bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2025–08–03
37 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Key players in the breast cancer microenvironment: From fibroblasts to immune cells.
  2. Tumor Microenvironment in Melanoma-Characteristic and Clinical Implications.
  3. Hypoxic link between cancer cells and the immune system: The role of adenosine and lactate.
  4. The immune microenvironment in endometrial carcinoma: mechanisms and therapeutic targeting.
  5. Lipid metabolic reprogramming in colorectal cancer: mechanisms and therapeutic strategies.
  6. Immune factors and their role in tumor aggressiveness in glioblastoma: Atypical cadherin FAT1 as a promising target for combating immune evasion.
  7. Breaking immune evasion in breast cancer by targeting COX-2/PGE2 pathway.
  8. Sympathetic nervous system in tumor progression and metabolic regulation: mechanisms and clinical potential.
  9. Plasticity and Functional Heterogeneity of Cancer-Associated Fibroblasts.
  10. The importance of tumor microenvironment modulations in the progression of pancreatic intraductal papillary mucinous neoplasms†.
  11. Comprehensive perspective about exosomes in breast cancer: Role in progression, diagnosis, monitoring, and treatment.
  12. Targeting Exosomal PD-L1 as a New Frontier in Cancer Immunotherapy.
  13. Macrophages at the Crossroads of Chronic Stress and Cancer.
  14. Targeting cancer stem cells with CAR-based immunotherapy: biology, evidence, and future directions.
  15. Derivation of resident macrophages and construction of tumor microenvironment in Flk-1-knockout chimeric mice produced via blastocyst complementation.
  16. Epigenetic mechanisms in HCC immune landscape: Therapeutic implications.
  17. Immune Modulation in Sarcoma: Targeting the Tumor Microenvironment.
  18. Lactylation: A new direction for tumor-targeted therapy.
  19. N2 Neutrophils and Tumor Progression in Breast Cancer: Molecular Pathways and Implications.
  20. Controlled Delivery of C-C Motif Chemokine Ligand 25 by a Hydrogel for Tumor Microenvironment Remodeling in Triple Negative Breast Cancer.
  21. Gut microbiota shapes cancer immunotherapy responses.
  22. Microglia limit brain tumor development by restricting tumor cell proliferation and inducing T-cell immunity.
  23. Immune evasion in cancer: mechanisms and cutting-edge therapeutic approaches.
  24. Activated astrocytes drive the accumulation of apolipoprotein E at the brain tumor edge.
  25. Manufacturing of CRISPR-edited primary mouse CAR T cells for cancer immunotherapy.
  26. The role of E3 ligases and deubiquitinases in PD-L1 regulation and the tumor microenvironment in renal cell carcinoma.
  27. Biomimetic Nanoparticles with Dual Targeting for Hepatocellular Carcinoma Promote Tumor Immune System Activation by Enhancing Extracellular ATP Homeostasis.
  28. Taurine and cancer: Biological properties and multifaceted roles in cancer progression.
  29. The Peripheral Tumor Neuro-Microenvironment: Deciphering Neural Landscape and Mechanistic Insights for Therapeutic Innovation.
  30. Development of tetraculture spheroids as a versatile 3D model for personalized breast cancer research.
  31. Tumor-Associated Macrophages and Collagen Remodeling in Mammary Carcinomas: A Comparative Analysis in Dogs and Humans.
  32. Dual role of hydrogen sulfide in the tumor microenvironment of prostate cancer (Review).
  33. Role of the orexin system in modulating the tumor microenvironment: implications for tumor progression and cancer therapy.
  34. Chemoradiation-Altered Micromilieu of Glioblastoma Cells Particularly Impacts M1-like Macrophage Activation.
  35. Prognostic Value of the Immunohistochemical Detection of Cellular Components of the Tumor Microenvironment in Oral Squamous Cell Carcinoma: A Systematic Review.
  36. CAR-iNKT cells: redefining the frontiers of cellular immunotherapy.
  37. Persistent accumulation of therapy-induced senescent cells: an obstacle to long-term cancer treatment efficacy.
  1. World J Clin Oncol. 2025 Jul 24. 16(7): 107339
    Key players in the breast cancer microenvironment: From fibroblasts to immune cells.
    Sacide Çakal, Buket Er Urgancı, Selda Şimşek.
      Breast cancer is one of the most common malignancies worldwide and is a major cause of cancer-related mortality among women. Beyond tumor cells, the tumor microenvironment (TME) also plays an important role in cancer progression, therapy resistance, and metastasis. The TME is a complex ecosystem consisting of stromal and immune cells, extracellular matrix (ECM), and various signaling molecules that dynamically interact with tumor cells. Cancer-associated fibroblasts remodel the ECM and secrete growth factors that promote tumor growth and invasion. Immune cells, such as tumor-associated macrophages, regulatory T cells, and myeloid-derived suppressor cells, often contribute to an immunosuppressive environment that hinders anti-tumor immune responses. The ECM provides structural support and acts as a reservoir for signaling molecules that influence cancer cell behavior. These components evolve together with tumor cells, facilitating immune evasion, therapy resistance, and epithelial-to-mesenchymal transition, which promotes metastasis. Understanding these interactions is necessary to develop novel therapeutic strategies that target both tumor and microenvironmental components. This minireview highlights the key stromal and immune elements within the breast cancer microenvironment, discussing their individual and collective roles in tumor progression and clinical outcomes, while emphasizing emerging therapeutic approaches aiming to reprogram the TME to improve treatment efficacy.
    Keywords:  Breast cancer; Cancer-associated fibroblasts; Cytokines; Epithelial-to-mesenchymal transition; Extracellular matrix; Metastasis; Targeted therapy; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.5306/wjco.v16.i7.107339
  2. Int J Mol Sci. 2025 Jul 15. pii: 6778. [Epub ahead of print]26(14):
    Tumor Microenvironment in Melanoma-Characteristic and Clinical Implications.
    Hubert Sikorski, Michał Aleksander Żmijewski, Anna Piotrowska.
      Cutaneous melanoma is an aggressive cancer with an increasing incidence worldwide, highlighting the need for research into its pathogenesis. The tumor microenvironment (TME) plays a critical role in melanoma progression and consists of cellular components and an extracellular matrix (ECM) rich in cytokines and signaling molecules. The most abundant stromal cells within the TME are cancer-associated fibroblasts (CAFs), which remodel the ECM and modulate immune responses. Among immune cells, tumor-associated macrophages (TAMs) predominate, and their polarization toward the M2 phenotype supports tumor progression. Tumor-infiltrating lymphocytes (TILs) have diverse functions, including cytotoxic T-cells, helper T-cells that modulate immune response, B-cells forming tertiary lymphoid structures (TLS), and regulatory T-cells with immunosuppressive properties. Dendritic cells (DCs) also play a complex role in the TME. A notable subpopulation are mature regulatory dendritic cells (mregDCs), which contribute to immune evasion. All of these TME components may drive tumorigenesis. Advancements in melanoma treatment-including immunotherapy and targeted therapies-have significantly improved outcomes in advanced-stage disease. In parallel, emerging approaches targeting the tumor microenvironment and gut microbiome, as well as personalized strategies such as neoantigen vaccines and cell-based therapies, are under active investigation and may further enhance therapeutic efficacy in the near future.
    Keywords:  cancer/melanoma-associated fibroblasts (CAFs); dendritic cells; immune checkpoint inhibitors (ICI); macrophages; melanoma; metastases; tumor microenvironment; tumor-infiltrating lymphocytes (TILs)
    DOI:  https://doi.org/10.3390/ijms26146778
  3. Oncol Res. 2025 ;33(8): 1803-1818
    Hypoxic link between cancer cells and the immune system: The role of adenosine and lactate.
    Eduardo Alvarado-Ortiz, Miguel Angel Sarabia-SáNCHEZ.
      The tumor microenvironment (TME) is characterized by a symbiosis between cancer cells and the immune cells. The scarcity of oxygen generates hostility that forces cancer cells to alter their biological features in solid tumors. In response to low oxygen availability, the Hypoxia Inducible Factors (HIF-1/2/3α) act as metabolic mediators, producing extracellular metabolites in the tumor microenvironment that influence the immune cells. The modulation of lactate and adenosine on immune evasion has been widely described; however, under hypoxic conditions, it has been barely addressed. Evidence has demonstrated an interplay between cancer and the immune cells, and the present review explores the findings that support HIFs bridging the gap between the rise of these metabolites and the immunosurveillance failure in a hypoxic context. Moreover, new insights based on systemic oxygen administration are discussed, which might counterbalance the effect mediated by lactate and adenosine, to recover anti-tumor immunity. Thus, the disruption of anti-tumor immunity has been the focus of recent research and this novel avenue opens therapeutic vulnerabilities that can be useful for cancer patients.
    Keywords:  Adenosine; Hypoxia; Hypoxia inducible factors (HIF-1/2/3α); Immune evasion; Lactate; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.32604/or.2025.065953
  4. Front Immunol. 2025 ;16 1586315
    The immune microenvironment in endometrial carcinoma: mechanisms and therapeutic targeting.
    Yilin Wang, Nana Liu, Xiangcui Guo, Ruobing Han, Jin Bai, Jiateng Zhong, Qianqing Wang.
      Endometrial carcinoma (EC) represents one of the most prevalent malignancies within the female reproductive system. The frequency of its occurrence is on the rise annually, and patients diagnosed at advanced stages face a less favorable prognosis. Recent studies have highlighted the significant influence of the tumor immune microenvironment (TME) on the initiation, progression, metastasis, and therapeutic resistance of endometrial cancer. The TME encompasses various components such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), immune cells, and the extracellular matrix (ECM). These elements contribute to an immunosuppressive milieu by secreting cytokines, extracellular vesicles (EVs), and engaging immune checkpoint pathways like PD-1/PD-L1, thereby supporting tumor immune evasion and resistance to treatment. This review synthesizes current understanding of the EC-TME, focusing on the distinct roles and interactions of its key constituents within the context of EC biology. Furthermore, we explore the rationale and progress for novel therapeutic strategies targeting the TME, such as immune checkpoint inhibitors, combination therapies, and nano delivery systems leveraging EVs, aiming to provide insights for improving EC patient outcomes.
    Keywords:  endometrial carcinoma; immune evasion; immunotherapy; targeted therapy; treatment resistance; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1586315
  5. Front Immunol. 2025 ;16 1603032
    Lipid metabolic reprogramming in colorectal cancer: mechanisms and therapeutic strategies.
    Wujianhong Liu, Shengrong Dong, Feiran Hao, Yaohui Gao, Qing Wei.
      Colorectal cancer (CRC) is the third most common cancer worldwide, and its high incidence, mortality, and treatment resistance highlight the urgency of exploring new therapeutic targets. As research into cancer metabolic reprogramming deepens, the central role of lipid metabolism abnormalities in CRC progression has gradually become apparent. In the tumor microenvironment (TME), conditions such as hypoxia, glucose deprivation, and lactic acid accumulation alter the energy demands of tumor cells, driving metabolic reprogramming in lipid uptake, synthesis, and oxidation. This reprogramming helps maintain high energy needs and supports the malignant growth of tumor cells. This lipid metabolic reprogramming provides tumor cells with the necessary energy and enhances their proliferation, invasion, immune evasion, and resistance characteristics. Moreover, the lipid metabolic reprogramming of tumor cells is closely related to various cells within the TME, and these interactions promote, to some extent, the remodeling of the tumor microenvironment, further driving tumor development. Emerging lipid detection technologies position specific lipid molecules as promising biomarkers for auxiliary diagnosis and prognostic evaluation. Concurrently, targeting key lipid metabolic pathways offers innovative strategies to optimize existing therapies and overcome drug resistance. This review summarizes the basic and abnormal mechanisms of lipid metabolism in CRC, lipid metabolic interactions in the tumor microenvironment, the regulatory network between the gut microbiota and lipid metabolism, and the progress in therapeutic strategies targeting lipid metabolism. By exploring the interaction between CRC and lipid metabolism in depth, this review aims to provide new ideas and theoretical support for the treatment, early intervention, and prognosis evaluation of CRC.
    Keywords:  CRC therapy; colorectal cancer; fatty acids; lipid metabolism; the tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1603032
  6. Cell Mol Biol Lett. 2025 Jul 25. 30(1): 89
    Immune factors and their role in tumor aggressiveness in glioblastoma: Atypical cadherin FAT1 as a promising target for combating immune evasion.
    Manvi Arora, Archismita Kundu, Subrata Sinha, Kunzang Chosdol.
      Immune evasion is one of the hallmarks of cancers, including glioblastoma, the most aggressive form of primary brain tumors. Multiple mechanisms are employed by tumor cells and its microenvironment to evade immune detection and foster tumor growth and progression. The secretion of immunosuppressive molecules such as transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), the expression of checkpoint proteins such programmed death-ligand 1 (PD-L1), and the recruitment of T-regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) leads to suppressed immune cell activity, favoring unchecked tumor growth. The FAT atypical cadherin 1 (FAT1) has shown context/tissue-dependent effects in cancers of different tissue origins, with either oncogenic or tumor suppressor roles. Our laboratory has reported FAT1 to have an oncogenic function in glioblastoma. In addition, FAT1 promotes an immunosuppressive microenvironment in glioblastoma, reducing T-cell and monocyte infiltration while increasing immunosuppressive cells such as MDSCs. It also upregulates pro-inflammatory mediators [cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), and interleukin-6 (IL-6)], fostering tumor-promoting signaling. This dual role in immune evasion and pro-tumorigenic inflammatory processes makes FAT1 a key driver of glioblastoma progression. This highlights the potential of FAT1 as a compelling therapeutic target. This article provides a concise overview of immune tolerance mechanisms in glioblastoma, and the crucial role of FAT1 in promoting immune tolerance and tumor advancement. In addition, this review highlights currently available immunotherapies in clinical use or undergoing trials, and the potential of FAT1 as a promising target for combinatorial therapeutic interventions.
    Keywords:   FAT1 ; Glioblastoma; Immunosuppression; Inflammation; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s11658-025-00769-9
  7. Mol Cell Endocrinol. 2025 Jul 23. pii: S0303-7207(25)00168-6. [Epub ahead of print]608 112617
    Breaking immune evasion in breast cancer by targeting COX-2/PGE2 pathway.
    Xuewei Zheng, Junxiang Wang, Yanan OuYang, Kaiyuan Yao, Jiayu Zheng, Li Zeng, Jingjing Wang, Hetao Chen, Haoming Du, Dongliao Fu, Linlin Shi, Anshun Zhao, Qinan Yin.
      The cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway plays a pivotal role in breast cancer (BC) progression by promoting immune suppression, tumor growth, and metastasis. PGE2 mediates these effects through EP receptors (EP1-EP4), suppressing anti-tumor immunity while fostering an immunosuppressive tumor microenvironment (TME). This includes the recruitment and activation of tumor-associated macrophages (TAMs), dendritic cells (DCs), cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), ultimately impairing cytotoxic T lymphocyte and natural killer (NK) cell function. Targeting the COX-2/PGE2 axis presents a promising strategy for BC treatment. Dual inhibition of EP2 and EP4 has demonstrated superior efficacy in reversing immune suppression compared to single-receptor blockade. Additionally, combining EP4 antagonists with immune checkpoint inhibitors (ICIs) such as anti-PD-1 and anti-CTLA-4 enhances T cell infiltration and tumoricidal activity, leading to improved therapeutic outcomes. Another emerging approach involves enhancing the activity of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the key enzyme responsible for PGE2 degradation, to counteract PGE2-driven immune evasion. PTGES1 inhibitors have shown great potential in overcoming the immunosuppressive TME in BC patients. Elevated TIL levels in TNBC and HER2-positive BC are associated with improved prognosis; however, COX-2 inhibitors such as celecoxib failed to enhance survival and carry potential cardiovascular risks, highlighting the need for TIL-stratified trials to refine immunotherapeutic strategies. This review highlights the immunosuppressive mechanisms of the COX-2/PGE2 pathway in BC and explores novel therapeutic strategies targeting this axis. Understanding the intricate crosstalk between PGE2 signaling and immune modulation may lead to the development of more effective BC treatments, particularly in combination with immunotherapies.
    Keywords:  Breast cancer; COX-2/PGE2 pathway; EP antagonisms; Immune cells; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.mce.2025.112617
  8. J Transl Med. 2025 Jul 25. 23(1): 836
    Sympathetic nervous system in tumor progression and metabolic regulation: mechanisms and clinical potential.
    Chen Sun, Yuqing Shen, Fuhua Wang, Tian Lu, Jianqiong Zhang.
      Tumor progression is characterized by profound metabolic alterations and dynamic interactions within the tumor microenvironment (TME), which enable rapid proliferation, immunoinvasion, and metastasis. The sympathetic nervous system (SNS), which has been best known for its role in stress regulation, has emerged as a critical regulator of tumor metabolism. The SNS influences glucose, lipid and glutamine metabolism in tumor cells and stromal components by releasing neurotransmitters such as norepinephrine (NE), creating a pro-tumor metabolic and immunosuppressive microenvironment. SNS signaling enhances glycolysis via upregulation of glucose transporter 1 (GLUT1) and glycolytic enzymes, and supports lipid metabolism through fatty acid synthesis and oxidation. In immune cells, SNS-driven metabolic shifts promote immunosuppressive phenotypes, particularly in T cells and macrophages. Concurrently, SNS signaling enhances glycolysis in endothelial cells, thereby facilitating angiogenesis within the TME. Together, these processes collectively sustain tumor growth, invasion, and resistance to therapy. Therapeutic strategies targeting SNS signaling, such as adrenergic receptors (ARs) blockers, show promise in disrupting these tumor-supportive networks. However, challenges such as the non-specific nature of SNS blockade and the complexity of TME interactions necessitate further research into ARs subtypes, tumor-specific metabolic vulnerabilities, and predictive biomarkers. This review highlights the therapeutic potential of targeting SNS signaling to reshape tumor metabolism and the microenvironment. By elucidating the metabolic impacts of its systemic and local arms, it provides a framework for integrating SNS-directed strategies with existing treatments to improve clinical outcomes.
    Keywords:  Cancer therapy; Metabolic reprogramming; Sympathetic nervous system; Tumor microenvironment; Tumor progression
    DOI:  https://doi.org/10.1186/s12967-025-06657-2
  9. Cancer Res. 2025 Jul 29.
    Plasticity and Functional Heterogeneity of Cancer-Associated Fibroblasts.
    Jacqueline M Flynn, Nikita Thadani, Erin E Gallagher, Isabella Azzaro, Cameron M Bodnar, Colin P McCarty, Gabriele Romano, Marie R Webster, Claudia Capparelli.
      Tumor heterogeneity and plasticity enable adaptation to metastatic microenvironments and resistance to therapies. Recent progress in single-cell analyses has permitted detailed characterization of the complexity and diversity of the different tumor components in multiple tumor types. Cancer-associated fibroblasts (CAFs) are a central component of the tumor microenvironment (TME) and play critical roles in cancer progression and therapeutic response. The identification of different CAF subtypes and elucidation of their functional plasticity is crucial to identify novel therapeutic approaches to target pro-tumorigenic CAFs and harness tumor suppressive CAFs to enhance the efficacy of cancer treatments. In this review, we discuss how intrinsic and extrinsic factors and the extensive crosstalk between cancer cells and the TME promote CAF heterogeneity and their contributions to cancer progression and therapeutic resistance. Understanding the roles of CAF plasticity and their intercellular interactions may drive the development of effective treatment strategies to improve patient prognosis.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-3037
  10. J Pathol. 2025 Jul 30.
    The importance of tumor microenvironment modulations in the progression of pancreatic intraductal papillary mucinous neoplasms†.
    Antonio Pea, Claudio Luchini.
      Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas have attracted substantial attention since they represent the most prevalent macroscopic precursor of pancreatic cancer. Most lesions show an epithelium with low-grade dysplasia and will remain indolent and unknown to the patient. Notably, a subgroup of IPMNs will progress to invasive cancer through a stepwise process characterized by the accumulation of specific genomic alterations and concomitant modifications of the tumor microenvironment (TME). The manuscript of Jamouss et al, recently published in The Journal of Pathology, expands the current knowledge on TME dynamics in IPMNs. The neoplastic progression of IPMNs is paralleled by a shift toward an immunosuppressive TME, with depletion of cytotoxic T cells, elevated expression of immune checkpoint molecules, including PD-L1 and VISTA, and increased density of macrophages. Overall, TME modifications are crucial in the progression of pancreatic IPMNs, calling for potential therapeutic strategies focused on TME modulations for cancer interception. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
    Keywords:  immune evasion; intraductal papillary mucinous neoplasm; pancreatic ductal adenocarcinoma; tumor microenvironment
    DOI:  https://doi.org/10.1002/path.6460
  11. Biomed Pharmacother. 2025 Jul 28. pii: S0753-3322(25)00568-2. [Epub ahead of print]190 118374
    Comprehensive perspective about exosomes in breast cancer: Role in progression, diagnosis, monitoring, and treatment.
    Solmaz Hashemi, Kosar Malekpour, Ali Hazrati, Reza Falak.
      Breast cancer (BC) is one of the most common diseases in women and can affect various aspects of society, including psychological, economic, and family dynamics. Established tumor cells use multiple methods to spread and develop tumor tissue. Understanding these mechanisms can aid in diagnosis, treatment, follow-up, and patient care. Tumor cells can produce exosomes that mediate intercellular communication, leading to tumor progression. MicroRNAs (miRNAs) are among the primary mediators of breast cancer progression, diagnosis, and treatment via exosomes, playing essential roles in regulating various cellular mechanisms in target cells. After being produced, exosomes are observed in the tumor microenvironment (TME) and blood, and after being taken up by various cells, they play a role in mechanisms that promote tumor growth, including proliferation, invasion, angiogenesis, and distant metastasis. Given the presence of tumor cell-derived exosomes (TEXs) in the blood, they can be used for the early diagnosis of breast cancer. Furthermore, although they have pathogenic effects, exosomes produced by tumor cells are rich sources of tumor antigens and can be utilized in breast cancer treatment after various manipulations and engineering methods. Other cellular sources, including immune cells, also produce exosomes for the treatment of breast cancer. Immune cell-derived exosomes (IEXs) can prevent tumor spread by activating antitumor immune responses through the induction of apoptosis, inhibition of tumor cell proliferation, and inhibition of tumor cell invasion.
    Keywords:  Breast cancer; Diagnosis; Exosomes; Treatment; Tumor progression
    DOI:  https://doi.org/10.1016/j.biopha.2025.118374
  12. Curr Issues Mol Biol. 2025 Jul 08. pii: 525. [Epub ahead of print]47(7):
    Targeting Exosomal PD-L1 as a New Frontier in Cancer Immunotherapy.
    Laura Denisa Dragu, Mihaela Chivu-Economescu, Ioana Madalina Pitica, Lilia Matei, Coralia Bleotu, Carmen Cristina Diaconu, Laura Georgiana Necula.
      This manuscript assesses the critical role of exosomal PD-L1 (ExoPD-L1) in immune suppression, tumor progression, and resistance to therapy. ExoPD-L1 has been identified as a key mediator of tumor immune evasion, contributing to systemic immunosuppression beyond the tumor microenvironment (TME) due to its capacity to travel to distant anatomical sites. In this context, the review aims to elaborate on the mechanisms by which exosomal PD-L1 interacts with T cell receptors and modulates both the tumor microenvironment and immune responses, impacting patient outcomes. We further explore emerging therapeutic strategies that target ExoPD-L1 to enhance the effectiveness of immunotherapy. Blocking ExoPD-L1 offers a novel approach to counteracting immune escape in cancer. Promising strategies include inhibiting exosome biogenesis with GW4869 or Rab inhibitors, neutralizing ExoPD-L1 with targeted antibodies, and silencing PD-L1 expression through RNA interference (RNAi) or CRISPR-based methods. While each approach presents certain limitations, their integration into combination therapies holds significant potential to improve the efficacy of immune checkpoint inhibitors. Future research should focus on optimizing these strategies for clinical application, with particular attention to improving delivery specificity and minimizing off-target effects.
    Keywords:  ExoPD-L1; cancer immunotherapy; exosome; immune evasion; therapy resistance
    DOI:  https://doi.org/10.3390/cimb47070525
  13. Int J Mol Sci. 2025 Jul 16. pii: 6838. [Epub ahead of print]26(14):
    Macrophages at the Crossroads of Chronic Stress and Cancer.
    Sanja Momčilović, Maja Milošević, Dušica M Kočović, Dragana Marković, Darko Zdravković, Sanja Vignjević Petrinović.
      Macrophages are a heterogenous population of cells that adopt specific phenotypes in response to signals from their dynamic microenvironment. Apart from being key players in innate immunity and in the maintenance of tissue homeostasis, macrophages are also important drivers of low-grade inflammation, which is associated with different chronic conditions including stress and cancer. The activation of macrophages during chronic stress and cancer results in their multifaceted pathogenic roles. Macrophages residing in the tumor microenvironment are commonly known as tumor-associated macrophages and favor or inhibit tumor growth depending on the microenvironmental cues and their activation state. Activated macrophages display a continuum of properties rather than a distinct proinflammatory or anti-inflammatory dichotomy. Emerging evidence suggests that prolonged tissue residency restricts the plasticity of macrophages, while recruited monocytes are more plastic and their differentiation into tumor-associated macrophages during stress can result in a dual imprinting from both the existing stress-induced inflammation and the tumor microenvironment. In addition, the immunomodulation of the tumor microenvironment and reprogramming of tumor-associated macrophages toward the anti-tumor phenotypes have emerged as promising therapeutic approaches. In this review, we will focus on how the persistent inflammatory state underlying chronic stress affects macrophages as well as the macrophages' contribution to various aspects of tumor growth and progression, highlighting a therapeutic potential of modulation of the macrophage-mediated immunosuppressive tumor microenvironment.
    Keywords:  immunomodulation; macrophages; microenvironment; stress; tumor
    DOI:  https://doi.org/10.3390/ijms26146838
  14. Cancer Cell Int. 2025 Jul 28. 25(1): 289
    Targeting cancer stem cells with CAR-based immunotherapy: biology, evidence, and future directions.
    Kaveh Hadiloo, Parsa Mostanadi, Ali Asadzadeh, Siavash Taremi, Abdolreza Esmaeilzadeh.
      Cancer stem cells (CSCs) are pivotal in tumor initiation, progression, and relapse, underscoring the need for targeted therapies to achieve lasting responses. This review delves into CSC biology, highlighting their tumor-initiating potential demonstrated through limiting dilution assays and their role in resistance to therapies. Although successful CAR therapies, such as anti-CD19 CAR T-cells, can induce complete responses without directly targeting CSCs, CAR strategies focusing on CSCs may offer promising avenues to prevent recurrence. We assess CAR therapies targeting CSC-specific antigens, including CD133 and GD2, in preclinical and clinical contexts, emphasizing their effectiveness against glioblastoma, breast cancer, and other malignancies. Nevertheless, challenges such as marker specificity and suppression by the tumor microenvironment (TME) persist. Future strategies, which may include dual-targeting and AI-driven marker discovery, aim to improve CSC elimination and advance personalized cancer immunotherapy.
    Keywords:  Cancer stem cells; Cell-based therapy; Chimeric antigen receptor; Immunotherapy; Targeted therapy; Tumor initiation
    DOI:  https://doi.org/10.1186/s12935-025-03846-3
  15. Sci Rep. 2025 Jul 29. 15(1): 27665
    Derivation of resident macrophages and construction of tumor microenvironment in Flk-1-knockout chimeric mice produced via blastocyst complementation.
    Satoko Ishii, Kazuto Yamazaki, Peng Li, Kenji Kubara, Yuta Ishizuka, Yukina Izumi, Tsutomu Kamisako, Hiroyoshi Ishizaki, Yuichi Ono, Naoaki Mizuno, Hideyuki Sato, Hideki Masaki, Motoo Watanabe, Masashi Ito, Hiromitsu Nakauchi.
      The tumor microenvironment (TME) is deeply involved in cancer progression and treatment resistance. Although humanized mouse models have been developed by transplanting human cells into immunodeficient mice, they fail to fully reconstitute the TME. Blastocyst complementation using Flk-1 (Vegfr2, Kdr) knockout hosts offers a potential solution. However, the generation of interspecies human-mouse chimeras using blastocyst complementation has not yet been successful. As a foundational step, this study aims to demonstrate that donor-derived TME can be constructed using this method in intraspecies chimeric mice. We generated chimeric mice by injecting Azami-Green (AG)-positive C57BL/6 (B6) mouse-derived embryonic stem cells (ESCs) into ICR Flk-1 knockout embryos. We observed that vascular endothelial cells (VECs), hematopoietic cells, and tissue-resident macrophages were derived from the injected AG-positive ESCs. We engrafted B6-derived tumor cells into the chimeras and identified tumor-infiltrating lymphocytes, tumor-associated macrophages, and VECs derived from donor cells. Moreover, tumor-infiltrating CD8+ T cells in these chimeric mice showed cytotoxic activity comparable to that in wild-type mice. We anticipate that this intraspecies chimeric mouse model can serve as a valuable tool for basic research. Furthermore, future humanized tumor models generated via blastocyst complementation have the potential to significantly advance anticancer drug development in the preclinical phase.
    Keywords:  Blastocyst complementation; Resident macrophages; Tumor microenvironment; Tumor model
    DOI:  https://doi.org/10.1038/s41598-025-12571-w
  16. Semin Immunol. 2025 Jul 29. pii: S1044-5323(25)00052-1. [Epub ahead of print]79 101980
    Epigenetic mechanisms in HCC immune landscape: Therapeutic implications.
    Maite G Fernandez-Barrena, Iker Uriarte, Pablo Sarobe, Matias A Avila.
      Hepatocellular carcinoma (HCC) is the most frequent primary liver tumor and is currently a major cause of cancer-related mortality worldwide. The arrival of immune checkpoint inhibitors (ICI), and their combination with anti-VEGF/VEGFR antibodies, has transformed the treatment of patients with advanced HCC. Still, only about 30 % of patients respond to therapy, and these cases are among those displaying an immune-enriched ("immune-hot") tumor microenvironment (TME). Therefore, the identification of combination strategies that can overcome ICI resistance is of high relevance. Epigenetic alterations are increasingly recognized to impact on tumor development, contributing to practically all the hallmarks of cancer. These mechanisms not only promote the growth and survival of cancer cells, also determine the phenotype of immune cells and other components of the TME, driving tumor progression and resistance to therapies. Emerging preclinical evidence in different tumor types indicates that the combination with the so-called epi-drugs can increase the efficacy and overcome resistance to ICI. Here, we provide an overview of the epigenetic rewiring occurring in cancer and immune cells that can hinder antitumor immunity and ICI's efficacy in HCC. We also discuss how epigenetically targeted therapies may be leveraged to synergize with ICI and potentially treat immune-cold HCCs.
    Keywords:  Epigenetics; Hepatocellular carcinoma; Immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.smim.2025.101980
  17. Oncology (Williston Park). 2025 Jul 24. null(6): 232-236
    Immune Modulation in Sarcoma: Targeting the Tumor Microenvironment.
    Viviana Cortiana Ms, Jenna Ghazal BSc, Harshitha Vallabhaneni Bs, Ahmed Hashim Azeez Md, Kennedy Itodo Bs, Chandler H Park Md Ms Facp, Yan Leyfman Md.
      Modifying the immune environment in sarcoma treatment has a critical role, which highlights the necessity to overcome inhibitory macrophages and facilitate cellular therapy modifications. A lecture by Seth M. Pollack, MD, addresses sarcomas and rare cancers that are impacting various tissues and adult health and emphasizes the importance of techniques such as T-cell receptor (TCR) therapy, cancer testis antigen (CTA), and chimeric antigen receptor (CAR) T-cell therapy for effective treatment. The study investigates the effects of altering the tumor microenvironment to support cellular therapy, aiming to understand the immune response in sarcomas. By targeting inhibitory macrophages and optimizing cellular treatment strategies, such as interferon gamma and canine CAR T cells, new therapeutic approaches can be developed to enhance patient outcomes and survival rates. This underscores how manipulating the immune environment can significantly improve treatment efficacy, offering a revolutionary approach to sarcoma therapy.
    DOI:  https://doi.org/10.46883/2025.25921045
  18. Biochim Biophys Acta Rev Cancer. 2025 Jul 30. pii: S0304-419X(25)00141-6. [Epub ahead of print] 189399
    Lactylation: A new direction for tumor-targeted therapy.
    Dan Deng, Yan Luo, Yun Hong, Xing Ren, Xuyu Zu, Jianbo Feng.
      Lactate, a central metabolite generated during glycolysis, functions not only as a by-product but also as a critical signalling mediator, profoundly influencing tumor progression and cellular destiny. Among the post-translational modifications, lactylation-a novel modification driven by lactate-has emerged as a transformative discovery, reshaping our understanding of lactate's role within the tumor microenvironment (TME). This modification bridges metabolic reprogramming and epigenetic regulation, unveiling previously unexplored dimensions of tumor biology. Recent findings demonstrate that protein lactylation in tumor cells, cancer stem cells, and immune cells infiltrating the TME can modulate transcriptional activities, thereby influencing tumor initiation, progression, and immune evasion. These insights position lactylation as a promising target for new therapeutic strategies in cancer. This review expounds on the underlying mechanisms of lactylation, including the identification of the "writers" and "erasers" involved in protein lactylation, and highlights the physiological significance of lactylation across diverse biological contexts. Furthermore, the paper emphasized on the latest advancements in understanding the modulatory functions of protein lactylation within pathological processes, the potential for targeting lactylation sites, and underscores the scientific significance for future investigative endeavours.
    Keywords:  Immunotherapy; Lactate; Lactylation; Post-translational modifications; Tumor microenvironment; Tumor-targeted therapy
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189399
  19. Breast Cancer (Dove Med Press). 2025 ;17 639-651
    N2 Neutrophils and Tumor Progression in Breast Cancer: Molecular Pathways and Implications.
    Emmanuel Ifeanyi Obeagu.
      Neutrophils, traditionally viewed as first-line defenders in innate immunity, are increasingly recognized for their dualistic roles in cancer. In breast cancer, a distinct subset known as N2 neutrophils exhibits pro-tumorigenic activity, facilitating angiogenesis, immune suppression, and metastasis. This narrative review synthesizes current evidence on the molecular mechanisms underlying N2 polarization-focusing on key pathways such as TGF-β, STAT3/6, and hypoxia-mediated signaling-and their implications in breast cancer progression. We further explore how N2 neutrophils interact with other immune cells within the tumor microenvironment to promote an immunosuppressive milieu. A unique contribution of this review lies in its integration of emerging single-cell and flow cytometry data to underscore neutrophil plasticity and subtype-specific differences in neutrophil activity across breast cancer variants. Therapeutic strategies targeting N2 neutrophils are critically examined, including small-molecule inhibitors, cytokine blockade, and neutrophil-targeted nanomedicine. However, major challenges persist-most notably the difficulty in selectively depleting or reprogramming N2 neutrophils without compromising essential antimicrobial functions. Additionally, the lack of validated N2-specific markers in clinical samples limits translational progress. Addressing these gaps is crucial for the development of safe, effective immunomodulatory therapies in breast cancer.
    Keywords:  N2 neutrophils; breast cancer; immune modulation; molecular pathways; tumor progression
    DOI:  https://doi.org/10.2147/BCTT.S542787
  20. Acta Biomater. 2025 Jul 23. pii: S1742-7061(25)00546-X. [Epub ahead of print]
    Controlled Delivery of C-C Motif Chemokine Ligand 25 by a Hydrogel for Tumor Microenvironment Remodeling in Triple Negative Breast Cancer.
    Meng Guan, Junfeng Ding, Ge Zhu, Kuirong Mao, Xiandi Meng, Xiuxiu Cong, Huizhu Tan, Yanbao Xin, Mengfei Zhao, Jiaxuan Li, Haorui Wang, Yue Lv, Huating Sun, Chaoliang He, Hongmei Chen, Yong-Guang Yang, Yanqiu Song, Yuning Zhang, Tianmeng Sun.
      Triple-negative breast cancer (TNBC), characterized by its heterogeneity and poor clinical prognosis, presents substantial unmet medical needs. Although exciting progress has been made in immunotherapy for TNBC, optimizing the composition of immune cells within the tumor microenvironment (TME) remains a critical challenge. In this study, we demonstrate that CCL25-transduced tumor cells significantly enhance the accumulation of CCR9+CD8+T cells within tumors, translating into inhibited TNBC tumor growth in vivo. To further exploit this mechanism, we developed an injectable, thermo-responsive hydrogel loaded with CCL25 for intratumoral delivery, aimed at recruiting CCR9+ cells into the TME. Our results revealed that the influence of CCL25 on the TME is both dose- and time-dependent, mediated through the precise regulation of CCR9+ cells infiltration into tumor tissues. Furthermore, CCL25-loaded hydrogel, when administered at an appropriate dose and timing, could enhance the therapeutic response to PD-1 inhibitors, credited to the activation of a T cell-dependent antitumor immunity. This innovative approach not only provides deeper insights into the role of the chemokine system in tumor biology but also suggests a promising strategy for enhancing the efficacy of TNBC immunotherapy. The potential of hydrogel-based chemokine delivery systems to remodel the TME could have significant implications for future cancer treatment. STATEMENT OF SIGNIFICANCE: In our study, we developed a thermo-responsive injectable hydrogel for intratumoral delivery of CCL25. Our findings demonstrate that CCL25@gel promotes the infiltration of CCR9+CD8+T cells into the tumor microenvironment in a dose- and time-dependent manner. Notably, at an optimal dose and administration schedule, CCL25@gel significantly enhances the therapeutic response to PD-1 inhibitors, thereby improving the efficacy of immunotherapy in triple-negative breast cancer (TNBC). These results highlight the potential of CCL25 in modulating the immune landscape of the tumor microenvironment and emphasize the importance of optimizing key delivery parameters-dose, timing, and frequency-to maximize therapeutic benefits. Moreover, this work provides valuable insights into chemokine-based immunotherapy for TNBC, offering new avenues for more effective treatment strategies.
    Keywords:  Chemokine delivery; Hydrogel; Triple negative breast cancer; Tumor immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.actbio.2025.07.049
  21. NPJ Biofilms Microbiomes. 2025 Jul 25. 11(1): 143
    Gut microbiota shapes cancer immunotherapy responses.
    Wanting Lei, Kexun Zhou, Ye Lei, Qiu Li, Hong Zhu.
      The gut microbiota significantly influences cancer immunotherapy efficacy by modulating immune responses, remodeling the tumor microenvironment (TME), and producing key metabolites. Strategies such as FMT, probiotics, and dietary interventions show promise in enhancing responses to ICIs and ACTs while reducing immune-related adverse events (irAEs). This review summarizes clinical and preclinical findings and discusses microbiota-based interventions and future directions for precision immunotherapy.
    DOI:  https://doi.org/10.1038/s41522-025-00786-8
  22. Mol Oncol. 2025 Aug 01.
    Microglia limit brain tumor development by restricting tumor cell proliferation and inducing T-cell immunity.
    Tzu-Chieh Sun, Ching-Fang Yu, Sheng-Yan Wu, Wei-Chung Cheng, Chi-Shiun Chiang, Fang-Hsin Chen.
      Tumor-associated macrophages (TAMs) in brain tumors contain two types of macrophages: tumor-associated microglia and infiltrating macrophages. This study explored whether these two populations have the same role in brain tumor progression. In an in vitro coculture model using the astrocytoma cells ALTS1C1 with either the microglial cell line BV2 or the peripheral macrophage cell line RAW264.7, only BV2, not RAW264.7, gathers ALTS1C1 into tumor cell clusters. These BV2-associated clusters limited ALTS1C1 proliferation but not BV2 cell growth. The in vivo studies show that the survival time of mice co-inoculated with ALTS1C1 and BV2 was prolonged from 30.4 ± 3.1 days to more than 77 days in immune-competent mice but not in immune-compromised mice. Examining the tumor microenvironment (TME) by immunohistochemical staining revealed that the co-inoculation of BV2 increased the CD8 T cells' infiltration and the expression of Granzyme B. Mice bearing with BV2-containing ALTS1C1 tumor exhibited a reduced level of circulating myeloid-derived suppressor cells (MDSCs) and an elevated level of CD8 T cells in peripheral blood compared to the ALTS1C1 tumor-bearing group. This study suggests tumor-associated microglia restrict brain tumor development by limiting tumor cell proliferation and inducing T-cell-associated antitumor immunity.
    Keywords:  T‐cell immunity; glioma; macrophage; microglia
    DOI:  https://doi.org/10.1002/1878-0261.70102
  23. Signal Transduct Target Ther. 2025 Jul 31. 10(1): 227
    Immune evasion in cancer: mechanisms and cutting-edge therapeutic approaches.
    Muhammad Tufail, Can-Hua Jiang, Ning Li.
      Immune evasion represents a significant challenge in oncology. It allows tumors to evade immune surveillance and destruction, thereby complicating therapeutic interventions and contributing to suboptimal patient outcomes. This review addresses the critical need to understand how cancers evade immune surveillance. It aims to provide a comprehensive overview of strategies of tumors to escape immune detection by examining tumor-induced immune suppression, immune checkpoint regulation, and genetic and epigenetic influences. Moreover, it explores the dynamic role of the tumor microenvironment (TME) in fostering immune resistance and highlights the impact of metabolic reprogramming on immune suppression. Additionally, this review focuses on how tumor heterogeneity influences immune evasion and discusses the limitations of current immunotherapies. The role of key signaling pathways, including programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), transforming growth factor-β (TGF-β), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) is analyzed to elucidate their contributions to immune escape. Emphasizing the complexities of immune evasion, this review underscores the importance of personalized approaches and the integration of multi-omics data to combat therapeutic resistance. Furthermore, it discusses novel and emerging therapeutic strategies, such as bispecific antibodies, oncolytic viruses, and nanotechnology-driven immunotherapies, showcasing innovative avenues in cancer treatment. The significance of this review lies in its potential to guide future research and innovations in immunotherapy, ultimately improving patient outcomes and advancing our understanding of cancer immunology.
    DOI:  https://doi.org/10.1038/s41392-025-02280-1
  24. Brain Tumor Pathol. 2025 Jul 31.
    Activated astrocytes drive the accumulation of apolipoprotein E at the brain tumor edge.
    Ting-Yi Chien, Chi-Shiun Chiang.
      While tumor-associated macrophages (TAMs) have been extensively studied, the role of tumor-associated astrocytes (TAAs) in glioma progression is less explored. Astrocytes are crucial in maintaining lipid homeostasis by synthesizing cholesterol and apolipoprotein E (APOE) in the brain. However, the contribution of astrocytes in supporting the metabolic needs of tumor cells within the tumor microenvironment (TME) is still poorly understood. This study aims to investigate how astrocytes contribute to the unique brain TME by examining the spatial distribution of APOE and its correlation with glial cells. This study examined the spatial distribution of APOE in gliomas with two murine brain tumor models: ALTS1C1 and GL261. To validate astrocyte APOE secretion, in situ hybridization (ISH) for APOE mRNA and immunofluorescence (IF) staining for GFAP were performed. Immunofluorescence (IF) staining showed that APOE was accumulated at the tumor edge. ISH analysis confirmed that activated astrocytes were the primary cells responsible for the increased APOE in this region. Flow cytometry and IF staining demonstrated that TAMs were also associated with increased APOE expression in the tumor core. This study provides the first evidence that astrocytes at the tumor edge are activated and upregulated for APOE secretion. These brain tumor edge-associated astrocytes are responsible for the accumulation of APOE in this region and create a unique metabolic environment, which may contribute to brain tumor invasion and resistance to therapy.
    Keywords:  Apolipoprotein E; Astrocytes; Macrophage; Spatial analysis; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s10014-025-00511-5
  25. Nat Protoc. 2025 Jul 25.
    Manufacturing of CRISPR-edited primary mouse CAR T cells for cancer immunotherapy.
    Puneeth Guruprasad, Ranjani Ramasubramanian, Siena Nason, Alberto Carturan, Shan Liu, Luca Paruzzo, Vladlena Hornet, Jacqueline Plesset, Ruchi P Patel, Vijay Bhoj, Gregory L Beatty, Marco Ruella.
      Editing chimeric antigen receptor (CAR) T cells by using CRISPR-Cas9 has become a routine strategy to improve their antitumor function or safety profile. Xenograft tumor models in immunodeficient mice are often used to evaluate the function of CRISPR-edited human CAR T cells. These models, however, lack functional immune systems and thus fail to recapitulate barriers such as the immunosuppressive tumor microenvironment (TME) that CAR T cells will encounter in patients. Thus, genetically modifying mouse CAR T cells for use in immune-intact models is an attractive approach to explore the impact of a given gene deletion on CAR T cells within a natural TME. Here, we describe a protocol to perform CRISPR-Cas9 editing in primary mouse T cells, thereby enabling studies of gene-edited CAR T within the TME and in the presence of a functional immune system. This protocol is integrated into a standard mouse CAR T manufacturing workflow, a process that typically spans ~5-6 days. The first stage of this protocol involves isolating mouse T cells, electroporating them with a ribonucleoprotein complex and activating them by using magnetic bead stimulation. The second stage involves transducing the CAR gene and expanding these cells, and the third stage focuses on validating knockout efficiency and the functionality of gene-edited mouse CAR T cells. This procedure requires a proficiency in aseptic cell culture techniques and a basic understanding of T cell biology. We anticipate that efficient and reliable genetic modification of mouse T cells will have wide-ranging applications for cancer immunotherapies and related fields.
    DOI:  https://doi.org/10.1038/s41596-025-01208-x
  26. Med Oncol. 2025 Jul 29. 42(9): 389
    The role of E3 ligases and deubiquitinases in PD-L1 regulation and the tumor microenvironment in renal cell carcinoma.
    Amzath Nazeer Akbar, Somnath Pandey, Pragasam Viswanathan.
      Renal cell carcinoma (RCC) is a complex and highly heterogeneous malignancy marked by an immunosuppressive tumor microenvironment, which facilitates immune evasion and disease progression. Programmed death-ligand 1 (PD-L1), a key immune checkpoint molecule expressed on tumor and immune cells, whose activation allows tumors to evade immune surveillance, plays a central role in modulating antitumor immunity in RCC. While the transcriptional and cytokine-mediated regulation of PD-L1 is well documented, emerging evidence emphasizes the critical influence of post-translational modifications particularly ubiquitination and deubiquitination in controlling PD-L1 stability and function. This review provides a comprehensive analysis of the ubiquitin-proteasome system (UPS), highlighting the roles of specific E3 ubiquitin ligases and deubiquitinases (DUBs) in modulating PD-L1 expression and their broader implications in RCC tumor biology. We further discuss how these proteins influence immune cell infiltration, tumor progression, and response to immunotherapy. The therapeutic potential of targeting UPS components, including proteasome inhibitors and proteolysis-targeting chimeras, is also explored. Understanding the UPS-mediated regulation of PD-L1 offers promising avenues for enhancing immunotherapeutic efficacy in RCC.
    Keywords:  Deubiquitinases; E3 ligases; PD-L1; Renal cell carcinoma; Tumor microenvironment; Ubiquitin–proteasome system
    DOI:  https://doi.org/10.1007/s12032-025-02878-z
  27. ACS Appl Mater Interfaces. 2025 Jul 31.
    Biomimetic Nanoparticles with Dual Targeting for Hepatocellular Carcinoma Promote Tumor Immune System Activation by Enhancing Extracellular ATP Homeostasis.
    Jianwei Lan, Xu Chu, Longhui Xie, Binjie Li, Youai Song, Liangchen Lei, Chen Ouyang, Zhuo Meng, Pengpeng Liu, Shulan Li, Quanyan Liu.
      Chemodynamic therapy (CDT) plays a crucial role in transforming the tumor microenvironment by inducing immunogenic cell death (ICD) to eliminate cancer cells. Nonetheless, the effectiveness of CDT in eliciting antitumor immunity is somewhat constrained. The persistent presence of immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs), in the tumor offsets some of the ICD effects triggered by CDT. Moreover, extracellular adenosine triphosphate (eATP), a crucial damage-related molecular pattern that initiates ICD, is quickly degraded into adenosine, an immunosuppressive metabolite, by CD39 molecules prevalent in the tumor environment, thereby evading immune destruction. In this report, we introduce a nanomaterial, CP@HMM (copper-doped carbon dots and POM1 encapsulated by a hybrid membrane composed of Hepa1-6 and a MDSCs membrane), which targets liver cancer cells and MDSCs and inhibits the ATP-adenosine metabolic pathway. The hybrid membrane, derived from hepatocellular carcinoma (HCC) cells and MDSCs, facilitates the targeted delivery of copper-doped carbon dots (Cu-CDs) to these cells. The potent Fenton-like reactions and the cytotoxicity of copper ions allow CP@HMM to not only kill tumor cells but also eradicate intratumoral MDSCs. Additionally, the CD39 inhibitor POM1 within the system prevents the degradation of eATP induced by the Cu-CDs treatment. This leads to increased eATP levels and drives antitumor immunity activation, including macrophage pyroptosis and dendritic cell maturation, which suppresses primary tumor progression and distant metastases while fostering immune memory to prevent tumor recurrence. Our findings suggest that CP@HMM is an effective drug-delivery system and offers a potential therapeutic alternative for patients with HCC, promising advancements in combined tumor immunotherapy strategies.
    Keywords:  chemodynamic therapy; extracellular ATP; hepatocellular carcinoma; hybrid membrane; primary and metastatic tumor
    DOI:  https://doi.org/10.1021/acsami.5c04278
  28. Biochim Biophys Acta Rev Cancer. 2025 Jul 29. pii: S0304-419X(25)00145-3. [Epub ahead of print] 189403
    Taurine and cancer: Biological properties and multifaceted roles in cancer progression.
    Rong Liu, Xinze Li, Zhenyu Hua, ZhiTong Liu, ZhengYue Wang, Xiang Li.
      Cancer remains one of the leading causes of mortality worldwide and poses a major threat to global health. Recent insights into the tumor microenvironment (TME) have highlighted the pivotal role of amino acid metabolism-one of the three core metabolic pathways-in driving tumor proliferation, metastasis, and resistance to therapy. Taurine, a conditionally essential amino acid abundantly present in various tissues, does not participate in protein synthesis but exhibits multiple biological functions, including antioxidant, anti-inflammatory, and cytoprotective effects. These properties are increasingly recognized as relevant in both physiological regulation and pathological conditions such as cancer. Emerging evidence suggests that taurine modulates tumor growth and progression through diverse mechanisms, including regulation of immune responses, redox homeostasis, cellular metabolism, and the TME. This review summarizes the multifaceted roles of taurine in tumorigenesis and its potential applications in cancer therapy, providing new perspectives for targeted intervention.
    Keywords:  Biological property; Cancer; Mechanism; Taurine; Therapy
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189403
  29. Crit Rev Oncol Hematol. 2025 Jul 29. pii: S1040-8428(25)00259-8. [Epub ahead of print] 104871
    The Peripheral Tumor Neuro-Microenvironment: Deciphering Neural Landscape and Mechanistic Insights for Therapeutic Innovation.
    Xiaoxiao Wang, Yuetong Pan, Yanting Zhou, Tianjing Tang, Fei Li, Hongyan Li.
      As the nascent field of cancer neuroscience experiences explosive growth, the critical importance of the peripheral nervous system (PNS) in the onset, progression, and therapeutic approaches of cancer has garnered considerable attention from researchers in recent years. The neural-tumor interactions mediated by PNS components in the tumor microenvironment (TME) constitute the neural landscape of peripheral cancers, where neural activity regulates metastatic competence through structural innervation networks, neurochemical signaling cascades, and immune microenvironment remodeling. Within the TME, the synergistic interplay among cancer cells, neurons, and schwann cells establishes a dynamic neural ecological niche that orchestrates both oncogenic expansion and aberrant neural reorganization. This reflects an innovative theoretical framework of microenvironment-driven neural plasticity in cancer pathogenesis. We pioneer the conceptualization of "tumor neuro-microenvironment (TNME)", elucidating the pivotal roles of the PNS in orchestrating TNME dynamics via intricate neural-tumor interactions. By deeply dissecting the interactive networks between the PNS and TNME, as well as their mechanistic insights, we articulate the latest advancements in targeted PNS interventions for cancer therapy. This showcases its tremendous potential in anti-cancer efforts, paving the way for novel perspectives and therapeutic approaches in neuroscience-oriented cancer treatment strategies.
    Keywords:  Cancer neuroscience; Cancer therapy; Neural-immune modulation; Peripheral nervous system; Tumor neuro-microenvironment
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.104871
  30. Sci Rep. 2025 Jul 28. 15(1): 27449
    Development of tetraculture spheroids as a versatile 3D model for personalized breast cancer research.
    Oliwia Piwocka, Karolina Sterzyńska, Agnieszka Malińska, Wiktoria M Suchorska, Katarzyna Kulcenty.
      The tumor microenvironment (TME) plays a pivotal role in cancer progression and drug resistance, influenced by the interaction of tumor cells with surrounding fibroblasts, immune, and endothelial cells. Developing robust multicellular tumor spheroids (MCTSs) that mimic the tumor microenvironment is crucial for studying cancer progression and therapeutic resistance. This study aimed to establish a reproducible method for generating MCTSs using a tetraculture system in four breast cancer cell lines: BT474, T47D, MDA-MB-231, and SK-BR-3. This approach incorporates primary cancer-associated fibroblasts (CAFs), macrophages (THP-1), and endothelial cells (Ea.hy926) alongside the cancer cells. MCTSs were generated using a simple method on ultra-low attachment plates, ensuring spheroid viability and uniformity across cell lines, confirmed by immunofluorescence and immunohistochemistry. MCTSs underwent extensive characterization, including invasion pattern analysis, macrophage polarization potential, cytotoxicity assay to assess chemotherapeutic resistance, and gene expression analysis to explore extracellular matrix (ECM) remodeling. The spheroids exhibited distinct morphologies, growth patterns, and cell distributions, reflecting unique microenvironment interactions and providing a reliable platform for studying TME. This versatile 3D model offers a promising platform for personalized therapy design, as it enables the incorporation of patient-derived cells regardless of tumor phenotype or inter-patient variability. Including key elements of the tumor microenvironment supports individualized drug testing and functional analysis, serving as a reproducible and ethically favorable alternative to animal models and patient-derived explants.
    Keywords:  3D culture; Breast cancer; Multicellular spheroids; Personalized cancer research; Tetraculture; Tumor-microenvironment; Tumoroids
    DOI:  https://doi.org/10.1038/s41598-025-12556-9
  31. Int J Mol Sci. 2025 Jul 18. pii: 6928. [Epub ahead of print]26(14):
    Tumor-Associated Macrophages and Collagen Remodeling in Mammary Carcinomas: A Comparative Analysis in Dogs and Humans.
    Ana Paula Vargas Garcia, Marisa Salvi, Luana Aparecida Reis, Bárbara Regina Melo Ribeiro, Cristiana Buzelin Nunes, Ana Maria de Paula, Geovanni Dantas Cassali.
      The tumor microenvironment (TME) plays a central role in cancer progression, with tumor-associated macrophages (TAMs) and extracellular matrix (ECM) components such as collagen being key modulators of invasiveness and immune regulation. Although macrophage infiltration and ECM remodeling are well-documented individually, their coordinated contribution to mammary carcinoma aggressiveness remains underexplored, particularly in comparative oncology models. This study analyzed 117 mammary carcinoma samples-59 from dogs and 58 from women-using immunohistochemistry, immunofluorescence, and second-harmonic-generation (SHG) microscopy. We quantified TAM density and phenotype (CD206, iNOS, and S100A8/A9), assessed collagen fiber organization, and examined correlations with clinical-pathological variables and overall survival. Increased TAM infiltration was associated with a higher histological grade, aggressive molecular subtypes, enhanced cell proliferation, and shortened survival in dogs. High TAM density also correlated with decreased collagen fiber length and increased alignment, suggesting active immune-matrix remodeling in aggressive tumors. Macrophage phenotyping revealed heterogeneous populations, with CD206+ cells predominating in high-grade tumors, while S100A8/A9+/iNOS+ phenotypes were enriched in less aggressive subtypes. The findings were consistent across species, reinforcing the relevance of canine models. Our results identify macrophage-collagen interactions as critical determinants of tumor aggressiveness in mammary carcinomas. This study bridges comparative oncology and translational research by proposing immune-ECM signatures as potential prognostic biomarkers and therapeutic targets. These insights contribute to the advancement of molecular oncology in Brazil by supporting innovative strategies that integrate immune modulation and matrix-targeted interventions in breast cancer.
    Keywords:  breast cancer; collagen fibers; comparative oncology; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3390/ijms26146928
  32. Mol Med Rep. 2025 Oct;pii: 272. [Epub ahead of print]32(4):
    Dual role of hydrogen sulfide in the tumor microenvironment of prostate cancer (Review).
    Hua Luo.
      Tumor microenvironment (TME) dynamics and the critical dual role of hydrogen sulfide (H2S) in prostate cancer (PCa) biology are discussed in the present review. PCa remains one of the most prevalent malignancies in men, with advanced castration‑resistant PCa presenting substantial therapeutic challenges. H2S, an endogenous gaseous signaling molecule, is a key regulator of biological processes, including immune modulation, cell proliferation and apoptosis, during tumor progression. H2S exhibits paradoxical effects in PCa by promoting tumorigenesis and exerting context‑dependent antitumor activity. H2S mediates these outcomes through key signaling pathways, including the PI3K/AKT and MAPK/ERK pathways, which regulate tumor cell survival and metastasis. The present review emphasizes how H2S regulates tumor cell dynamics and immune interactions in a concentration‑dependent manner within the TME, making it a promising therapeutic target to overcome resistance to conventional treatments. Future research should prioritize translating these findings into clinical strategies, particularly through the development of H2S‑modulating therapies tailored to the TME, offering potential for overcoming resistance in advanced PCa.
    Keywords:  hydrogen sulfide; prostate cancer; signaling pathways; tumor microenvironment
    DOI:  https://doi.org/10.3892/mmr.2025.13637
  33. Biochem Biophys Res Commun. 2025 Jul 25. pii: S0006-291X(25)01125-8. [Epub ahead of print]778 152410
    Role of the orexin system in modulating the tumor microenvironment: implications for tumor progression and cancer therapy.
    Monika Żuwała, Marcelina Janik, Marian Lewandowski.
      The orexin system is involved in wakefulness, eating behaviour, energy homeostasis, motivation and addiction. It influences central arousal systems, together with the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis. The two known orexin receptors are widely distributed throughout the mammalian brain, as well as in peripheral tissues. They belong to the G-protein coupled receptors and trigger the action of specific signaling pathways. Many neurotransmitters and neuropeptides, including orexin, have been implicated in cancers, not just those of the nervous system. Their role in cancer initiation and progression remains unclear. Referring to the orexin receptors, they have been reported in several types of cancer cells. In this review, we highlight the role of orexin receptors in modulating the tumour microenvironment. Their reported expression and regulatory effects on adipocytes, endothelial cells and immune cells, as well as cancer cells, suggest that OXRs are potent regulators of tumour initiation and progression. OXRs have been shown to be elements in the machinery that shape cancer-associated exosomes and trigger the cellular mechanisms that deal with hypoxia, both of which are critical for tumour initiation and progression. On the other hand, the potential of OXRs in restoring anti-cancer immunity and overcoming chemo-resistance may become a therapeutic adjunct. An important aspect of orexin action is its role in the management of chemotherapy-induced fatigue and its potential to regulate the composition of the gut microbiota - suggested as a potential regulator of cancer progression. Overall, the supportive role of the orexin system in cancer treatment should be considered.
    Keywords:  Cancer; Chemotherapy; Microbiota; Orexin; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152410
  34. Int J Mol Sci. 2025 Jul 08. pii: 6574. [Epub ahead of print]26(14):
    Chemoradiation-Altered Micromilieu of Glioblastoma Cells Particularly Impacts M1-like Macrophage Activation.
    Mona Shojaei, Benjamin Frey, Florian Putz, Rainer Fietkau, Udo S Gaipl, Anja Derer.
      Glioblastoma is a highly aggressive brain tumor with an overall poor prognosis due to its immunosuppressive tumor microenvironment (TME). Microglia and tumor-associated macrophages (TAMs) with pro-tumorigenic properties are dominant populations of immune cells in the glioblastoma TME. To date, several studies targeting TAMs to fight tumor progression in different tumor entities have been initiated. However, the impact of standard therapy schemes of glioblastoma cells on macrophage polarization, activation, and phagocytosis remains controversial. The same applies to the relevance of PD-1/PD-L1 blockade in the interaction between macrophages and tumor cells. Our study, therefore, investigated patient-oriented treatment of GLIOBLASTOMA by examining the phagocytic capacity of polarized M1- and M2-like macrophages using GL261-luc2 tumor cells as a preclinical model system. Additionally, we analyzed the expression of activation and immune checkpoint markers on these macrophage subtypes following contact with tumor cells and their microenvironment. These factors were also determined after PD-1 blockade was initiated. The analyses revealed that the immunoregulatory M2-like macrophages generally exhibited a higher phagocytosis rate than the pro-inflammatory M1-like macrophages; however, this was not influenced by the pretreatment of glioblastoma cells with chemo- or radiotherapy. This could not be improved by blocking the PD-1 receptor. Furthermore, there were no modulations in the expression of differentiation, activation, or immune checkpoint molecules of M1- and M2-like macrophages after cell-to-cell contact with glioblastoma cells. But the medium conditioned by tumor cells strongly altered M1-like macrophages toward a more activated state, whereas M2-like cells were only mildly influenced. This was further enhanced by tumor cell treatment, with the most prominent effect after irradiation. These results suggest that conventional GLIOBLASTOMA tumor cell treatment affects the immunogenic status of macrophage subtypes, which is relevant for enhancing the anti-tumor immune response in brain tumors.
    Keywords:  PD-1; PD-L1/L2; TAM; chemoradiation; glioblastoma; immune checkpoint molecule; macrophages
    DOI:  https://doi.org/10.3390/ijms26146574
  35. Curr Issues Mol Biol. 2025 Jul 12. pii: 544. [Epub ahead of print]47(7):
    Prognostic Value of the Immunohistochemical Detection of Cellular Components of the Tumor Microenvironment in Oral Squamous Cell Carcinoma: A Systematic Review.
    Hannah Gil de Farias Morais, Caroline Fernandes da Costa, Maurília Raquel de Souto Medeiros, Bárbara de Assis Araújo, Everton Freitas de Morais, Ricardo D Coletta, Roseana de Almeida Freitas.
      This study aims to investigate the prognostic impact of cellular components of the tumor microenvironment (TME), analyzed through immunohistochemistry, in oral squamous cell carcinoma (OSCC). This review was conducted following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Searches were performed in EMBASE, Medline/PubMed, Cochrane Collaboration Library, Web of Science, ScienceDirect, Scopus, and Google Scholar. After applying the study criteria, 59 articles were included, involving the analysis of cancer-associated fibroblasts (CAFs), immune cells, and endothelial cells. It was found that TME rich in α-SMA-positive CAFs, tumor-associated macrophages, and dendritic cells contribute to the invasion and progression of OSCC, resulting in a poorer prognosis. In contrast, the presence of high amounts of NK CD57+ cells, CD8+/CD45RO+ T cells, and PNAd+ endothelial cells are associated with anti-tumor immune responses in OSCC and improved survival rates. CD3+ and CD4+ T cells, Treg cells, B cells, and mast cells have shown little to no evidence of prognostic utility. Several stromal components of TME were found to have a strong impact on the aggressiveness of OSCC, reaffirming the potential use of these biomarkers as prognostic tools and therapeutic targets.
    Keywords:  immunohistochemistry; oral cancer; oral squamous cell carcinoma; prognosis; tumor microenvironment
    DOI:  https://doi.org/10.3390/cimb47070544
  36. Front Immunol. 2025 ;16 1625426
    CAR-iNKT cells: redefining the frontiers of cellular immunotherapy.
    Magdalena Niedzielska, Amy Chalmers, Martyna C Popis, Efrat Altman-Sharoni, Stephen Addis, Rebekka Beulen, Nils-Petter Rudqvist, Eleni Chantzoura, Marco A Purbhoo, Dhan Chand, Mark A Exley.
      Despite significant advances in cancer therapies, many malignancies remain resistant to current treatments due to complex immunosuppressive mechanisms, limited neoantigen expression, and dynamic tumor adaptations, underscoring the need for innovative therapeutic strategies. Adoptive cell therapy (ACT), particularly with chimeric antigen receptors (CARs and recombinant TCRs) targeting cancer-associated antigens, has emerged as a transformative strategy. However, conventional CAR-T cell therapies face substantial limitations such as manufacturing challenges, severe toxicities, and limited efficacy against solid tumors. Invariant natural killer T (iNKT) cells, a unique lymphocyte subset bridging innate and adaptive immunity, have emerged as a compelling alternative platform for CAR-based therapies, due to their distinctive ability to persist, penetrate in and remodel the tumor microenvironment (TME). Unlike conventional T cells, iNKT cells exhibit rapid activation without priming, potent cytotoxicity, and extensive immunomodulatory functions. Furthermore, the inherent immunomodulatory properties of iNKT cells through interactions with the monomorphic antigen-presenting molecule CD1d or stress ligands augment endogenous anti-tumor immunity by activating NK cells and cytotoxic T lymphocytes, promoting dendritic cell maturation, and reducing immunosuppressive myeloid cells, unlike other Innate T cells. CAR-engineered iNKT (CAR-iNKT) cells therefore leverage multiple targeting mechanisms through their native semi-invariant T-cell receptor (TCR), NK receptors (NKRs) and engineered CARs, enabling broader and more effective tumor recognition while actively reshaping immunosuppressive TME. Notably, iNKT cells lack alloreactivity, circumventing the risk of graft-versus-host disease (GvHD), positioning CAR-iNKT cells as ideal candidates for "off-the-shelf" allogeneic therapies that can overcome the limitations of existing immunotherapies.
    Keywords:  CAR; CD1d; adoptive cell therapy (ACT); cancer immunotherapy; iNKT cells
    DOI:  https://doi.org/10.3389/fimmu.2025.1625426
  37. Int J Oral Sci. 2025 Aug 01. 17(1): 59
    Persistent accumulation of therapy-induced senescent cells: an obstacle to long-term cancer treatment efficacy.
    Jingjing Luo, Tongxu Sun, Zhenghui Liu, Yangfan Liu, Junjiang Liu, Shimeng Wang, Xueke Shi, Hongmei Zhou.
      In the ever-evolving landscape of cancer therapy, while cancer treatments such as chemotherapy, radiotherapy, and targeted therapy aim to eradicate malignant cells, they also inadvertently trigger cellular senescence in both cancerous and microenvironmental tissues. Therapy-induced senescence (TIS) can act as a barrier against tumor growth by halting cell proliferation in the short term, but the long-term persistence of therapy-induced senescent (TISnt) cells may pose a significant challenge in cancer management. Their distinct characteristics, like senescence-associated secretory phenotype (SASP), metabolic dysregulation, and immune evasion, make them exhibit remarkable heterogeneity to orchestrate the tumor microenvironment (TME), resulting in therapy resistance. However, how these TISnt cells functioning differently in cancer progression, and the intricate mechanisms by which they remodel the senescence-associated immunosuppressive microenvironment present challenges for improving anticancer therapy. Therefore, this review summarizes the heterogeneous TISnt cell phenotypes contributing to an accumulated senescent state, outlines their multidimensional interactions in the senescent microenvironment, and discusses current senescence-targeting strategies. Building on the current understanding of TIS, we propose potential avenues for improving TIS-targeting methodologies in the context of head and neck cancer, a representative heterogeneous malignancy, which can substantially enhance the efficacy of the "one-two punch" sequential treatment approach for head and neck cancer.
    DOI:  https://doi.org/10.1038/s41368-025-00380-w
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