bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2025–03–30
thirty papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Myeloid-Derived Suppressor Cells: Implications in Cancer Immunology and Immunotherapy.
  2. The influence of fatty acid metabolism on T cell function in lung cancer.
  3. The immunosuppressive role of MDSCs in HCC: mechanisms and therapeutic opportunities.
  4. The Role of the Tumor Microenvironment (TME) in Advancing Cancer Therapies: Immune System Interactions, Tumor-Infiltrating Lymphocytes (TILs), and the Role of Exosomes and Inflammasomes.
  5. Myeloid cells are involved in tumor immunity, metastasis and metabolism in tumor microenvironment.
  6. The impact of the tumor microenvironment in the dual burden of obesity-cancer link.
  7. The Role of Cholesterol Metabolism and Its Regulation in Tumor Development.
  8. Cross-Talk Between Cancer and Its Cellular Environment-A Role in Cancer Progression.
  9. Genetically engineered macrophages reverse the immunosuppressive tumor microenvironment and improve immunotherapeutic efficacy in TNBC.
  10. Characterization of the Pancreatic Neuroendocrine Neoplasm Immune Microenvironment.
  11. Contemporary understanding of myeloid-derived suppressor cells in the acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) tumor microenvironment.
  12. Tumor Microenvironment Dynamics of Triple-Negative Breast Cancer Under Radiation Therapy.
  13. Battlegrounds of treatment resistance: decoding the tumor microenvironment.
  14. Editorial: Metabolic reprogramming in cancer.
  15. Decoding the Tumor-Associated Microbiota: From Origins to Nanomedicine Applications in Cancer Therapy.
  16. Myeloid Cells in the Immunosuppressive Microenvironment as Immunotargets in Osteosarcoma.
  17. Breast Cancer and Tumor Microenvironment: The Crucial Role of Immune Cells.
  18. Differentiation of Cytotoxic CD8+ T Cell Subsets Under Tumor Progression: Can CD69 Be a New Therapeutic Target?
  19. Chemokines: Orchestration of the Tumor Microenvironment and Control of Hepatocellular Carcinoma Progression.
  20. Breast cancer-derived exosomal miR-105-5p facilitates the transformation of NFs into CAFs through LATS2-NF-κB signaling.
  21. Immunogenomic cancer evolution: A framework to understand cancer immunosuppression.
  22. Metabolic Reprogramming of Anti-cancer T Cells: Targeting AMPK and PPAR to Optimize Cancer Immunotherapy.
  23. MDSC checkpoint blockade therapy: a new breakthrough point overcoming immunosuppression in cancer immunotherapy.
  24. The mutual effects of stearoyl-CoA desaturase and cancer-associated fibroblasts: A focus on cancer biology.
  25. For and against tumor microenvironment: Nanoparticle-based strategies for active cancer therapy.
  26. Targeting B7-H3 in solid tumors: Development and evaluation of novel CAR-T Cell therapy.
  27. Nanomedicines Targeting Metabolic Pathways in the Tumor Microenvironment: Future Perspectives and the Role of AI.
  28. Chemokines and their receptors in the esophageal carcinoma tumor microenvironment: key factors for metastasis and progression.
  29. Targeting legumain-mediated cell-cell interaction sensitizes glioblastoma to immunotherapy in preclinical models.
  30. Reversing cancer immunosuppression via K+ capture and repolarization of tumor-associated macrophages.
  1. Front Biosci (Landmark Ed). 2025 Mar 20. 30(3): 25203
    Myeloid-Derived Suppressor Cells: Implications in Cancer Immunology and Immunotherapy.
    Juan F Santibanez.
      Myeloid-derived suppressor cells (MDSCs) are believed to be key promoters of tumor development and are recognized as a hallmark of cancer cells' ability to evade the immune system evasion. MDSC levels often increase in peripheral blood and the tumor microenvironment (TME). These cells exert immunosuppressive functions, weakening the anticancer immune surveillance system, in part by repressing T-cell immunity. Moreover, MDSCs may promote tumor progression and interact with cancer cells, increasing MDSC expansion and favoring an immunotolerant TME. This review analyzes the primary roles of MDSCs in cancer and T-cell immunity, discusses the urgent need to develop effective MDSC-targeted therapies, and highlights the potential synergistic combination of MDSC targeting with chimeric antigen receptors and immune checkpoint inhibitors.
    Keywords:  MDSC; T-cell lymphocyte immunosuppression; cancer; myeloid-derived suppressor cells; tumor progression
    DOI:  https://doi.org/10.31083/FBL25203
  2. FEBS J. 2025 Mar 25.
    The influence of fatty acid metabolism on T cell function in lung cancer.
    Jessica Petiti, Ludovica Arpinati, Alessio Menga, Giovanna Carrà.
      The tumor microenvironment (TME) is a complex ecosystem, encompassing a variety of cellular and non-cellular elements surrounding and interacting with cancer cells, overall promoting tumor growth, immune evasion, and therapy resistance. In the context of solid tumors, factors, such as hypoxia, nutritional competition, increased stress responses, glucose demand, and PD-1 signals strongly influence metabolic alterations in the TME, highly contributing to the maintenance of a tumor-supportive and immune-suppressive milieu. Cancer cell-induced metabolic alterations partly result in an increased fatty acid (FA) metabolism within the TME, which strongly favors the recruitment of immune-suppressive M2 macrophages and myeloid-derived suppressor cells, crucial contributors to T-cell exhaustion, tumor exclusion, and decreased effector functions. The drastic pro-tumoral changes induced by the tumor metabolic rewiring result in signaling loops that support tumor progression and metastatic spreading, and negatively impact therapy efficacy. As tumor- and immune metabolism are increasingly gaining attention due to their potential therapeutic implications, we discuss the effects of altered lipid metabolism on tumor progression, immune response, and therapeutic efficacy in the context of lung cancer. In particular, we focus our analysis on the tumor-induced metabolic alterations experienced by T lymphocytes and the possible strategies to overcome immunotherapy resistance by targeting specific metabolic pathways in T cells.
    Keywords:  T‐cell function; cancer metabolism; fatty acid metabolism; lung cancer
    DOI:  https://doi.org/10.1111/febs.70081
  3. Cell Commun Signal. 2025 Mar 27. 23(1): 155
    The immunosuppressive role of MDSCs in HCC: mechanisms and therapeutic opportunities.
    Xiling Liu, Xichun Kang, Haiyan Kang, Huimin Yan.
      Hepatocellular carcinoma (HCC) is a prevalent malignancy with a significant global burden. Despite substantial advancements in HCC treatment in recent years, therapeutic efficacy remains constrained by immune evasion mechanisms within the tumor microenvironment (TME). Myeloid-derived suppressor cells (MDSCs), as critical immunosuppressive elements of the TME, have garnered increasing attention for their role in tumor progression. Recent studies emphasize their central involvement in promoting immune evasion, tolerance, and immunosuppression in HCC. This review examines the contributions of MDSCs to HCC pathogenesis, elucidates their underlying mechanisms, and discusses ongoing clinical trials, emphasizing their potential as therapeutic targets for improving clinical outcomes.
    DOI:  https://doi.org/10.1186/s12964-025-02170-7
  4. Int J Mol Sci. 2025 Mar 18. pii: 2716. [Epub ahead of print]26(6):
    The Role of the Tumor Microenvironment (TME) in Advancing Cancer Therapies: Immune System Interactions, Tumor-Infiltrating Lymphocytes (TILs), and the Role of Exosomes and Inflammasomes.
    Atef M Erasha, Hanem El-Gendy, Ahmed S Aly, Marisol Fernández-Ortiz, Ramy K A Sayed.
      Understanding how different contributors within the tumor microenvironment (TME) function and communicate is essential for effective cancer detection and treatment. The TME encompasses all the surroundings of a tumor such as blood vessels, fibroblasts, immune cells, signaling molecules, exosomes, and the extracellular matrix (ECM). Subsequently, effective cancer therapy relies on addressing TME alterations, known drivers of tumor progression, immune evasion, and metastasis. Immune cells and other cell types act differently under cancerous conditions, either driving or hindering cancer progression. For instance, tumor-infiltrating lymphocytes (TILs) include lymphocytes of B and T cell types that can invade malignancies, bringing in and enhancing the ability of immune system to recognize and destroy cancer cells. Therefore, TILs display a promising approach to tackling the TME alterations and have the capability to significantly hinder cancer progression. Similarly, exosomes and inflammasomes exhibit a dual effect, resulting in either tumor progression or inhibition depending on the origin of exosomes, type of inflammasome and tumor. This review will explore how cells function in the presence of a tumor, the communication between cancer cells and immune cells, and the role of TILs, exosomes and inflammasomes within the TME. The efforts in this review are aimed at garnering interest in safer and durable therapies for cancer, in addition to providing a promising avenue for advancing cancer therapy and consequently improving survival rates.
    Keywords:  cancer therapy; exosomes; immune cells; inflammasomes; tumor infiltrating lymphocytes (TILs); tumor microenvironment (TME)
    DOI:  https://doi.org/10.3390/ijms26062716
  5. Cell Biol Toxicol. 2025 Mar 25. 41(1): 62
    Myeloid cells are involved in tumor immunity, metastasis and metabolism in tumor microenvironment.
    Chenbo Zhang, Ying Song, Huanming Yang, Kui Wu.
      Bone marrow-derived cells in the tumor microenvironment, including macrophages, neutrophils, dendritic cells, myeloid-derived suppressor cells, eosinophils and basophils, participate in the generation, development, invasion and metastasis of tumors by producing different cytokines and interacting with other cell types, and play a pro-tumor or anti-tumor role in regulating tumor immunity. Due to the complexity of cell types in the tumor microenvironment and the unknown process of tumor development and metastasis, cancer treatment to achieve better survival status remains challenging. In this article, we summarize the effects of myeloid cells in tumor microenvironment on tumor immunity, cancer migration, and crosstalk with metabolism (including glucose metabolism, lipid metabolism, and amino acid metabolism), which will help to further study the tumor microenvironment and seek targeted therapeutic strategies for patients.
    Keywords:  Amino acid metabolism; Cancer metastasis; Glucose metabolism; Myeloid cells; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s10565-025-10012-y
  6. Semin Cancer Biol. 2025 Mar 22. pii: S1044-579X(25)00048-3. [Epub ahead of print]112 36-42
    The impact of the tumor microenvironment in the dual burden of obesity-cancer link.
    Serena Sagliocchi, Lucia Acampora, Biagio Barone, Felice Crocetto, Monica Dentice.
      Obesity induces systemic perturbations of tissue homeostasis, leading to dyslipidemia, insulin resistance and chronic state of inflammation. Evidence from clinical and preclinical studies links excess of adiposity with increased cancer incidence and suggests that chronic inflammation may contribute to increased cancer risk in obese patients. Over the last decades of obesity research, multifaced and complicated effects of abnormal or excessive expansion of Adipose Tissue have been uncovered. In particular, it is widely described how obesity can exacerbate the tumorigenesis for instance by fueling soluble signals and adipokines and by enhancing tissue inflammation and altering the hormonal balance. Less is known about the paracrine effects of the cancer-associated adipocytes on the tumor cells and still poorly explored is the reciprocal communication between cancer cells and the adipose component of the tumor microenvironment (TME). In this review, we will address the mechanisms by which the peritumoral Adipose Tissue can influence the dynamics of tumoral cells. We will discuss how obesity-induced changes in the tumor microenvironment may enhance tumor growth and aggressive characteristics leading to increased invasiveness and metastatic progression of cancer that leads to a worsen cancer survival in obese subjects. We conclude that targeting the peritumoral adipose component of the TME would be a therapeutic option to prevent cancer development.
    Keywords:  Cancer Associated Adipocytes; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.semcancer.2025.03.001
  7. Cancer Med. 2025 Apr;14(7): e70783
    The Role of Cholesterol Metabolism and Its Regulation in Tumor Development.
    Yongmei Wu, Wenqian Song, Min Su, Jing He, Rong Hu, Youbo Zhao.
       BACKGROUND: Within the tumor microenvironment, tumor cells undergo metabolic reprogramming of cholesterol due to intrinsic cellular alterations and changes in the extracellular milieu. Furthermore, cholesterol reprogramming within this microenvironment influences the immune landscape of tumors, facilitating immune evasion and consequently promoting tumorigenesis. These biological changes involve modifications in numerous enzymes associated with cholesterol uptake and synthesis, including NPC1L1, SREBP, HMGCR, SQLE, and PCSK9.
    REVIEW: This review systematically summarizes the role of cholesterol metabolism and its associated enzymes in cancer progression, examines the mechanisms through which dysregulation of cholesterol metabolism affects immune cells within the tumor microenvironment, and discusses recent advancements in cancer therapies that target cholesterol metabolism.
    CONCLUSION: Targeting cholesterol metabolism-related enzymes can inhibit tumor growth, reshape immune landscapes, and rejuvenate antitumor immunity, offering potential therapeutic avenues in cancer treatment.
    Keywords:  cancer; cholesterol; immune; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.1002/cam4.70783
  8. Cells. 2025 Mar 10. pii: 403. [Epub ahead of print]14(6):
    Cross-Talk Between Cancer and Its Cellular Environment-A Role in Cancer Progression.
    Eliza Turlej, Aleksandra Domaradzka, Justyna Radzka, Dominika Drulis-Fajdasz, Julita Kulbacka, Agnieszka Gizak.
      The tumor microenvironment is a dynamic and complex three-dimensional network comprising the extracellular matrix and diverse non-cancerous cells, including fibroblasts, adipocytes, endothelial cells and various immune cells (lymphocytes T and B, NK cells, dendritic cells, monocytes/macrophages, myeloid-derived suppressor cells, and innate lymphoid cells). A constantly and rapidly growing number of studies highlight the critical role of these cells in shaping cancer survival, metastatic potential and therapy resistance. This review provides a synthesis of current knowledge on the modulating role of the cellular microenvironment in cancer progression and response to treatment.
    Keywords:  cancer; cancer-associated cells; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells14060403
  9. Mol Ther. 2025 Mar 20. pii: S1525-0016(25)00198-4. [Epub ahead of print]
    Genetically engineered macrophages reverse the immunosuppressive tumor microenvironment and improve immunotherapeutic efficacy in TNBC.
    Ranran Jiang, Liechi Yang, Xin Liu, Yujun Xu, Lulu Han, Yuxin Chen, Ge Gao, Meng Wang, Tong Su, Huizhong Li, Lin Fang, Nan Sun, Hongwei Du, Junnian Zheng, Gang Wang.
      The main challenges in current immunotherapy for triple-negative breast cancer (TNBC) lie in the immunosuppressive tumor microenvironment (TME). Considering tumor-associated macrophages (TAMs) are the most abundant immune cells in the TME, resetting TAMs is a promising strategy for ameliorating the immunosuppressive TME. Here, we developed genetically engineered macrophages (GEMs) with gene-carrying adenoviruses, to maintain the M1-like phenotype and directly deliver the immune regulators IL-12 and CXCL9 into local tumors, thereby reversing the immunosuppressive TME. In tumor bearing mice, GEMs demonstrated targeted enrichment in tumors and successfully reprogramed TAMs to M1-like macrophages. Moreover, GEMs significantly enhanced the accumulation, proliferation, and activation of CD8+ T cells, mature dendritic cells (DCs), and natural killer (NK) cells within tumors, while diminishing M2-like macrophages, immunosuppressive myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). This treatment efficiently suppressed tumor growth. In addition, combination therapy with GEMs and anti-programmed cell death protein 1 (αPD-1) further improved IFN-γ+CD8+ T cell percentages and tumor inhibition efficacy in an orthotopic murine TNBC model. Therefore, this study provides a novel strategy for reversing the immunosuppressive TME and improving immunotherapeutic efficacy through live macrophage-mediated gene delivery.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.03.024
  10. Cancer Med. 2025 Apr;14(7): e70798
    Characterization of the Pancreatic Neuroendocrine Neoplasm Immune Microenvironment.
    Filipe Reis Neves, Ana Luís Martins, Rui Caetano Oliveira, Rui Martins.
       INTRODUCTION: A tumor is composed of more than tumoral cells. In recent years, there has been an increase in interest and knowledge of the tumor microenvironment (TME).
    METHODS: The TME is an integral part of the tumor, composed of several cells: immune, stromal, and endothelial, among others, thus offering a wide range of tumor interactions and multiple possibilities for targeted therapies and environment modulation. While the TME in pancreatic ductal adenocarcinoma is widely studied, it is not very true for the TME of pancreatic neuroendocrine neoplasms (PNENs).
    DISCUSSION AND CONCLUSION: The incidence of PNENs is increasing and, therefore, it is important to comprehend their biology for the evolution of efficient therapies since many of the PNENs develop metastasis, including the G1 PNENs. This paper focuses on a review of the role of the TME in PNENs.
    Keywords:  immunotherapy; pancreatic cancer; tumor microenvironment
    DOI:  https://doi.org/10.1002/cam4.70798
  11. Expert Rev Anticancer Ther. 2025 Mar 27. 1-22
    Contemporary understanding of myeloid-derived suppressor cells in the acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) tumor microenvironment.
    Abdulrahman Alhajahjeh, Maximilian Stahl, Tae K Kim, Tariq Kewan, Jessica M Stempel, Amer M Zeidan, Jan Philipp Bewersdorf.
       INTRODUCTION: Myeloid-derived suppressor cells (MDSCs) are a key immunosuppressive component in the tumor microenvironment, contributing to immune evasion and disease progression in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
    AREAS COVERED: We searched PubMed for literature that evaluated the effect of MDSCs in myeloid diseases. MDSCs impact outcomes by facilitating leukemic stem cell survival, impairing immune checkpoint efficacy, and modulating the bone marrow niche. While these immunosuppressive properties can mitigate graft-versus-host disease post-transplantation, sustained MDSC-mediated immunosuppression can also increase the risk of leukemia relapse.We review MDSC development and function, including metabolic reprogramming, epigenetic modifications, and cytokine-mediated pathways. Therapeutic strategies targeting MDSCs, such as depletion, functional reprogramming, and inhibition of key metabolic and immune pathways, show promising data in preclinical models. However, clinical translation remains hindered by challenges in MDSC quantification and standardization of functional assays. This review underscores the potential of combining MDSC-targeted therapies with conventional and novel treatments to improve patient outcomes in AML and MDS.
    EXPERT OPINION: Future studies should focus on standardizing MDSC assessment, elucidate their dynamic roles in therapy, and optimize combination approaches for clinical application.
    Keywords:  AML; MDS; MDSC; immunology; targeted therapy
    DOI:  https://doi.org/10.1080/14737140.2025.2483855
  12. Int J Mol Sci. 2025 Mar 20. pii: 2795. [Epub ahead of print]26(6):
    Tumor Microenvironment Dynamics of Triple-Negative Breast Cancer Under Radiation Therapy.
    Suryakant Niture, Subhajit Ghosh, Jerry Jaboin, Danushka Seneviratne.
      Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of estrogen receptors (ER), progesterone receptors (PR), and HER2 expression. While TNBC is relatively less common, accounting for only 10-15% of initial breast cancer diagnosis, due to its aggressive nature, it carries a worse prognosis in comparison to its hormone receptor-positive counterparts. Despite significant advancements in the screening, diagnosis, and treatment of breast cancer, TNBC remains an important public health burden. Following treatment with chemotherapy, surgery, and radiation, over 40% of TNBC patients experience relapse within 3 years and achieve the least benefit from post-mastectomy radiation. The tumor microenvironment environment (TME) is pivotal in TNBC initiation, progression, immune evasion, treatment resistance, and tumor prognosis. TME is a complex network that consists of immune cells, non-immune cells, and soluble factors located in the region adjacent to the tumor that modulates the therapeutic response differentially between hormone receptor-positive breast cancer and TNBC. While the mechanisms underlying the radiation resistance of TNBC remain unclear, the immunosuppressive TME of TNBC has been implicated in chemotherapeutic resistance. Radiation therapy (RT) is known to alter the TME; however, immune changes elicited by radiation are poorly characterized to date, and whether these immune changes contribute to radiation resistance remains unknown. This review delves into the distinct characteristics of the TNBC TME, explores how RT influences TME dynamics, and examines mechanisms underlying tumor radiosensitization, radioresistance, and immune responses.
    Keywords:  immune response; radiation therapy; radioresistance; triple-negative breast cancer; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms26062795
  13. Naunyn Schmiedebergs Arch Pharmacol. 2025 Mar 25.
    Battlegrounds of treatment resistance: decoding the tumor microenvironment.
    Mobina Bayat, Javid Sadri Nahand.
      The tumor microenvironment (TME) emerges as a formidable actor in the cancer treatment landscape, wielding the power to thwart therapeutic efficacy across various modalities, including chemotherapy, radiotherapy, immunotherapy, targeted therapy, and hormonal therapy. This intricate ecosystem comprising diverse cellular constituents, signaling molecules, and the extracellular matrix fosters a dynamic interplay that profoundly influences tumor behavior and treatment outcomes. This review explores the mechanisms through which the TME drives resistance to standard therapies, emphasizing key factors such as hypoxia, immune evasion, and metabolic reprogramming. Furthermore, we illuminate innovative strategies aimed at reprogramming this hostile environment, including the application of therapeutic vaccines, CAR T cell therapy, and combination immunotherapies designed to enhance anti-tumor responses. By advocating for multidimensional approaches that dismantle the TME's barriers to effective treatment, this review calls for a transformative shift in cancer treatment paradigms. By bridging the gap between the TME's complexities and targeted therapeutic strategies, we pave the way for targeted interventions that promise to enhance clinical outcomes and improve patient prognosis in the relentless battle against cancer.
    Keywords:  Targeted therapy; Treatment resistance; Tumor microenvironment; Tumor-immune therapy
    DOI:  https://doi.org/10.1007/s00210-025-04055-5
  14. Front Pharmacol. 2025 ;16 1583986
    Editorial: Metabolic reprogramming in cancer.
    Valentina Audrito, Elisa Giovannetti.
      
    Keywords:  cancer; metabolic pathways; metabolic plasticity; metabolic reprogramming; metabolites; tumor microenvironment; tumorigenesis
    DOI:  https://doi.org/10.3389/fphar.2025.1583986
  15. Biology (Basel). 2025 Feb 27. pii: 243. [Epub ahead of print]14(3):
    Decoding the Tumor-Associated Microbiota: From Origins to Nanomedicine Applications in Cancer Therapy.
    Ruiqi Wang, Weizheng Li, Hongqian Cao, Lei Zhang.
      Growing evidence reveals that the tumor microbiome-comprising distinct microbial communities within neoplastic tissues-exerts a profound influence on cancer initiation, progression, and therapeutic response. These microbes actively reshape the tumor microenvironment (TME) through metabolite secretion, the modulation of immune pathways, and direct interactions with host cells, thereby affecting tumor biology and therapeutic outcomes. Despite substantial heterogeneity among cancer types, recent insights underscore the tumor microbiome's potential as both a diagnostic/prognostic biomarker and a targetable component for innovative treatments. In this review, we synthesize emerging knowledge on the mechanistic roles of tumor-associated microbiota in shaping the TME, with a focus on how these discoveries can guide novel therapeutic strategies. We further explore interdisciplinary advances, including the convergence of microbiomics and nanotechnology, to enhance drug delivery, circumvent resistance, and foster TME remodeling. By highlighting these cutting-edge developments, our review underscores the transformative potential of integrating tumor microbiome research into precision oncology and advancing more personalized cancer therapies.
    Keywords:  cancer therapy; immune modulation; nanotechnology; precision medicine; tumor microenvironment; tumor-associated microbiota
    DOI:  https://doi.org/10.3390/biology14030243
  16. Immunotargets Ther. 2025 ;14 247-258
    Myeloid Cells in the Immunosuppressive Microenvironment as Immunotargets in Osteosarcoma.
    Cyrus J Sholevar, Natalie M Liu, Tasneem Mukarrama, Jinhwan Kim, Jessica Lawrence, Robert J Canter.
      Osteosarcoma is an aggressive primary malignant bone tumor associated with high rates of metastasis and poor 5-year survival rates with limited improvements in approximately 40 years. Standard multimodality treatment includes chemotherapy and surgery, and survival rates have remained stagnant. Overall, response rates to immunotherapy like immune checkpoint inhibitors have been disappointing in osteosarcoma despite exciting results in other epithelial tumor types. The poor response of osteosarcoma to current immunotherapies is multifactorial, but a key observation is that the tumor microenvironment in osteosarcoma is profoundly immunosuppressive, and increasing evidence suggests a significant role of suppressive myeloid cells in tumor progression and immune evasion, particularly by myeloid-derived suppressor cells. Targeting suppressive myeloid cells via novel agents are attractive strategies to develop novel immunotherapies for osteosarcoma, and combination strategies will likely be important for durable responses. In this review, we will examine mechanisms of the immunosuppressive microenvironment, highlight pre-clinical and clinical data of combination strategies including colony-stimulating factor 1 (CSF-1) receptor, phosphoinositide 3-kinase (PI3K), CXCR4, and checkpoint inhibition, as well as the role of canine models in elucidating myeloid cells as targets in osteosarcoma immunotherapy.
    Keywords:  MDSC; immunotherapy; macrophage; sarcoma; tumor microenvironment
    DOI:  https://doi.org/10.2147/ITT.S485672
  17. Curr Oncol. 2025 Feb 28. pii: 143. [Epub ahead of print]32(3):
    Breast Cancer and Tumor Microenvironment: The Crucial Role of Immune Cells.
    Tânia Moura, Paula Laranjeira, Olga Caramelo, Ana M Gil, Artur Paiva.
      Breast cancer is the most common type of cancer in women and the second leading cause of death by cancer. Despite recent advances, the mortality rate remains high, underlining the need to develop new therapeutic approaches. The complex interaction between cancer cells and the tumor microenvironment (TME) is crucial in determining tumor progression, therapy response, and patient prognosis. Understanding the role of immune cells in carcinogenesis and tumor progression can help improve targeted therapeutic options, increasing the likelihood of a favorable prognosis. Therefore, this review aims to critically analyze the complex interaction between tumor cells and immune cells, emphasizing the clinical and therapeutic implications. Additionally, we explore advances in immunotherapies, with a focus on immune checkpoint inhibitors.
    Keywords:  breast cancer; immune cells; immune checkpoints inhibitors; immune system; tumor microenvironment
    DOI:  https://doi.org/10.3390/curroncol32030143
  18. Cancer Sci. 2025 Mar 25.
    Differentiation of Cytotoxic CD8+ T Cell Subsets Under Tumor Progression: Can CD69 Be a New Therapeutic Target?
    Ryo Koyama-Nasu, Yangsong Wang, Hinata Miyano, Motoko Y Kimura.
      Tumor-specific CD8+ T cells play a pivotal role in anti-tumor immunity. Here, we review the heterogeneity of CD8+ T cell subsets during tumor progression. While both acute and chronic viral infections induce distinct CD8+ T cell responses, chronic responses are also observed during tumor development. Chronic immune responses have traditionally been considered to represent a dysfunctional state of CD8+ T cells, whereas the identification of TCF1+ stem-like CD8+ T cells has highlighted their importance in anti-tumor immunity. During tumor progression, TCF1+ stem-like CD8+ T cells differentiate into cytotoxic Tim-3+ terminally differentiated CD8+ T cells through mechanisms that remain largely unknown. We recently identified CD69 as an important regulator of chronic CD8+ T cell responses and showed that blocking CD69 function, either through the administration of anti-CD69 antibody (Ab) or genetic knockout, enhanced the generation of cytotoxic Tim-3+ terminally differentiated CD8+ T cells in both tumor-draining lymph nodes (TDLNs) and the tumor microenvironment (TME), thereby enhancing the anti-tumor immune response. These findings suggest that CD69 is an attractive therapeutic target that controls the chronic anti-tumor CD8+ T cell response.
    Keywords:  CD69; chronic CD8+ T cell response; tumor‐draining lymph nodes; tumor‐specific CD8+ T cells
    DOI:  https://doi.org/10.1111/cas.70055
  19. Cancer Med. 2025 Apr;14(7): e70789
    Chemokines: Orchestration of the Tumor Microenvironment and Control of Hepatocellular Carcinoma Progression.
    Jiezuan Yang, Haifeng Lu, Lanjuan Li.
      Chemokines, a family of chemotactic cytokines, play a central role in shaping the tumor microenvironment (TME) and in influencing the progression of hepatocellular carcinoma (HCC), a well-known inflammation-related cancer. This review addresses the intricate interplay between chemokines and HCC and highlights their multifaceted role. We discuss how altered expression of chemokines within the TME contributes to the development of HCC by orchestrating the recruitment of immune cells, ultimately leading to immunosuppression. In addition, we are investigating the contribution of chemokines to important features of HCC progression, including angiogenesis and epithelial-mesenchymal transition (EMT). The potential of chemokines as serum biomarkers for HCC diagnosis and their potential as novel therapeutic targets are also explored. This comprehensive review emphasizes the importance of chemokines in the pathogenesis of HCC and their potential for a better understanding and treatment of this difficult disease.
    Keywords:  chemokine; hepatocellular carcinoma; prognosis; receptor; tumor microenvironment
    DOI:  https://doi.org/10.1002/cam4.70789
  20. Acta Biochim Biophys Sin (Shanghai). 2025 Mar 28.
    Breast cancer-derived exosomal miR-105-5p facilitates the transformation of NFs into CAFs through LATS2-NF-κB signaling.
    Xiaodi Ding, Zhimei Sheng, Jiayu Cui, Meimei Cui, Liying Zhang, Ruijun Feng, Yongming Wang, Wei Sun, Xiurong Zhang, Lihong Shi, Baogang Zhang.
      Studies of cell-to-cell activities in the tumor microenvironment (TME) have identified multiple potential targets for oncotherapy. The interplay between tumor cells and neighboring cancer-associated fibroblasts (CAFs) persists in all stages of tumor progression. In this study, we reveal that exosomes from breast cancer cells can be endocytosed into fibroblasts and transform normal fibroblasts (NFs) into CAFs and that the ability of exosomes from highly metastatic breast cancer cells is greater than that of those from poorly metastatic breast cancer cells. Further investigation reveals that exosomes from highly metastatic breast cancer cells contain much more miR-105-5p than those from poorly metastatic breast cells do and that exosomal miR-105-5p facilitates the transformation of NFs to CAFs. A detailed study reveals that RBMY1A1-dependent sorting of miR-105-5p into fibroblasts and subsequent internalization of miR-105-5p promote the transformation of NFs to CAFs by downregulating LATS2 expression and activating NF-κB signaling, which concurrently facilitates the EMT of breast cancer cells. Thus, our results indicate that exosomal miR-105-5p may be a potential target for novel therapeutic strategies to prevent the coevolution of breast cancer cells and CAFs.
    Keywords:  breast cancer; cancer-associated fibroblasts; exosomes; miRNAs; tumor microenvironment
    DOI:  https://doi.org/10.3724/abbs.2025017
  21. Sci Immunol. 2025 Mar 28. 10(105): eabo5570
    Immunogenomic cancer evolution: A framework to understand cancer immunosuppression.
    Shogo Kumagai, Yusaku Momoi, Hiroyoshi Nishikawa.
      The process of tumor development involves tumor cells eluding detection and suppression of immune responses, which can cause decreased tumor cell antigenicity, expression of immunosuppressive molecules, and immunosuppressive cell recruitment to the tumor microenvironment (TME). Immunologically and genomically integrated analysis (immunogenomic analysis) of patient specimens has revealed that oncogenic aberrant signaling is involved in both carcinogenesis and immune evasion. In noninflamed cancers such as epidermal growth factor receptor (EGFR)-mutated lung cancers, genetic abnormalities in cancer cells contribute to the formation of an immunosuppressive TME by recruiting immunosuppressive cells, which cannot be fully explained by the cancer immunoediting hypothesis. This review summarizes the latest findings regarding the links between cancer genetic abnormalities and immunosuppression causing clinical resistance to immunotherapy. We propose the concepts of immunogenomic cancer evolution, in which cancer cell genomic evolution shapes the immunosuppressive TME, and immunogenomic precision medicine, in which cancer immunotherapy can be combined with molecularly targeted reagents that modulate the immunosuppressive TME.
    DOI:  https://doi.org/10.1126/sciimmunol.abo5570
  22. Indian J Clin Biochem. 2025 Apr;40(2): 165-175
    Metabolic Reprogramming of Anti-cancer T Cells: Targeting AMPK and PPAR to Optimize Cancer Immunotherapy.
    Abduldaheem Turki Jalil, Hassan Hadi Al-Kazzaz, Firas A Hassan, Safaa Halool Mohammed, Muna S Merza, Tahani Aslandook, Ahmed Elewadi, Ali Fadhil, Ali Alsalamy.
      Cancer treatment era has been revolutionized by the novel therapeutic methods such as immunotherapy in recent years. Immunotherapy-based approaches are considered effective and reliable methods that has brought hope to eradicate certain cancers. Nonetheless, there are some issues, considered as critical obstacles in successful cancer immunotherapy. Such issues are attributed to the ability of the tumor cells in providing a tolerant microenvironment that impairs the immune responses, and help the cancer cells evade the immunogenic cell death. It has been suggested that the re-activation and maintenance of effector immune cells may become possible by metabolic reprogramming. Several signaling pathways have been noticed with the possibility of metabolic reprogramming of tumor-specific T cells, to overcome the metabolic restrictions in the tumor microenvironment; and among them, AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptors (PPAR) have been investigated the most as the main energy sensors and regulators of mitochondrial biogenesis. The synergic effects of AMPK activators and/or PPAR agonists in cancer immunotherapy have been reported. In this review, we compare the roles of AMPK activators and PPAR agonists, and the efficacy of their combination in metabolic reprogramming of cytotoxic T cells in favoring cancer immunotherapy.
    Keywords:  AMPK; Cancer immunotherapy; PPAR; T cell metabolic reprogramming; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12291-023-01166-9
  23. Cancer Gene Ther. 2025 Mar 26.
    MDSC checkpoint blockade therapy: a new breakthrough point overcoming immunosuppression in cancer immunotherapy.
    Abdulrahman Ibrahim, Nada Mohamady Farouk Abdalsalam, Zihao Liang, Hafiza Kashaf Tariq, Rong Li, Lukman O Afolabi, Lawan Rabiu, Xuechen Chen, Shu Xu, Zhiming Xu, Xiaochun Wan, Dehong Yan.
      Despite the success of cancer immunotherapy in treating hematologic malignancies, their efficacy in solid tumors remains limited due to the immunosuppressive tumor microenvironment (TME), which is mainly formed by myeloid-derived suppressor cells (MDSCs). MDSCs not only exert potent immunosuppressive effects that hinder the success of immune checkpoint inhibitors (ICIs) and adaptive cellular therapies, but they also promote tumor advancement through non-immunological pathways, including promoting angiogenesis, driving epithelial-mesenchymal transition (EMT), and contributing to the establishment of pre-metastatic environments. While targeting MDSCs alone or in combination with conventional therapies has shown limited success, emerging evidence suggests that MDSC checkpoint blockade in combination with other immunotherapies holds great promise in overcoming both immunological and non-immunological barriers. In this review, we discussed the dual roles of MDSCs, with a particular emphasis on their underexplored checkpoints blockade strategies. We discussed the rationale behind combination strategies, their potential advantages in overcoming MDSC-mediated immunosuppression, and the challenges associated with their development. Additionally, we highlight future research directions aimed at optimizing combination immunotherapies to enhance cancer therapeutic effectiveness, particularly in solid tumor therapies where MDSCs are highly prevalent.
    DOI:  https://doi.org/10.1038/s41417-025-00886-9
  24. Exp Cell Res. 2025 Mar 22. pii: S0014-4827(25)00104-1. [Epub ahead of print]447(2): 114508
    The mutual effects of stearoyl-CoA desaturase and cancer-associated fibroblasts: A focus on cancer biology.
    Suleiman Ibrahim Mohammad, Asokan Vasudevan, Ahmad Hussein Alzewmel, Safia Obaidur Rab, Suhas Ballal, Rishiv Kalia, J Bethanney Janney, Subhashree Ray, Kamal Kant Joshi, Hatif Abdulrazaq Yasin.
      The tumor microenvironment (TME) 's primary constituents that promote cancer development are cancer-associated fibroblasts (CAFs). Metabolic remodeling has been shown to control CAF activity, particularly aberrant lipid metabolism. SCD1 can be thought of as the primary enzyme controlling the fluidity of lipid bilayers by gradually converting saturated fatty acids into monounsaturated fatty acids. Furthermore, its crucial function in the onset and spread of cancer is well acknowledged. Even with the increasing amount of research on changes in lipid metabolism, this problem remains a relatively understudied aspect of cancer research. Blocking several fatty acid synthesis-related enzymes highly expressed in cancerous cells inhibits cell division and encourages apoptosis. This is the situation with SCD1, whose overexpression has been linked to several changed tumors and cells. Both genetic and pharmacological silencing of SCD1 in cancer cells prevents glucose-mediated lipogenesis and tumor cell growth. However, its role in CAFs, hence, cancer biology, has been less studied. This study aimed to review the role of SCD1 in CAF biology, shedding light on their function in cancer cell biology.
    Keywords:  CAFs; Lipid metabolism; Malignancy; SCD1
    DOI:  https://doi.org/10.1016/j.yexcr.2025.114508
  25. Mater Today Bio. 2025 Apr;31 101626
    For and against tumor microenvironment: Nanoparticle-based strategies for active cancer therapy.
    Soroush Karimi, Roksana Bakhshali, Soheil Bolandi, Zahra Zahed, Seyedeh Sahar Mojtaba Zadeh, Masoumeh Kaveh Zenjanab, Rana Jahanban Esfahlan.
      Cancer treatment is challenged by the tumor microenvironment (TME), which promotes drug resistance and cancer cell growth. This review offers a comprehensive and innovative perspective on how nanomedicine can modify the TME to enhance therapy. Strategies include using nanoparticles to improve oxygenation, adjust acidity, and alter the extracellular matrix, making treatments more effective. Additionally, nanoparticles can enhance immune responses by activating immune cells and reducing suppression within tumors. By integrating these approaches with existing therapies, such as chemotherapy and radiotherapy, nanoparticles show promise in overcoming traditional treatment barriers. The review discusses how changes in the TME can enhance the effectiveness of nanomedicine itself, creating a reciprocal relationship that boosts overall efficacy. We also highlight novel strategies aimed at exploiting and overcoming the TME, leveraging nanoparticle-based approaches for targeted cancer therapy through precise TME modulation.
    Keywords:  Cancer therapy; Engineered nanoparticle; Tumor microenvironment modulation
    DOI:  https://doi.org/10.1016/j.mtbio.2025.101626
  26. Immunobiology. 2025 Mar 14. pii: S0171-2985(25)00022-1. [Epub ahead of print]230(3): 152888
    Targeting B7-H3 in solid tumors: Development and evaluation of novel CAR-T Cell therapy.
    Ning Li, Chunhua Zhang, Xiaoyu Li, Shufen Liu, Youhua Xu, Xifei Yang.
      Ovarian and gastric cancers, representative of many solid tumors, remain among the most challenging malignancies to treat due to limited therapeutic options and poor outcomes at advanced stages. Although immunotherapies have revolutionized cancer treatment, their efficacy in solid tumors has been hindered by issues such as antigen heterogeneity and the immunosuppressive tumor microenvironment. This study presents the development and evaluation of third-generation chimeric antigen receptor T (CAR-T) cells targeting B7-H3, an immune checkpoint molecule widely overexpressed in solid tumors. The B7-H3 CAR-T cells exhibited robust and selective cytotoxicity against B7-H3-positive tumor cells, sparing normal tissues. In preclinical animal models, these cells significantly inhibited tumor growth, demonstrating higher targeting specificity and preferential accumulation in tumor sites. These results highlight B7-H3-targeted CAR-T cells as a potential breakthrough in immunotherapy for solid tumors, offering a foundation for future clinical trials to refine their safety and efficacy.
    Keywords:  B7-H3; CAR-T cells; Immunotherapy; Solid tumors; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.imbio.2025.152888
  27. Metabolites. 2025 Mar 13. pii: 201. [Epub ahead of print]15(3):
    Nanomedicines Targeting Metabolic Pathways in the Tumor Microenvironment: Future Perspectives and the Role of AI.
    Shuai Fan, Wenyu Wang, Wenbo Che, Yicheng Xu, Chuan Jin, Lei Dong, Qin Xia.
      Background: Tumor cells engage in continuous self-replication by utilizing a large number of resources and capabilities, typically within an aberrant metabolic regulatory network to meet their own demands. This metabolic dysregulation leads to the formation of the tumor microenvironment (TME) in most solid tumors. Nanomedicines, due to their unique physicochemical properties, can achieve passive targeting in certain solid tumors through the enhanced permeability and retention (EPR) effect, or active targeting through deliberate design optimization, resulting in accumulation within the TME. The use of nanomedicines to target critical metabolic pathways in tumors holds significant promise. However, the design of nanomedicines requires the careful selection of relevant drugs and materials, taking into account multiple factors. The traditional trial-and-error process is relatively inefficient. Artificial intelligence (AI) can integrate big data to evaluate the accumulation and delivery efficiency of nanomedicines, thereby assisting in the design of nanodrugs. Methods: We have conducted a detailed review of key papers from databases, such as ScienceDirect, Scopus, Wiley, Web of Science, and PubMed, focusing on tumor metabolic reprogramming, the mechanisms of action of nanomedicines, the development of nanomedicines targeting tumor metabolism, and the application of AI in empowering nanomedicines. We have integrated the relevant content to present the current status of research on nanomedicines targeting tumor metabolism and potential future directions in this field. Results: Nanomedicines possess excellent TME targeting properties, which can be utilized to disrupt key metabolic pathways in tumor cells, including glycolysis, lipid metabolism, amino acid metabolism, and nucleotide metabolism. This disruption leads to the selective killing of tumor cells and disturbance of the TME. Extensive research has demonstrated that AI-driven methodologies have revolutionized nanomedicine development, while concurrently enabling the precise identification of critical molecular regulators involved in oncogenic metabolic reprogramming pathways, thereby catalyzing transformative innovations in targeted cancer therapeutics. Conclusions: The development of nanomedicines targeting tumor metabolic pathways holds great promise. Additionally, AI will accelerate the discovery of metabolism-related targets, empower the design and optimization of nanomedicines, and help minimize their toxicity, thereby providing a new paradigm for future nanomedicine development.
    Keywords:  TME; artificial intelligence; metabolism; nanomedicine; tumor
    DOI:  https://doi.org/10.3390/metabo15030201
  28. Front Oncol. 2025 ;15 1523751
    Chemokines and their receptors in the esophageal carcinoma tumor microenvironment: key factors for metastasis and progression.
    Pan Liu, Zhiqiang Sun.
      Esophageal carcinoma (ESCA) is a highly malignant tumor with the highest incidence in Eastern Asia. Although treatment modalities for ESCA have advanced in recent years, the overall prognosis remains poor, as most patients are diagnosed at an advanced stage of the disease. There is an urgent need to promote early screening for ESCA to increase survival rates and improve patient outcomes. The development of ESCA is closely linked to the complex tumor microenvironment (TME), where chemokines and their receptors play pivotal roles. Chemokines are a class of small-molecule, secreted proteins and constitute the largest family of cytokines. They not only directly regulate tumor growth and proliferation but also influence cell migration and localization through specific receptor interactions. Consequently, chemokines and their receptors affect tumor invasion and metastatic spread. Furthermore, chemokines regulate immune cells, including macrophages and regulatory T cells, within the TME. The recruitment of these immune cells further leads to immunosuppression, creating favorable conditions for tumor growth and metastasis. This review examines the impact of ESCA-associated chemokines and their receptors on ESCA, emphasizing their critical involvement in the ESCA TME.
    Keywords:  chemokine; chemokine receptor; esophageal carcinoma; immunosuppression; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2025.1523751
  29. J Clin Invest. 2025 Mar 25. pii: e186034. [Epub ahead of print]
    Targeting legumain-mediated cell-cell interaction sensitizes glioblastoma to immunotherapy in preclinical models.
    Lizhi Pang, Songlin Guo, Yuyun Huang, Fatima Khan, Yang Liu, Fei Zhou, Justin D Lathia, Peiwen Chen.
      Tumor-associated macrophages (TAMs) are the most prominent immune cell population in the glioblastoma (GBM) tumor microenvironment (TME) and play critical roles in promoting tumor progression and immunosuppression. Here we identified that TAM-derived legumain (LGMN) exhibited a dual role in regulating the biology of TAMs and GBM cells. LGMN promoted macrophage infiltration in a cell-autonomous manner by activating the GSK3b-STAT3 pathway. Moreover, TAM-derived LGMN activated the integrin aV-AKT-P65 signaling to drive GBM cell proliferation and survival. Targeting LGMN-directed macrophage (inhibiting GSK3b and STAT3) and GBM cell (inhibiting integrin aV) mechanisms resulted in an anti-tumor effect in immunocompetent GBM mouse models that was further enhanced when combined with anti-PD1 therapy. Our study reveals a paracrine and autocrine mechanism of TAM-derived LGMN in promoting GBM progression and immunosuppression, providing effective therapeutic targets for improving immunotherapy in GBM.
    Keywords:  Brain cancer; Immunology; Immunotherapy; Macrophages; Oncology
    DOI:  https://doi.org/10.1172/JCI186034
  30. Nanoscale Horiz. 2025 Mar 27.
    Reversing cancer immunosuppression via K+ capture and repolarization of tumor-associated macrophages.
    Si-Ye Tong, Cong-Min Huo, Yu-Cheng Zuo, Shuo Gao, David Tai Leong, Wei Xue, Jing-Yi Zhu.
      Immunosuppression from the tumor microenvironment plays a key role in the failure of cancer immunotherapy. The presence of potassium ions (K+) from dying tumor cells creates an immunosuppressive environment that encourages tumor-associated macrophages (TAMs) to adopt a pro-tumor M2-like phenotype. Alleviating immune suppression from the high K+ environment might boost innate immunity and fight tumor growth. Herein, disulfide-rich mesoporous silica modified with 18-crown-6 ether was developed as a nanocarrier (D-C) to load ML133, encapsulating with the DiR-embedded macrophage membrane (CM) to create D-C/M@CM/DiR. We first saturated the phagocytosis of the mononuclear phagocyte system (MPS) with blank nanocarriers to enhance the tumor accumulation of D-C/M@CM/DiR, which was coated with the same CM. 18-Crown-6 ether captures K+ to reduce immunosuppression, while ML133 promotes the polarization of TAMs to an anti-tumor M1 phenotype by targeting the K+ channel protein Kir2.1 on their membranes. This strategy activates the anti-tumor immune response and effectively inhibits tumor growth.
    DOI:  https://doi.org/10.1039/d5nh00050e
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