bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2026–01–11
sixteen papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Modulating N1 and N2 neutrophils in breast cancer: potential therapeutic approaches - a narrative review.
  2. CAR-NK Engineering to Overcome TME Barriers.
  3. The dual role of glucocorticoids in the breast cancer immune microenvironment: mechanisms and therapeutic implications.
  4. CAR-T Cell Exhaustion in Cancer over the Past Decade: Mitochondrial Metabolism as a Target for Counteraction.
  5. Post-translational modifications of immune checkpoints: molecular mechanisms, tumor microenvironment remodeling, and therapeutic implications.
  6. CD47/SIRPα Immune Checkpoint Modulation: A Synergistic Strategy for Next-Generation CAR Therapies.
  7. ADA1-Driven Metabolic Refueling Enhances CAR T Cell Therapy for Solid Tumors.
  8. Iron and metabolic rewiring in cancer.
  9. [Molecular Mechanism of Neutrophils Driving the Progression of Lung Adenocarcinoma].
  10. Intratumoral Microbiome: Impact on Cancer Progression and Cellular Immunotherapy.
  11. The metabolism-immune axis in colorectal cancer: remodeling the tumor microenvironment through metabolite signaling.
  12. Lymphatic Endothelial Cells and Organ-Associated Lymphangiogenesis in Tumor Microenvironment.
  13. Epigenetics and the Tumor Microenvironment in Neuroendocrine Tumors.
  14. [Mechanisms of Resistance to Chimeric Antigen Receptor T Cell Therapy in Hematological Malignancies and Coping Strategies--Review].
  15. Monocytes Provoke Breast Cancer Cells to Express PD-L1 via a Cell-to-Cell Interaction Involving CD44 and Moesin.
  16. Modeling cancer-associated fibroblast plasticity and breast cancer interactions using patient-derived scaffolds.
  1. Ann Med Surg (Lond). 2026 Jan;88(1): 621-629
    Modulating N1 and N2 neutrophils in breast cancer: potential therapeutic approaches - a narrative review.
    Emmanuel Ifeanyi Obeagu.
      Neutrophils play a dual role in breast cancer progression, acting as anti-tumorigenic (N1) or pro-tumorigenic (N2) subtypes based on cues from the tumor microenvironment (TME). This review examines the mechanisms driving neutrophil polarization, focusing on how the TME promotes N2 dominance to support tumor growth, angiogenesis, and metastasis. Therapeutic strategies targeting these processes, including cytokine modulation, immune checkpoint inhibitors, and small-molecule drugs, are discussed. Emerging insights into neutrophil biology highlight the potential to reprogram N2 neutrophils into N1 phenotypes, offering promising avenues for enhancing cancer immunotherapy and improving breast cancer outcomes. Neutrophils are critical components of the tumor microenvironment, influencing breast cancer progression through distinct subtypes: anti-tumorigenic N1 and pro-tumorigenic N2 neutrophils. This review delves into the polarization of neutrophils by tumor-derived factors and their contrasting roles in breast cancer biology. N2 neutrophils drive angiogenesis, immunosuppression, and metastasis, while N1 neutrophils counteract these processes. Current therapeutic approaches, including TGF-β inhibitors, chemokine modulation, and immune checkpoint therapies, aim to shift the balance toward N1 neutrophils.
    Keywords:  N1 neutrophils; N2 neutrophils; breast cancer; therapeutic modulation; tumor microenvironment
    DOI:  https://doi.org/10.1097/MS9.0000000000004531
  2. Cells. 2025 Dec 22. pii: 21. [Epub ahead of print]15(1):
    CAR-NK Engineering to Overcome TME Barriers.
    Fahmida Islam, Aleta Pupovac, Richard L Boyd, Alan O Trounson.
      Chimeric antigen receptor (CAR)-based immunotherapy has shown considerable promise in cancer treatment by redirecting immune effector cells to recognize and eliminate tumor cells in an antigen-specific manner. While CAR-T cells bearing tumor-specific CARs have shown remarkable success in treating some hematological malignancies, their clinical application is limited by cytokine release syndrome, neurotoxicity, and graft-versus-host disease. In contrast, CAR-natural killer (NK) cells retain their multiple forms of natural anti-tumor capabilities without the pathological side effects and are compatible with allogeneic "off-the-shelf" application by not requiring prior activation signaling. Despite CAR-NK therapies showing promising results in hematological malignancies, they remain limited as effector cells against solid tumors. This is primarily due to the complex, immunosuppressive tumor microenvironment (TME), characterized by hypoxia, nutrient depletion, lactate-induced acidosis, and inhibitory soluble factors. Collectively, these significantly impair NK cell functionality. This review examines challenges faced by CAR-NK therapy in combating solid tumors and outlines strategies to reduce them. Barriers include tumor antigen heterogeneity, immune escape, trogocytosis-mediated fratricide, rigid structural and metabolic barriers in the TME, immunosuppressive factors, and defective homing and cell persistence of CAR-NK cells. We also emphasize the impact of combining other complementary immunotherapies (e.g., multi-specific immune engagers and immunomodulatory agents) that further strengthen CAR-NK efficacy. Finally, we highlight critical research gaps in CAR-NK therapy and propose that cutting-edge technologies are required for successful clinical translation in solid tumor treatment.
    Keywords:  CAR-NK cells; TME; antigen heterogeneity; immune escape
    DOI:  https://doi.org/10.3390/cells15010021
  3. Front Immunol. 2025 ;16 1719277
    The dual role of glucocorticoids in the breast cancer immune microenvironment: mechanisms and therapeutic implications.
    Bianping Liang, Xinglan Wang, Yunrui Fu, Mingxue Wang.
      Glucocorticoids (GCs), such as dexamethasone (Dex), are widely used in breast cancer treatment to alleviate chemotherapy-induced side effects. However, their immunomodulatory effects on the tumor microenvironment (TME) exhibit a dual nature. On one hand, Dex may delay tumor progression by suppressing pro-inflammatory cytokine release, modulating T-cell function, and inhibiting angiogenesis. On the other hand, Dex can promote the formation of an immunosuppressive TME by activating the glucocorticoid receptor (GR) signaling pathway, thereby accelerating breast cancer metastasis. This review summarizes the molecular mechanisms by which Dex influences breast cancer lung metastasis through its regulation of immune cells (e.g., T cells, B cells, myeloid cells), cytokine networks, and metabolic reprogramming in the TME. Additionally, potential strategies targeting GR or combining immunotherapy are discussed.Therefore, this mini review aims to elucidate the complex mechanisms of Dex in the breast cancer TME and ultimately guide the translation of mechanistic discoveries into clinical breakthroughs.
    Keywords:  breast cancer; glucocorticoids; immunosuppression; lung metastasis; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1719277
  4. Cancer Lett. 2026 Jan 02. pii: S0304-3835(26)00003-0. [Epub ahead of print]639 218240
    CAR-T Cell Exhaustion in Cancer over the Past Decade: Mitochondrial Metabolism as a Target for Counteraction.
    Lingling Si, Di Wei, Jinghao Pan, Renato B Baleeiro, Louisa S Chard Dunmall, Yaohe Wang.
      Chimeric antigen receptor T (CAR-T) cell therapy has emerged as a transformative advancement in cancer immunotherapy, but remains limited by multiple challenges. The exhaustion of T cells represents a critical obstacle limiting the success of immunotherapeutic interventions. Targeting mitochondrial metabolism offers a promising approach to mitigate exhaustion and enhance CAR-T persistence. Mechanistically, mitochondrial dysfunction within the tumor microenvironment disrupts energy metabolism, reactive oxygen species (ROS) homeostasis, and cell survival, impairing CAR-T function. Here, we review the current challenges facing the clinical application of CAR-T therapy in cancers and summarize mitochondrial-centered approaches to overcome some of these obstacles by optimizing mitochondrial metabolic pathways. We emphasize the essential role of mitochondrial metabolism in augmenting therapeutic efficacy and persistence of CAR-T cells. Future breakthroughs will depend on robust clinical evidence and precise metabolic modulation to enhance CAR-T therapies.
    Keywords:  CAR-T therapy; Combination therapy; Metabolic reprogramming; Mitochondrial metabolism; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2026.218240
  5. J Biomed Sci. 2026 Jan 04. 33(1): 3
    Post-translational modifications of immune checkpoints: molecular mechanisms, tumor microenvironment remodeling, and therapeutic implications.
    Hung-Chia Hsieh, Lun-Ling Ling, Yi-Ching Wang.
      Immune checkpoints play pivotal roles in regulating immune responses and maintaining tolerance. In cancer, these molecules are hijacked to suppress antitumor immunity, resulting in therapeutic resistance to immune checkpoint blockade (ICB). Recent advances have highlighted the critical role of post-translational modifications (PTMs), including phosphorylation, ubiquitination, glycosylation, palmitoylation, UFMylation, acetylation, SUMOylation, methylation, and ISGylation, in modulating checkpoint stability, trafficking, and function across diverse immune and tumor cell types. These dynamic PTMs reshape the tumor microenvironment (TME) by controlling immune cell function, antigen presentation, and inflammatory signaling. This review comprehensively outlines the mechanistic contributions of PTMs to immune checkpoint regulation, emphasizing how these PTMs orchestrate immune evasion and clinical outcomes. Special focus is given to PTMs of PD-L1, PD-1, TIM-3, TIGIT, CTLA-4, LAG-3, VISTA, BTLA, and SIRPα. We also discuss how targeting PTM-regulating enzymes or specific modification motifs offers a promising therapeutic strategy to overcome ICB resistance. Understanding the PTMs landscape provides critical insight into resistance mechanisms and unveils promising opportunities for rational combination therapies aimed at reprogramming the immunosuppressive TME and enhancing antitumor immunity.
    Keywords:  Cancer immunotherapy; Combination therapy; Immune checkpoints; Post-translational modifications; Targeted therapy; Treatment resistance; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12929-025-01202-1
  6. Mol Cancer Ther. 2026 Jan 10.
    CD47/SIRPα Immune Checkpoint Modulation: A Synergistic Strategy for Next-Generation CAR Therapies.
    Mohammad Javad Yousefi-Hashemabad, Amirhossein Kamroo, Ali Rezvanimehr, Kiarash Saleki, Erfan Barootchi, Aida Mehrani, Alireza Kordi, Andia Saleki, Pardis Zamani, Amirhossein Bazdar, Abdolrahman S Nateri, Shayan Barootchi, Nima Rezaei.
      Cancer immunotherapy has been revolutionized through the implementation of the state-of-the-art "chimeric antigen receptor" (CAR)-mediated therapies. CAR-based technologies, which encompass CAR T cells, CAR macrophages, and CAR-NK cells, show great promise in the treatment of various cancers. Despite the success of CAR-based therapies in treating malignancies, they face numerous challenges, including dysfunction of effector innate and adaptive immune cells, immunosuppressive tumor microenvironment (TME), antigen heterogeneity, and on-target/off-tumor bio-toxicity. The CD47/SIRPα axis is recognized as a critical innate immune checkpoint and is important in regulating myeloid-derived clearance of tumor cells and the innate-adaptive cells' cross-talk in cancer immunity. This signaling axis has risen as a promising target to boost the CAR-based immunotherapies by overcoming phagocytic inhibition and modulating immune evasion. This narrative review explores the integration of CD47/SIRPα modulation as an adjunct to CAR therapies. CD47/SIRPα immune-modulation revealed its potential to boost infiltration, persistence, and phagocytic activity of the immune cells. However, its blockade also poses challenges, including hematologic toxicities, CAR T cell clearance, and compensatory escape pathways. Future work will depend on selective targeting, combinatorial checkpoint modulation, and engineered CAR designs that preserve safety while unlocking durable responses. Herein, we discuss pre-clinical and clinical advancements, safety considerations, and cutting-edge advancements.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-25-0531
  7. Cancers (Basel). 2025 Dec 22. pii: 34. [Epub ahead of print]18(1):
    ADA1-Driven Metabolic Refueling Enhances CAR T Cell Therapy for Solid Tumors.
    Alex Wade Song, Xiaotong Song.
      CAR T cell therapy, while highly effective for hematological malignancies, continues to face significant hurdles in the treatment of solid tumors. Key challenges include severe nutrient deprivation and the presence of immunosuppressive metabolites such as adenosine in the tumor microenvironment, which limit CAR T cell persistence and antitumor activity. This review focuses on current progress and future directions for ADA1-based metabolic reprogramming as a targeted approach to enhance CAR T cell function. We discuss recent advances, particularly the engineering of CAR T cells to express ADA1, which facilitates the local conversion of immunosuppressive adenosine into inosine, thereby supporting T cell metabolism and improving therapeutic outcomes. Preclinical studies, including our own, demonstrate that ADA1-expressing CAR T cells exhibit reduced exhaustion, greater metabolic flexibility, and enhanced antitumor efficacy in solid tumor models. The selective clearance of adenosine and supplementation of inosine directly address the metabolic barriers within the tumor microenvironment and provide an effective strategy to bolster CAR T cell responses. Integration of ADA1-driven metabolic refueling with future innovations in CAR design holds promise for overcoming key obstacles in solid tumor immunotherapy. We conclude by highlighting the potential of ADA1-based strategies and offering our perspective on their translation toward clinical application.
    Keywords:  CAR T cells; adenosine; adenosine deaminase; inosine; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers18010034
  8. Oncogenesis. 2026 Jan 09.
    Iron and metabolic rewiring in cancer.
    Marina Ciscar, César Rodríguez-Santana, Naiara Santana-Codina.
      Iron enables tumor cells to maintain pro-tumoral functions including DNA synthesis and repair, drug resistance and metabolic processes such as oxidative phosphorylation and regulation of reactive oxygen species. To meet these demands, tumor cells rewire iron metabolism to increase iron uptake and use. Therefore, disrupting iron metabolism either by limiting availability or by exploiting iron accumulation to induce ferroptosis, might be a promising strategy for cancer therapy. Recent studies suggest that other cell populations in the tumor microenvironment, including immune cells and cancer-associated fibroblasts, depend on iron and can contribute to iron dysregulation in tumors. Here, we will discuss how iron-dependent pathways contribute to tumor development, with a focus on iron sulfur cluster proteins and heme and their effects on metabolism. In addition, we will describe the relevance of iron crosstalk within the tumor microenvironment in promoting tumor growth, metabolic reprogramming and immune evasion. Finally, we will explore the therapeutic potential of targeting iron-dependent processes beyond the scope of ferroptosis.
    DOI:  https://doi.org/10.1038/s41389-025-00595-w
  9. Zhongguo Fei Ai Za Zhi. 2025 Oct 20. 28(10): 769-776
    [Molecular Mechanism of Neutrophils Driving the Progression of Lung Adenocarcinoma].
    Xiaoya Li, Long Li.
      Lung cancer is one of the most prevalent and lethal malignant tumors worldwide, with lung adenocarcinoma (LUAD) being a major subtype. In recent years, research has revealed that the tumor microenvironment (TME) plays a crucial role in the development and progression of LUAD. Notably, the role of neutrophils has increasingly garnered attention. Studies have shown that neutrophils can differentiate into various phenotypes within the TME, exhibiting multiple pro-tumorigenic functions. Additionally, neutrophils can secrete neutrophil extracellular traps (NETs) in response to certain stimuli. Although NETs possess anti-tumor characteristics, an increasing number of studies have uncovered their multifaceted pro-tumor functions. This review describes the role of neutrophils in the initiation, development, and metastasis of LUAD, focusing on immunoregulation, cellular metabolism, genetics, and various molecular mechanisms.
.
    Keywords:  Lung neoplasms; Molecular mechanism; Neutrophil extracellular traps; Neutrophils; Tumor microenvironment
    DOI:  https://doi.org/10.3779/j.issn.1009-3419.2025.106.29
  10. Cancers (Basel). 2025 Dec 29. pii: 100. [Epub ahead of print]18(1):
    Intratumoral Microbiome: Impact on Cancer Progression and Cellular Immunotherapy.
    Georgy Leonov, Antonina Starodubova, Oleg Makhnach, Dmitry Goldshtein, Diana Salikhova.
      The intratumoral microbiota, comprising bacteria, fungi, and viruses within the tumor microenvironment, actively influences carcinogenesis. Key mechanisms include the induction of host DNA damage, modulation of critical oncogenic signaling pathways such as WNT-β-catenin, NF-κB, and PI3K, and the orchestration of inflammatory processes. The microbiome's interaction with the host immune system is complex and bidirectional. On one hand, specific microbes can foster a pro-tumorigenic niche by suppressing the activity of cytotoxic T cells and natural killer (NK) cells or by promoting the accumulation of immunosuppressive cell types like tumor-associated macrophages (TAMs). On the other hand, microbial components can serve as neoantigens for T cell recognition or produce metabolites that reprogram the immune landscape to enhance anti-tumor responses. The composition of this microbiome is emerging as a crucial factor influencing the outcomes of immunotherapies. Prospective investigations in cancer immunotherapy ought to prioritize mechanistic inquiry employing integrative multi-omics methodologies. The execution of meticulously designed clinical trials for the validation of microbial biomarkers, and the systematic, evidence-based development of microbiome-targeted therapeutic interventions aimed at enhancing antitumor immune responses.
    Keywords:  CAR-T cells; antitumor immunity; cell therapy; gut-tumor axis; immune response; intratumoral microbiome; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers18010100
  11. Front Immunol. 2025 ;16 1735873
    The metabolism-immune axis in colorectal cancer: remodeling the tumor microenvironment through metabolite signaling.
    Shaofan Hu, Hui Heng, Fang Yang, Meng Wang, Guoxiang Liu, Yuancai Xiang, Hongming Miao.
      Metabolic reprogramming is a defining hallmark of tumors, and plays a pivotal role in sustaining malignant growth by rewiring core bioenergetic and biosynthetic pathways. Beyond supporting tumor cell proliferation, survival, and metastasis, it profoundly shapes the tumor microenvironment through nutrient competition, accumulation of immunosuppressive metabolites, and modulation of immune cell function, thereby facilitating immune evasion and therapy resistance. This review comprehensively elaborates on metabolic reprogramming in colorectal cancer, covering key alterations in glucose metabolism (Warburg effect), tricarboxylic acid cycle remodeling, lipid biosynthesis/oxidation, cholesterol metabolism, and amino acid (glutamine, methionine, tryptophan, arginine) metabolism. It further dissects how these metabolic shifts impact the tumor microenvironment in colorectal cancer, including their effects on effector immune cells (CD8+ T cells, NK cells), immunosuppressive populations (Tregs, MDSCs, M2-TAMs), and antigen-presenting cells. Additionally, this review highlights the role of the gut microbiota and their metabolites (e.g., SCFAs, secondary bile acids and indoles) in remodeling the immune microenvironment via metabolic crosstalk. Overall, this work provides a comprehensive understanding of CRC metabolic reprogramming and its microenvironmental impacts, offering critical insights to guide the development of novel metabolism-targeted therapeutic strategies for CRC.
    Keywords:  colorectal cancer (CRC); gut microbiota; immune evasion; metabolic reprogramming; metabolism-targeted therapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1735873
  12. Cells. 2025 Dec 23. pii: 28. [Epub ahead of print]15(1):
    Lymphatic Endothelial Cells and Organ-Associated Lymphangiogenesis in Tumor Microenvironment.
    Rui-Cheng Ji.
      Lymphatic vessels are a kind of heterogeneous and versatile component of the lymphatic system, with a unique ability to respond to environmental changes in different organs. The heterogeneity and plasticity of lymphatic endothelial cells (LECs) and defective lymphatic architecture are critical for organ-specific lymphatic function. Moreover, lymphatic vessels have a dual effect on tumor microenvironment (TME), and lymphangiogenesis, an active and dynamic player, is a hallmark of cancer progression and treatment resistance. Dysregulation of lymphatic vessels and uncontrolled lymphangiogenesis contribute to the pathogenesis of many diseases, including cancer. Increasing evidence has indicated that lymphangiogenesis provides a critical target for inhibiting lymphatic metastasis, in which immune checkpoint inhibitors, either alone or combined with chemotherapy, may have a therapeutic value. This article reviews the current status of tumor-associated lymphangiogenesis and lymphatic remodeling, as well as the crosstalk among LECs, immune cells and cancer cells, which will help to further understand the role of lymphangiogenesis in cancer progression, metastasis, and therapy.
    Keywords:  cancer metastasis; immunotherapy; lymphangiogenesis; lymphatic endothelial cells; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells15010028
  13. Cancers (Basel). 2025 Dec 25. pii: 69. [Epub ahead of print]18(1):
    Epigenetics and the Tumor Microenvironment in Neuroendocrine Tumors.
    Alice Castenetto, Teresa Gagliano.
      Background: Neuroendocrine neoplasms (NENs) represent a heterogeneous group of malignancies arising from neuroendocrine cells and are most commonly localized in the gastroenteropancreatic and pulmonary systems. Overall, most NENs are characterized by a low mutational burden. Consequently, increasing research attention has focused on epigenetic mechanisms and the tumor microenvironment, which may actively contribute to tumor pathogenesis. Moreover, epigenetic modifications represent plausible mediators of communication in the crosstalk between neuroendocrine cancer cells and components of the tumor microenvironment, as observed in other non-neuroendocrine malignancies. Objectives: The aim of this review is to summarize current knowledge on the role of epigenetic regulation and the tumor microenvironment in the pathogenesis of neuroendocrine tumors and to discuss their potential as targets for more effective therapeutic strategies. Methods: We reviewed research articles published over the past decades that investigated the involvement of epigenetic mechanisms and the tumor microenvironment in NENs. Results: Several studies highlight the pivotal role of epigenetic alterations and tumor microenvironment interactions in NEN biology, influencing tumor development, progression, and therapeutic response. Conclusions: Further studies are warranted to deepen understanding in this field, as this may lead to the development of more effective therapies and improved clinical outcomes for patients with neuroendocrine neoplasms.
    Keywords:  crosstalk; epigenetics; neuroendocrine neoplasms; targets; therapeutic strategies; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers18010069
  14. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2025 Dec;33(6): 1820-1824
    [Mechanisms of Resistance to Chimeric Antigen Receptor T Cell Therapy in Hematological Malignancies and Coping Strategies--Review].
    Jun-Xia He, Ya-Ming Xi.
      Chimeric antigen receptor (CAR) T cell therapy has made a major breakthrough in the treatment of hematological malignancies. However, more and more studies have shown that factors such as T-cell exhaustion, tumor antigen modulation, immunosuppressive tumor microenvironment, and CAR-T cell dysfunction can lead to relapse and CAR-T cell resistence in hematologic malignancies. Developing dual-targeted CAR-T cells, exploring new immune targets, blocking CAR-T cell exhaustion, combining CAR-T cells with other therapies, implementing bridging therapies, and designing novel immunotherapies may be strategies to address CAR-T cell resistance. This article reviews the mechanisms of resistance to CAR-T cell therapy in hematological malignancies and the corresponding coping strategies.
    Keywords:  chimeric antigen receptor T cells; hematological malignancies; mechanisms of resistance; coping strategies
    DOI:  https://doi.org/10.19746/j.cnki.issn.1009-2137.2025.06.042
  15. J Immunother. 2025 Nov 13.
    Monocytes Provoke Breast Cancer Cells to Express PD-L1 via a Cell-to-Cell Interaction Involving CD44 and Moesin.
    Saya Matsumoto, Tsunao Kishida, Shin-Ichiro Kotani, Kenta Yamamoto, Mano Horinaka, Shusuke Yasuda, Toshiyuki Sakai, Yasuto Naoi, Tetsuya Taguchi, Osam Mazda.
       SUMMARY: Triple-negative breast cancers (TNBCs), especially metastatic recurrent TNBCs, have a poorer prognosis than many other breast cancers. In recent years, immunotherapy using immune checkpoint inhibitors has been conducted for TNBC patients. Although a limited proportion of patients show excellent response, about half of the patients do not significantly respond to the immunotherapy. Monocytes are the progenitors of macrophages that are most abundantly seen in the tumor microenvironment (TME), but the influence of monocytes on breast cancer cells (BCCs) has not been fully clarified. Thus, we examined whether monocytes prompted BCCs to express PD-L1. As results, BCCs expressed higher levels of PD-L1 and its mRNA after co-culture with monocytes. RNA sequencing analysis revealed overexpression of Moesin mRNA in the BCCs co-cultured with monocytes. siRNA-mediated knockdown of Moesin restored the increase in PD-L1 expression. An addition of CD44 antibody canceled the augmentation of PD-L1 expression caused by the co-culture, suggesting that Moesin and CD44 may be essentially involved in the cell-to-cell interaction between monocytes and BCCs to induce PD-L1 expression. These findings may suggest a novel machinery of tumor escape from anti-tumor immunity, potentially providing implications for improving immunotherapy against TNBCs that are resistant to current immune checkpoint blockade therapy.
    Keywords:  CD44; PD-L1; breast cancer; moesin; monocytes
    DOI:  https://doi.org/10.1097/CJI.0000000000000585
  16. Biomed Pharmacother. 2026 Jan 06. pii: S0753-3322(25)01146-1. [Epub ahead of print]194 118952
    Modeling cancer-associated fibroblast plasticity and breast cancer interactions using patient-derived scaffolds.
    Santiago Ruiz-Martínez, Anna Gustafsson, Elin Johansson, Elena Garre, Khalil Helou, Anders Ståhlberg, Göran Landberg.
      Breast cancer progression is intricately influenced by the tumor microenvironment (TME), where cancer-associated fibroblasts (CAFs) play a central role in modulating tumor behavior. To model these interactions, we employed patient-derived scaffolds (PDSs) with preserved native extracellular matrix (ECM) architecture to investigate fibroblast activation and tumor-stroma crosstalk. Mass spectrometry of 63 breast cancer PDSs revealed distinct matrisome clusters associated with tumor grade, recurrence, and CAF-like enrichment, including myofibroblast (myCAFs) and inflammatory CAFs. Normal fibroblasts cultured on PDSs exhibited progressive activation, marked by upregulation of CAF markers (FAP, CD10, PDGFRα), secretory factors (IL6, HGF), and ECM-remodeling genes. Fibroblasts also displayed transcriptional changes linked to cytoskeletal remodeling and cellular plasticity. In transwell co-culture, MDA-MB-231 cells enhanced fibroblast IL6 secretion and altered fibroblast phenotypes, while PDS-grown fibroblasts modulated cancer cell proliferation and stemness transcriptional programs in a subtype-dependent manner. Spatial context also influenced fibroblast activation in direct co-culture. These findings underscore the dynamic, bidirectional nature of tumor-stroma interactions and support PDSs as a physiologically relevant platform for dissecting CAF heterogeneity, ECM-driven modulation, and their potential impact on breast cancer progression.
    Keywords:  Breast cancer; Cancer-associated fibroblasts; Patient-derived scaffolds; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.biopha.2025.118952
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