immunopharmacol. 2024 Aug 23. pii: S1567-5769(24)01488-7. [Epub ahead of print]141 112967
    Chemotherapy-mediated lncRNA-induced immune cell plasticity in cancer immunopathogenesis.
    Jingyuan Lu, Haowei Ma, Qian Wang, Zhiheng Song, Jinli Wang.
      Tumor cells engage with the immune system in a complex manner, utilizing evasion and adaptability mechanisms. The development of cancer and resistance to treatment relies on the ability of immune cells to adjust their phenotype and function in response to cues from the tumor microenvironment, known as immunological cell plasticity. This study delves into the role of long non-coding RNAs (lncRNAs) in enhancing immune cell flexibility in cancer, focusing on their regulatory actions in the tumor microenvironment and potential therapeutic implications. Through a comprehensive review of existing literature, the study analyzes the impact of lncRNAs on macrophages, T-cells, and MDSCs, as well as the influence of cytokines and growth factors like TNF, IL-6, HGF, and TGFβ on immunological cell plasticity and tumor immunoediting. LncRNAs exert a strong influence on immune cell plasticity through mechanisms such as transcriptional regulation, post-transcriptional modifications, and chromatin remodeling. These RNA molecules intricately modulate gene expression networks, acting as scaffolding, decoys, guides, and sponges. Moreover, both direct cell-cell interactions and soluble chemicals in the tumor microenvironment contribute to enhancing immune cell activation and survival. Understanding the influence of lncRNAs on immune cell flexibility sheds light on the biological pathways of immune evasion and cancer progression. Targeting long non-coding RNAs holds promise for amplifying anti-tumor immunity and overcoming drug resistance in cancer treatment. However, further research is necessary to determine the therapeutic potential of manipulating lncRNAs in the tumor microenvironment.
    Keywords:  Cancer; Chemotherapy; Immune system; Plasticity; lncRNA
    DOI:  https://doi.org/10.1016/j.intimp.2024.112967
  20. J Funct Biomater. 2024 Aug 16. pii: 229. [Epub ahead of print]15(8):
    Mannan-Decorated Lipid Calcium Phosphate Nanoparticle Vaccine Increased the Antitumor Immune Response by Modulating the Tumor Microenvironment.
    Liusheng Wu, Lei Yang, Xinye Qian, Wang Hu, Shuang Wang, Jun Yan.
      With the rapid development of tumor immunotherapy, nanoparticle vaccines have attracted much attention as potential therapeutic strategies. A systematic review and analysis must be carried out to investigate the effect of mannose modification on the immune response to nanoparticles in regulating the tumor microenvironment, as well as to explore its potential clinical application in tumor therapy. Despite the potential advantages of nanoparticle vaccines in immunotherapy, achieving an effective immune response in the tumor microenvironment remains a challenge. Tumor immune escape and the overexpression of immunosuppressive factors limit its clinical application. Therefore, our review explored how to intervene in the immunosuppressive mechanism in the tumor microenvironment through the use of mannan-decorated lipid calcium phosphate nanoparticle vaccines to improve the efficacy of immunotherapy in patients with tumors and to provide new ideas and strategies for the field of tumor therapy.
    Keywords:  antitumor immune response; calcium phosphate (CaP); nanoparticle vaccine; review; tumor microenvironment
    DOI:  https://doi.org/10.3390/jfb15080229
  21. Life Sci. 2024 Aug 23. pii: S0024-3205(24)00605-2. [Epub ahead of print]355 123015
    Cancer Stem Cell markers: Symphonic masters of chemoresistance and immune evasion.
    Miguel Angel Sarabia-Sánchez, José Manuel Tinajero-Rodríguez, Elizabeth Ortiz-Sánchez, Eduardo Alvarado-Ortiz.
      Cancer Stem Cells (CSCs) are highly tumorigenic, chemoresistant, and immune evasive. They emerge as a central driver that gives rise to the bulk of tumoral mass, modifies the tumor microenvironment (TME), and exploits it, leading to poor clinical outcomes for patients with cancer. The existence of CSCs thus accounts for the failure of conventional therapies and immune surveillance. Identifying CSCs in solid tumors remains a significant challenge in modern oncology, with the use of cell surface markers being the primary strategy for studying, isolating, and enriching these cells. In this review, we explore CSC markers, focusing on the underlying signaling pathways that drive CSC self-renewal, which simultaneously makes them intrinsically chemoresistant and immune system evaders. We comprehensively discuss the autonomous and non-autonomous functions of CSCs, with particular emphasis on their interactions with the tumor microenvironment, especially immune cells. This reciprocal network enhances CSCs malignancy while compromising the surrounding niche, ultimately defining therapeutic vulnerabilities associated with each CSC marker. The most common CSCs surface markers addressed in this review-CD44, CD133, ICAM1/CD54, and LGR5-provide insights into the interplay between chemoresistance and immune evasion, two critically important phenomena in disease eradication. This new perspective on the state-of-the-art of CSCs will undoubtedly open new avenues for therapy.
    Keywords:  CD133; CD44; CD54; Cancer stem cell; Chemoresistance; Immune evasion; LGR5
    DOI:  https://doi.org/10.1016/j.lfs.2024.123015
  22. Cancers (Basel). 2024 Aug 10. pii: 2814. [Epub ahead of print]16(16):
    Role of MicroRNA-204 in Regulating the Hallmarks of Breast Cancer: An Update.
    Mercedes Bermúdez, Marcela Guadalupe Martínez-Barajas, Lesly Jazmín Bueno-Urquiza, Jorge Armando López-Gutiérrez, Carlos Esteban Villegas-Mercado, César López-Camarillo.
      microRNA-204-5p (miR-204) is a small noncoding RNA with diverse regulatory roles in breast cancer (BC) development and progression. miR-204 is implicated in the instauration of fundamental traits acquired during the multistep development of BC, known as the hallmarks of cancer. It may act as a potent tumor suppressor by inhibiting key cellular processes like angiogenesis, vasculogenic mimicry, invasion, migration, and metastasis. It achieves this by targeting multiple master genes involved in these processes, including HIF-1α, β-catenin, VEGFA, TGFBR2, FAK, FOXA1, among others. Additionally, miR-204 modulates signaling pathways like PI3K/AKT and interacts with HOTAIR and DSCAM-AS1 lncRNAs, further influencing tumor progression. Beyond its direct effects on tumor cells, miR-204 shapes the tumor microenvironment by regulating immune cell infiltration, suppressing pro-tumorigenic cytokine production, and potentially influencing immunotherapy response. Moreover, miR-204 plays a crucial role in metabolic reprogramming by directly suppressing metabolic genes within tumor cells, indirectly affecting metabolism through exosome signaling, and remodeling metabolic flux within the tumor microenvironment. This review aims to present an update on the current knowledge regarding the role of miR-204 in the hallmarks of BC. In conclusion, miR-204 is a potential therapeutic target and prognostic marker in BC, emphasizing the need for further research to fully elucidate its complex roles in orchestrating aggressive BC behavior.
    Keywords:  breast cancer; hallmarks of cancer; miR-204; microRNAs
    DOI:  https://doi.org/10.3390/cancers16162814
  23. Cell Death Discov. 2024 Aug 26. 10(1): 380
    The role of cancer-associated fibroblasts and exosomal miRNAs-mediated intercellular communication in the tumor microenvironment and the biology of carcinogenesis: a systematic review.
    Reza Nedaeinia, Simin Najafgholian, Rasoul Salehi, Mohammad Goli, Maryam Ranjbar, Hamid Nickho, Shaghayegh Haghjooy Javanmard, Gordon A Ferns, Mostafa Manian.
      CAFs (cancer-associated fibroblasts) are highly flexible cells of the cancer microenvironment. They produce the extracellular matrix (ECM) constituents that form the structure of the tumor stroma but are also a source of metabolites, growth factors, chemokines, and exosomes that impact every aspect of the tumor, including its response to treatment. It is believed that exosomal miRNAs facilitate intercellular signaling, which is essential for the development of cancer. The role of miRNAs and CAFs in the tumor microenvironment (TME) and carcinogenesis is reviewed in this paper. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) 2020 guidelines were used to perform a systematic review. Several databases, including Web of Science, Medline, Embase, Cochrane Library, and Scopus, were searched using the following keywords: CAFs, CAF, cancer-associated fibroblasts, stromal fibroblasts, miRNA, exosomal miRNAs, exosome and similar terms. We identified studies investigating exosomal miRNAs and CAFs in the TME and their role in carcinogenesis. A total of 12,572 papers were identified. After removing duplicates (n = 3803), 8774 articles were screened by title and abstract. Of these, 421 were excluded from further analysis. It has been reported that if exosomal miRNAs in CAFs are not functioning correctly, this may influence the secretory phenotype of tip cells and contribute to increased tumor invasiveness, tumor spread, decreased treatment efficacy, and a poorer prognosis. Under their influence, normal fibroblasts (NFs) are transformed into CAFs. Furthermore, they participate in metabolic reprogramming, which allows for fast proliferation of the cancer cell population, adaptation to growing energy demands, and the capacity to avoid immune system identification.
    DOI:  https://doi.org/10.1038/s41420-024-02146-5
  24. Curr Issues Mol Biol. 2024 Aug 05. 46(8): 8576-8599
    Dysregulation of Transposon Transcription Profiles in Cancer Cells Resembles That of Embryonic Stem Cells.
    Anna I Solovyeva, Roman V Afanasev, Marina A Popova, Natella I Enukashvily.
      Transposable elements (TEs) comprise a substantial portion of the mammalian genome, with potential implications for both embryonic development and cancer. This study aimed to characterize the expression profiles of TEs in embryonic stem cells (ESCs), cancer cell lines, tumor tissues, and the tumor microenvironment (TME). We observed similarities in TE expression profiles between cancer cells and ESCs, suggesting potential parallels in regulatory mechanisms. Notably, four TE RNAs (HERVH, LTR7, HERV-Fc1, HERV-Fc2) exhibited significant downregulation across cancer cell lines and tumor tissues compared to ESCs, highlighting potential roles in pluripotency regulation. The strong up-regulation of the latter two TEs (HERV-Fc1, HERV-Fc2) in ESCs has not been previously demonstrated and may be a first indication of their role in the regulation of pluripotency. Conversely, tandemly repeated sequences (MSR1, CER, ALR) showed up-regulation in cancer contexts. Moreover, a difference in TE expression was observed between the TME and the tumor bulk transcriptome, with distinct dysregulated TE profiles. Some TME-specific TEs were absent in normal tissues, predominantly belonging to LTR and L1 retrotransposon families. These findings not only shed light on the regulatory roles of TEs in both embryonic development and cancer but also suggest novel targets for anti-cancer therapy. Understanding the interplay between cancer cells and the TME at the TE level may pave the way for further research into therapeutic interventions.
    Keywords:  HERV-Fc1; HERV-Fc2; HERVH; cancer cell lines; cancer-associated fibroblasts; embryonic stem cells; pluripotency; repeatome; retroviruses; transposons; tumor; tumor microenvironment
    DOI:  https://doi.org/10.3390/cimb46080505
  25. Int J Mol Sci. 2024 Aug 16. pii: 8929. [Epub ahead of print]25(16):
    Biomarkers Identification in the Microenvironment of Oral Squamous Cell Carcinoma: A Systematic Review of Proteomic Studies.
    Silvia Pomella, Ombretta Melaiu, Loredana Cifaldi, Roberto Bei, Marco Gargari, Vincenzo Campanella, Giovanni Barillari.
      An important determinant for oral squamous cell carcinoma (OSCC) onset and outcome is the composition of the tumor microenvironment (TME). Thus, the study of the interactions occurring among cancer cells, immune cells, and cancer-associated fibroblasts within the TME could facilitate the understanding of the mechanisms underlying OSCC development and progression, as well as of its sensitivity or resistance to the therapy. In this context, it must be highlighted that the characterization of TME proteins is enabled by proteomic methodologies, particularly mass spectrometry (MS). Aiming to identify TME protein markers employable for diagnosing and prognosticating OSCC, we have retrieved a total of 119 articles spanning 2001 to 2023, of which 17 have passed the selection process, satisfying all its criteria. We have found a total of 570 proteins detected by MS-based proteomics in the TME of OSCC; among them, 542 are identified by a single study, while 28 are cited by two or more studies. These 28 proteins participate in extracellular matrix remodeling and/or energy metabolism. Here, we propose them as markers that could be used to characterize the TME of OSCC for diagnostic/prognostic purposes. Noteworthy, most of the 28 individuated proteins share one feature: being modulated by the hypoxia that is present in the proliferating OSCC mass.
    Keywords:  CAFs; biomarkers; oral squamous cell carcinoma; proteomic; stroma; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms25168929
  26. Biomedicines. 2024 Aug 09. pii: 1816. [Epub ahead of print]12(8):
    Differential Regulation of Wingless-Wnt/c-Jun N-Terminal Kinase Crosstalk via Oxidative Eustress in Primary and Metastatic Colorectal Cancer Cells.
    Gitana Maria Aceto, Sara Pagotto, Francesco Domenico Del Pizzo, Concetta Saoca, Federico Selvaggi, Rosa Visone, Roberto Cotellese, M'hammed Aguennouz, Rossano Lattanzio, Teresa Catalano.
      In the tumor microenvironment (TME), ROS production affects survival, progression, and therapy resistance in colorectal cancer (CRC). H2O2-mediated oxidative stress can modulate Wnt/β-catenin signaling and metabolic reprogramming of the TME. Currently, it is unclear how mild/moderate oxidative stress (eustress) modulates Wnt/β-catenin/APC and JNK signaling relationships in primary and metastatic CRC cells. In this study, we determined the effects of the H2O2 concentration inducing eustress on isogenic SW480 and SW620 cells, also in combination with JNK inhibition. We assessed cell viability, mitochondrial respiration, glycolysis, and Wnt/β-catenin/APC/JNK gene and protein expression. Primary CRC cells were more sensitive to H2O2 eustress combined with JNK inhibition, showing a reduction in viability compared to metastatic cells. JNK inhibition under eustress reduced both glycolytic and respiratory capacity in SW620 cells, indicating a greater capacity to adapt to TME. In primary CRC cells, H2O2 alone significantly increased APC, LEF1, LRP6, cMYC and IL8 gene expression, whereas in metastatic CRC cells, this effect occurred after JNK inhibition. In metastatic but not in primary tumor cells, eustress and inhibition of JNK reduced APC, β-catenin, and pJNK protein. The results showed differential cross-regulation of Wnt/JNK in primary and metastatic tumor cells under environmental eustress conditions. Further studies would be useful to validate these findings and explore their therapeutic potential.
    Keywords:  H2O2; JNK; Wnt/β-catenin; adenomatous polyposis coli; colorectal cancer progression; metastasis; oxidative stress; tumor metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3390/biomedicines12081816
  27. Cell Death Dis. 2024 Aug 28. 15(8): 633
    LncRNA HAGLROS promotes breast cancer evolution through miR-135b-3p/COL10A1 axis and exosome-mediated macrophage M2 polarization.
    Ziqi Meng, Rui Zhang, Xuwei Wu, Zhengri Piao, Meihua Zhang, Tiefeng Jin.
      Long non-coding RNAs (lncRNAs) play an important role in breast cancer progression, but the function of lncRNAs in regulating tumor-associated macrophages (TAMs) remains unclear. As carriers of lncRNAs, exosomes play an important role as mediators in the communication between cancer cells and the tumor microenvironment. In this study, we found that lncRNA HAGLROS was highly expressed in breast cancer tissues and plasma exosomes, and its high expression was related to the poor prognosis of breast cancer patients. Functionally, breast cancer cell-derived exosomal lncRNA HAGLROS promotes breast cancer cell proliferation, migration, epithelial-mesenchymal transition (EMT) process and angiogenesis by inducing TAM/M2 polarization. Mechanistically, lncRNA HAGLROS competitively binds to miR-135-3p to prevent the degradation of its target gene COL10A1. Collectively, these results indicated that the lncRNA HAGLROS/miR-135b-3p/COL10A1 axis promoted breast cancer progression, and revealed the interactive communication mechanism between breast cancer cells and TAMs, suggesting that lncRNA HAGLROS may be a potential biomarker and therapeutic target for breast cancer.
    DOI:  https://doi.org/10.1038/s41419-024-07020-x
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