bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2025–06–15
twenty papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Lipid Metabolism Reprogramming in Tumor-Associated Macrophages Modulates Their Function in Primary Liver Cancers.
  2. Tumor microenvironment and immunotherapy: from bench to bedside.
  3. Oxygen gradients in tumor tissues implications for breast cancer metastasis - a narrative review.
  4. Interactions in hepatic tumor microenvironment: Potential targets and modulations for effective therapy.
  5. Neutrophils as key regulators of tumor microenvironment in breast cancer: a focus on N1 and N2 polarization.
  6. Regulation and Function of Tumor-Associated Macrophages (TAMs) in Colorectal Cancer (CRC): The Role of the SRIF System in Macrophage Regulation.
  7. The role of the gut microbiota in shaping the tumor microenvironment and immunotherapy of breast cancer.
  8. The balance between N1 and N2 neutrophils implications for breast cancer immunotherapy: a narrative review.
  9. Tumor-associated macrophages in radiotherapy: Mechanisms of polarization, immune regulation and therapeutic strategies.
  10. Targeting Lineage-Specific Functions of NR4A1 for Cancer Immunotherapy.
  11. Immune microenvironment in hepatocellular carcinoma: from pathogenesis to immunotherapy.
  12. Pro- and Anti-Inflammatory Role of Complement in Cancer.
  13. New Insights Into Adipokines and the Tumor Microenvironment in Breast Cancer.
  14. The rules of different B cell subtypes in colorectal cancer: friends or foes?
  15. Roles and functions of tumor-infiltrating lymphocytes and tertiary lymphoid structures in gastric cancer progression.
  16. Nano-drug delivery strategies affecting cancer-associated fibroblasts to reduce tumor metastasis.
  17. The Metabolic Orchestration of Immune Evasion in Glioblastoma: From Molecular Perspectives to Therapeutic Vulnerabilities.
  18. Targeting inflammasomes as an immunotherapeutic strategy for cancer.
  19. Klf4 -dependent pivotal role of smooth muscle-derived Gli1 + lineage progenitor cells in lung cancer progression.
  20. Inflammatory signaling pathways in neutrophils: implications for breast cancer therapy.
  1. Cancers (Basel). 2025 May 31. pii: 1858. [Epub ahead of print]17(11):
    Lipid Metabolism Reprogramming in Tumor-Associated Macrophages Modulates Their Function in Primary Liver Cancers.
    Barbara Oliviero, Anna Caretti, Mario U Mondelli, Stefania Mantovani.
      Lipids are a complex class of biomolecules with pivotal roles in the onset, progression, and maintenance of cancers. Lipids, derived from the tumor microenvironment (TME) or synthesized by cancer cells themselves, govern a large variety of pro-tumorigenic functions. In recent years, lipid metabolism and the reprogramming of liver cancer cells have received increasing attention, revealing that altered regulation of diverse lipid species, including triacylglycerols, phospholipids, sphingolipids, ceramides, fatty acids, and cholesterol, actively contributes to the initiation and progression of primary liver cancer. Lipid metabolic reprogramming also modifies the TME by influencing the recruitment, activation, and function of immune cells. Tumor-associated macrophages (TAM) are essential components of TME that sustain cancer growth, promoting invasion and mediating immune evasion. Macrophage polarization toward a tumor-supportive phenotype is associated with metabolic reprogramming. Indeed, lipid accumulation and enhanced fatty acid oxidation in TAM contribute to polarization to a M2 phenotype. In this review, we examine lipid metabolism in hepatocellular carcinoma and cholangiocarcinoma, focusing on TAM lipid metabolic reprogramming.
    Keywords:  cholangiocarcinoma; hepatocellular carcinoma; immunosuppression; lipids; macrophages; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers17111858
  2. Med Oncol. 2025 Jun 08. 42(7): 244
    Tumor microenvironment and immunotherapy: from bench to bedside.
    Avipsa Sinha, Debasmita Ghosh, Dipanjan Karati.
      The tumor microenvironment (TME) is a multifaceted and ever-changing assemblage of cells and extracellular constituents. These components are closely linked to the onset and progression of malignancies, as well as their treatment. The TME is characterized by aberrant vasculature, altered extracellular matrix, immune cells, secreted factors, and cancer-associated fibroblasts and macrophages. The importance of the tumor microenvironment (TME) in understanding the course of cancer and resistance to treatment has been highlighted. The TME can suppress immune responses and promote tumor survival by inducing immunosuppressive mechanisms, such as regulatory T cells, myeloid-derived suppressor cells (MDSCs), and checkpoint molecule expression (e.g., PD-L1). Recent research has focused on understanding the interactions between immune cells within the TME to develop strategies that can remodel this environment and increase the effectiveness of immunotherapy. However, the efficacy of immunotherapeutic strategies is frequently hindered by the immunosuppressive nature of the TME. This abstract explores how these dynamics have led to the development of novel immunotherapeutic strategies aimed at reprogramming the TME to enhance antitumor immune responses. Novel approaches targeting TME therapy, such as immune checkpoint blockade (ICB), metabolic inhibitors, and key enzymes of immune metabolism, have been used to treat of cancer immunotherapy. Additionally, new and promising treatments including CAR-T cell therapy, oncolytic viruses, and cytokine-mediated TME modulation have shown promising results. This review provides a general overview of the TME, its components, its impact on immunotherapy outcomes, and emerging approaches to enhance therapeutic efficacy by remodeling the TME.
    Keywords:  CAR-T-cell therapy; Extracellular matrix; Oncolytic viruses; Regulatory T cells; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12032-025-02818-x
  3. Ann Med Surg (Lond). 2025 Jun;87(6): 3372-3380
    Oxygen gradients in tumor tissues implications for breast cancer metastasis - a narrative review.
    Emmanuel Ifeanyi Obeagu.
      Oxygen gradients within tumor tissues play a pivotal role in breast cancer metastasis, influencing critical biological processes that contribute to disease progression. Tumors often develop regions of hypoxia due to rapid growth and insufficient blood supply, which drives adaptation mechanisms that promote metastatic behavior. These low-oxygen areas trigger the activation of hypoxia-inducible factors (HIFs), which regulate genes involved in angiogenesis, epithelial-to-mesenchymal transition (EMT), and immune evasion. Such processes increase the capacity of cancer cells to migrate, invade distant organs, and survive under harsh conditions, contributing significantly to metastasis in breast cancer. The interaction between oxygen gradients and the tumor microenvironment (TME) is complex, with hypoxia inducing significant alterations in immune responses. Hypoxic regions of tumors often foster an immunosuppressive microenvironment by recruiting regulatory immune cells that inhibit the function of cytotoxic T cells and natural killer cells. This immune evasion not only allows the tumor to grow but also facilitates the spread of cancer cells to secondary sites. Furthermore, hypoxia-induced angiogenesis provides the necessary vasculature for metastatic cells to enter the bloodstream and seed distant organs, further enhancing the metastatic potential of breast cancer.
    Keywords:  breast cancer; hypoxia-inducible factors; metastasis; oxygen gradients; tumor microenvironment
    DOI:  https://doi.org/10.1097/MS9.0000000000003121
  4. Pathol Res Pract. 2025 Jun 04. pii: S0344-0338(25)00267-5. [Epub ahead of print]272 156074
    Interactions in hepatic tumor microenvironment: Potential targets and modulations for effective therapy.
    Farag M A Altalbawy, Ahmed Hussein Zwamel, Gaurav Sanghvi, R Roopashree, Mukesh Kumari, Aditya Kashyap, S Gayathri, Rajashree Panigrahi.
      The hepatic tumor microenvironment (TME) exhibits complex interactions among diverse cellular components. Hepatocellular carcinoma cells actively communicate with the surrounding stroma and extracellular matrix (ECM). These interactions create an immunosuppressive and pro-tumorigenic environment. Cancer-associated fibroblasts (CAFs) are able to liberate several factors that promote tumor progression and ECM. Metabolic reprogramming and hypoxia in TME influence tumor growth and response to antitumor drugs through bidirectional signaling between tumor and stromal cells. Similarly, activated stellate cells contribute to matrix remodeling and tumor expansion. Tumor-associated macrophages (TAMs), regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and Kupffer cells can support immune evasion. Recent studies have identified key molecular mediators in these cellular networks. Several targeting strategies show promise in preclinical models. These include immune checkpoint inhibitors (ICIs), immunomodulators, stromal cell modulators, and matrix-degrading agents. However, the effectiveness of conventional therapies remains limited by microenvironmental barriers. Recent progress in the knowledge of TME, nanoparticles, immunomodulators, and even natural-derived molecules with immunoregulatory effects has shown promise in preclinical studies. This review aims to analyze critical interactions within the hepatic TME and evaluate emerging therapeutic approaches that target these interactions for improved treatment outcomes.
    Keywords:  CD8 + T lymphocytes; Hepatic cancer; Hepatocellular carcinoma; Immune checkpoint inhibitors; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.prp.2025.156074
  5. Ann Med Surg (Lond). 2025 Jun;87(6): 3509-3522
    Neutrophils as key regulators of tumor microenvironment in breast cancer: a focus on N1 and N2 polarization.
    Emmanuel Ifeanyi Obeagu, Christian C Ezeala.
      Neutrophils, the most abundant type of white blood cells in the human body, play a vital role in the immune response against infections and tissue injury. However, in the context of cancer, their function becomes more complex and context-dependent. In breast cancer, neutrophils are key players in shaping the tumor microenvironment (TME), a highly dynamic ecosystem where various cell types, extracellular matrix components, and soluble factors interact to influence tumor progression, immune evasion, and metastasis. Neutrophils in the TME are not just passive participants but actively engage in altering tumor biology, either supporting or inhibiting tumor growth depending on their polarization status. Neutrophils exhibit plasticity in their phenotype and function, which can be categorized into two polarized forms: N1 and N2. N1 neutrophils are associated with antitumor responses, promoting immune activation, direct cytotoxicity against tumor cells, and facilitating the clearance of cancerous cells through the release of reactive oxygen species, cytokines, and chemokines. Conversely, N2 neutrophils contribute to tumor progression by fostering an immunosuppressive environment, promoting angiogenesis, enhancing tumor cell migration and invasion, and aiding in the establishment of metastatic niches. This dichotomy of neutrophil polarization plays a crucial role in determining breast cancer progression, metastasis, and response to treatment.
    Keywords:  N1 polarization; N2 polarization; breast cancer; neutrophils; tumor microenvironment
    DOI:  https://doi.org/10.1097/MS9.0000000000003269
  6. Int J Mol Sci. 2025 Jun 01. pii: 5336. [Epub ahead of print]26(11):
    Regulation and Function of Tumor-Associated Macrophages (TAMs) in Colorectal Cancer (CRC): The Role of the SRIF System in Macrophage Regulation.
    Agnieszka Geltz, Jakub Geltz, Aldona Kasprzak.
      Colorectal cancer (CRC) remains the leading cause of morbidity and mortality for both men and women worldwide. Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) of solid tumors, including CRC. These macrophages are found in the pro-inflammatory M1 and anti-inflammatory M2 forms, with the latter increasingly recognized for its tumor-promoting phenotypes. Many signaling molecules and pathways, including AMPK, EGFR, STAT3/6, mTOR, NF-κB, MAPK/ERK, and HIFs, are involved in regulating TAM polarization. Consequently, researchers are investigating several potential predictive and prognostic markers, and novel TAM-based therapeutic targets, especially in combination therapies for CRC. Macrophages of the gastrointestinal tract, including the normal colon and rectum, produce growth hormone-releasing inhibitory peptide/somatostatin (SRIF/SST) and five SST receptors (SSTRs, SST1-5). While the immunosuppressive function of the SRIF system is primarily known for various tissues, its role within CRC-associated TAMs remains underexplored. This review focuses on the following three aspects of TAMs: first, the role of macrophages in the normal colon and rectum within the broader context of macrophage biology; second, the various bioactive factors and signaling pathways associated with TAM function, along with potential strategies targeting TAMs in CRC; and third, the interaction between the SRIF system and macrophages in both normal tissues and the CRC microenvironment.
    Keywords:  colorectal cancer; macrophages; polarization; role of SRIF system in immune system; somatostatin; somatostatin receptors; tumor-associated macrophages
    DOI:  https://doi.org/10.3390/ijms26115336
  7. Front Microbiol. 2025 ;16 1591745
    The role of the gut microbiota in shaping the tumor microenvironment and immunotherapy of breast cancer.
    Xiaoying Ren, Lixiang Zheng, Ling Huang, Jiangbo Zhao.
      Breast cancer is the most prevalent malignancy among women worldwide and is a major contributor to cancer-related mortality. The tumor microenvironment (TME), composed of tumor cells, immune infiltrates, fibroblasts, and vascular components, is critically involved in tumor initiation, metastatic progression, and therapeutic response. In recent years, therapies targeting the TME have undergone rapid advancements, with the objective of enhancing antitumor immunity. Concurrently, mounting evidence underscores the pivotal role of the gut microbiota and its metabolites in modulating host immunity, influencing metabolic homeostasis, inflammation, and immune equilibrium. The composition and diversity of the gut microbiome influence breast cancer progression and patients' responses to immunotherapy. Therefore, modulating the gut microbiota is a promising strategy to enhance the clinical outcomes of TME-targeted immunotherapies. In this review, we discuss the influence of gut microbiota and its derived metabolites on breast cancer progression and immunotherapy prognosis and explore potential strategies to optimize immunotherapy through gut microbiota modulation.
    Keywords:  breast cancer; dietary intervention; fecal microbiota transplantation; gut microbiota; immunotherapy; prebiotics; tumor microenvironment
    DOI:  https://doi.org/10.3389/fmicb.2025.1591745
  8. Ann Med Surg (Lond). 2025 Jun;87(6): 3682-3690
    The balance between N1 and N2 neutrophils implications for breast cancer immunotherapy: a narrative review.
    Emmanuel Ifeanyi Obeagu.
      Neutrophils, essential components of the innate immune system, exhibit remarkable plasticity in the tumor microenvironment, shifting between anti-tumoral (N1) and pro-tumoral (N2) phenotypes. This functional dichotomy is particularly significant in breast cancer, where N1 neutrophils contribute to tumor suppression by enhancing cytotoxicity and immune activation, while N2 neutrophils promote tumor progression through immunosuppression, angiogenesis, and metastasis. The tumor microenvironment, driven by factors such as TGF-β, IL-6, and hypoxia, orchestrates this polarization, profoundly influencing disease progression and therapeutic outcomes. The interplay between neutrophil polarization and breast cancer immunotherapy presents both challenges and opportunities. Pro-tumoral N2 neutrophils often hinder the efficacy of immune checkpoint inhibitors and other immunotherapies by suppressing T-cell function and facilitating tumor immune evasion. Conversely, strategies to reprogram neutrophils toward the N1 phenotype, including TGF-β inhibitors, CXCR2 antagonists, and epigenetic modulators, show promise in restoring anti-tumoral activity. Novel approaches, such as nanoparticle-mediated delivery of neutrophil-targeting agents, further expand the potential for precision immunotherapy by selectively modulating neutrophil phenotypes.
    Keywords:  N1 neutrophils; N2 neutrophils; breast cancer; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1097/MS9.0000000000003361
  9. Int Immunopharmacol. 2025 Jun 05. pii: S1567-5769(25)00999-3. [Epub ahead of print]161 115009
    Tumor-associated macrophages in radiotherapy: Mechanisms of polarization, immune regulation and therapeutic strategies.
    Junguang Xu, Jintao Mo, Yihan Jiang, Tianpeng Yang, Zipeng Lu, Liu Han, Jinyan Ding, Fang Shi, Rui Liu.
      Macrophages have been shown to play a pivotal role in tumor radiotherapy (RT), particularly in the formation of tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). The number and polarization state of TAMs have been demonstrated to be closely related to the prognosis of tumors. Studies show that the polarization and infiltration of TAMs regulate tumor growth, metastasis and immune escape through multiple mechanisms such as exosomes and cytokines. In RT, TAMs can affect the radiosensitivity of tumors by promoting immunosuppression, angiogenesis and matrix remodeling. However, emerging studies in recent years have demonstrated that TAMs do not always promote tumor progression, and their phenotypes and functions exhibit significant heterogeneity and plasticity, and can even exert anti-tumor effects under certain conditions. A comprehensive understanding of the dynamic changes of TAMs under different RT regimens and their regulatory mechanisms on tumor immune microenvironment (TIME) are crucial for optimizing RT strategies. This review aims to comprehensively illustrate the dual roles of TAMs in tumor radiotherapy and focuses on how to precisely regulate the function and phenotype of TAMs through immunomodulation and targeted therapeutic strategies with the aim of overcoming radioresistance and enhancing tumor radiosensitivity. It is expected to enhance the understanding of the complex relationship between TAMs and RT, and to provide new ideas and a theoretical basis for the development of more effective combined treatment strategies.
    Keywords:  Immune regulation; M1/M2 polarization; Radiosensitivity; Radiotherapy; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.intimp.2025.115009
  10. Int J Mol Sci. 2025 May 30. pii: 5266. [Epub ahead of print]26(11):
    Targeting Lineage-Specific Functions of NR4A1 for Cancer Immunotherapy.
    Jeremy Kleberg, Akhila Nataraj, Yufeng Xiao, Bristy R Podder, Zeng Jin, Tanzia Islam Tithi, Guangrong Zheng, Keiran S M Smalley, Emily K Moser, Stephen Safe, Chandra K Maharjan, Ryan Kolb, Weizhou Zhang.
      Orphan nuclear receptor 4A1 (NR4A1, Nur77) plays a crucial role in regulating immune cell metabolism and function within the tumor microenvironment (TME), thus influencing cancer progression and serving as a potential therapeutic target for cancer immunotherapy. A comprehensive review discussing the multifaceted roles of NR4A1 in immune cells and the exploitation of that knowledge for therapeutic development is lacking in the field. This review explores diverse functions of NR4A1 in tumor-associated immune cells, including T cells, monocytes, natural killer cells, B cells, dendritic cells, macrophages, and neutrophils. NR4A1 contributes to immune regulation by impacting cytokine production, cell differentiation, and immune cell exhaustion. We highlight how NR4A1 in immune cells within the TME may be either a positive (e.g., macrophages in colon cancer) or negative prognostic factor (e.g., T cells in melanoma), depending on the cancer and immune cell context. Additionally, this review also highlights potential therapeutic strategies targeting NR4A1, leading to its inhibition, activation, or degradation to restore immune cell function and enhance anti-tumor immunity. Such therapies could potentially improve patient outcomes by altering immune cell behaviors, blocking intrinsic tumor growth pathways, or via both mechanisms. However, the development of NR4A1-targeted therapies will be dependent on further research to better understand lineage-specific roles of NR4A1 and the underlying mechanisms across different cancer types and immune cells.
    Keywords:  NR4A1; cancer; immune cells; immunotherapies; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms26115266
  11. Cell Mol Immunol. 2025 Jun 11.
    Immune microenvironment in hepatocellular carcinoma: from pathogenesis to immunotherapy.
    Deniz Seyhan, Manon Allaire, Yaojie Fu, Filomena Conti, Xin Wei Wang, Bin Gao, Fouad Lafdil.
      Hepatocellular carcinoma (HCC) is an increasingly prevalent and deadly disease that is initiated by different etiological factors, such as alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatohepatitis (MASH), viral hepatitis, and other hepatotoxic and hepatocarcinogenic agents. The tumor microenvironment (TME) of HCC is characterized by several different fibroblastic and immune cell types, all of which affect the initiation, progression and metastasis of this malignant cancer. This complex immune TME can be divided into an innate component that includes macrophages, neutrophils, dendritic cells, myeloid-derived suppressor cells, mucosal-associated invariant T cells, natural killer cells, natural killer T cells, and innate lymphoid cells, as well as an adaptive component that includes CD4+ T cells, CD8+ T cells, regulatory T cells, and B cells. In this review, we discuss the latest findings shedding light on the direct or indirect roles of these immune cells (and fibroblastic-like cells such as hepatic stellate cells) in the pathogenesis of HCC. Henceforth, further characterization of this heterogeneous TME is highly important for studying the progression of HCC and developing novel immunotherapeutic treatment options. In line with this, we also review novel groundbreaking experimental techniques and animal models aimed at specifically elucidating this complex TME and discuss emerging immune-based therapeutic strategies intended to treat HCC and predict the efficacy of these immunotherapies.
    Keywords:  Hepatocellular carcinoma; Immune microenvironment; Immunotherapy.
    DOI:  https://doi.org/10.1038/s41423-025-01308-4
  12. Eur J Immunol. 2025 Jun;55(6): e51767
    Pro- and Anti-Inflammatory Role of Complement in Cancer.
    Pradipta Pal, Praneet Wahi, Arvind Sahu, Girdhari Lal.
      The complement system bridges innate and adaptive immunity, and its role in the tumor microenvironment (TME) is complex and context-dependent. Multiple recent studies have demonstrated the complement system's pro- and anti-tumor effects. In the present review, we discuss the role of complement in shaping the functions of various immune cells, including T cells, macrophages, natural killer (NK) cells, neutrophils, and dendritic cells within the TME. We also highlighted how complement proteins drive the pro- or anti-inflammatory immune responses, the associated cellular and molecular mechanisms, their influence on anti-tumor immunity, and some clinical trials targeting complement systems. A comprehensive and critical understanding of the complement system in oncoimmunology may aid in designing effective tumor-specific therapeutic strategies.
    Keywords:  anaphylatoxins; complement proteins; complement receptors; complement regulators; tumor microenvironment
    DOI:  https://doi.org/10.1002/eji.202451767
  13. Cancer Control. 2025 Jan-Dec;32:32 10732748251347917
    New Insights Into Adipokines and the Tumor Microenvironment in Breast Cancer.
    Xin Ma, Shaofeng Yang, Donghai Li.
      Breast cancer remains the malignant tumor with the highest incidence among female patients globally, and its treatment represents a well-recognized clinical challenge. Recent studies have demonstrated that the tumor microenvironment (TME) exerts a substantial influence on breast cancer progression, whereby alterations in its internal molecular components ultimately impact disease outcomes. Key factors implicated in this process include adipokines and microRNAs (miRNAs). This review provides a detailed description of how different adipocytokines exert specific mechanistic effects on breast cancer cells. By integrating adipokines with miRNAs, the discussion explores their combined roles in the initiation and progression of breast cancer, addressing a previously unaddressed research gap in studies focusing solely on individual adipokines. Furthermore, by examining the interactions between miRNAs and signaling pathways, this analysis offers a holistic perspective on the TME network, thereby fostering new therapeutic insights for breast cancer management.
    Keywords:  adipokines; breast cancer; signaling pathway; tumor microenvironment
    DOI:  https://doi.org/10.1177/10732748251347917
  14. Future Oncol. 2025 Jun 09. 1-12
    The rules of different B cell subtypes in colorectal cancer: friends or foes?
    Yuanchao Shi, Qianwen Luo, Jingwei Duan, Bo Tang, Quanlin Guan.
      Tumor-infiltrating B cells (TIBs) are the most important cell type involved in the immune response. TIBs display considerable intratumor heterogeneity due to genetic variation, epigenetic differences and transcriptional plasticity in the tumor microenvironment (TME). Owing to the unique anatomical location of CRC, the B cell subpopulation exhibits more extensive heterogeneity. Many studies have shown that TIBs have gradually become a key predictor of immunotherapy for malignant cancers, including CRC. TIBs have essential functions, including antigen presentation and antibody secretion, and they promote T-cell activation and myeloid chemotaxis. However, owing to the complex TME, TIBs not only promote the antitumor immune response but also inhibit the immune response. With the in-depth study of tumor-infiltrating T cells, tumor-associated myeloid cells and the interactions among these cells in the TME, the special role of immune cells in the TME has gradually become clear. However, the influence of TIBs in the TME and their interactions with nonimmune cells in the TME remain unclear. Here, we summarize the current progress in TIBs based on single-cell RNA sequencing in CRC in recent years, focusing on specific effector or regulatory characteristics of different B cell subclusters in the CRC TME.
    Keywords:  Colorectal cancer (CRC); immune response; single-cell RNA sequencing (scRNA-seq); tumor microenvironment (TME); tumor-infiltrating B cells (TIBs)
    DOI:  https://doi.org/10.1080/14796694.2025.2511588
  15. Front Immunol. 2025 ;16 1595070
    Roles and functions of tumor-infiltrating lymphocytes and tertiary lymphoid structures in gastric cancer progression.
    Zhiyuan Yao, Gengchen Li, Di Pan, Zichen Pei, Yan Fang, Haonan Liu, Zhengxiang Han.
      Gastric cancer (GC), a leading cause of cancer mortality, exhibits profound molecular heterogeneity and immunosuppressive tumor microenvironment (TME) features that limit therapeutic efficacy. This review elucidates the dual roles of tertiary lymphoid structures (TLS) and tumor-infiltrating lymphocytes (TILs) in GC progression. TLS, ectopic lymphoid organs formed under chronic inflammation, correlate with improved survival and immunotherapy sensitivity by fostering effector T/B cell interactions and antigen presentation. Conversely, immunosuppressive TME components like regulatory T cells (Tregs) and tumor-associated macrophages (TAMs) drive immune evasion via cytokine-mediated suppression and checkpoint activation (PD-1/PD-L1). CD8+ T cells exert context-dependent effects, with high infiltration reducing recurrence risk but paradoxically inducing exhaustion in PD-L1-rich microenvironments. Th17 and memory T cells further modulate disease through IL-17-driven angiogenesis and CD45RO+ immune memory dynamics. Multi-omics-based TLS scoring and combinatorial therapies emerge as promising strategies to overcome resistance.
    Keywords:  biomarkers; gastric cancer; immune checkpoint inhibitors; progression; tertiary lymphoid structures; tumor microenvironment; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.3389/fimmu.2025.1595070
  16. Acta Pharm Sin B. 2025 Apr;15(4): 1841-1868
    Nano-drug delivery strategies affecting cancer-associated fibroblasts to reduce tumor metastasis.
    Linghui Zou, Peng Xian, Qing Pu, Yangjie Song, Shuting Ni, Lei Chen, Kaili Hu.
      Tumor metastasis is the leading cause of high mortality in most cancers, and numerous studies have demonstrated that the malignant crosstalk of multiple components in the tumor microenvironment (TME) together promotes tumor metastasis. Cancer-associated fibroblasts (CAFs) are the major stromal cells and crosstalk centers in the TME of various kinds of tumors, such as breast cancer, pancreatic cancer, and prostate cancer. Recently, the CAF-induced pro-tumor metastatic TME has gained wide attention, being considered as one of the effective targets for tumor therapy. With in-depth research, CAFs have been found to promote tumor metastasis through multiple mechanisms, such as inducing epithelial-mesenchymal transition in tumor cells, remodeling the extracellular matrix, protecting circulating tumor cells, and facilitating the formation of a pre-metastatic niche. To enhance the anti-tumor metastasis effect, therapeutic strategies designed by combining nano-drug delivery systems with CAF modulation are undoubtedly a desirable choice, as evidenced by the research over the past decades. Herein, we introduce the physiological properties of CAFs, detail the possible mechanisms whereby CAFs promote tumor metastasis, categorize CAFs-based nano-drug delivery strategies according to their anti-metastasis functions and discuss the current challenges, possible solutions, as well as the future directions in order to provide a theoretical basis and reference for the utilization of CAFs-based nano-drug delivery strategies to promote tumor metastasis therapy.
    Keywords:  Cancer-associated fibroblasts; Circulating tumor cells; Epithelial–mesenchymal transition; Extracellular matrix; Nano-drug delivery system; Pre-metastatic niche; Tumor metastasis; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.apsb.2025.02.040
  17. Cancers (Basel). 2025 Jun 04. pii: 1881. [Epub ahead of print]17(11):
    The Metabolic Orchestration of Immune Evasion in Glioblastoma: From Molecular Perspectives to Therapeutic Vulnerabilities.
    Ravi Medikonda, Matthew Abikenari, Ethan Schonfeld, Michael Lim.
      Glioblastoma (GBM) is a highly aggressive primary brain cancer with dismal prognoses despite current standards of care. Immunotherapy is being explored for GBM, given its promising results in other solid malignancies; however, the results from early clinical studies in GBM are disappointing. It has been discovered that GBM has numerous mechanisms of immune resistance, including the physical blood-brain barrier, high intratumoral and intertumoral heterogeneity, and numerous cellular and molecular components in the tumor microenvironment (TME) that promote immunosuppression. Furthermore, GBM utilizes numerous metabolic pathways to establish a survival advantage in the TME. Recently, it has begun to become evident that these complex metabolic pathways that promote GBM growth and invasion also contribute to tumor immune resistance. Aerobic glycolysis provides tumor cells with ample ATP while depleting key glucose and increasing acidity in the TME. Increased glutamine, tryptophan, and arginine metabolism deprives T cells of these necessary amino acids for proper anti-tumor function. Sphingolipid metabolism promotes an immunosuppressive phenotype in the TME and affects immune cell trafficking. This review will discuss, in detail, the key metabolic pathways relevant to GBM pathophysiology which also modulate host immunosuppression.
    Keywords:  arginine depletion; glioblastoma; immune evasion; immunometabolism; sphingolipid pathways; tryptophan metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers17111881
  18. J Transl Med. 2025 Jun 08. 23(1): 634
    Targeting inflammasomes as an immunotherapeutic strategy for cancer.
    Luanluan Huang, Xiaoyan Chen, Ruiqi Liu, Ding Nan, Wenxuan Bao, Lixian Yang, Xiaomeng Dai, Jianming Tang, Haibo Zhang, Yanwei Lu.
      Inflammasomes are essential regulators of innate immunity, inflammation, and cellular apoptosis, and they have surfaced as significant modulators of cancer progression and regulation. Inflammasomes are macromolecular complexes assembled in response to damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). They induce inflammation via the oligomerization and activation of caspases. These cysteine proteases cleave the pro-inflammatory cytokines IL-1β and IL-18 into their physiologically active mature versions. Recent discoveries reveal that inflammasomes are implicated not only in infections but also in malignancies, suggesting a significant connection between inflammation and tumor development. This article emphasizes that inflammasomes cause pyroptosis in a variety of immune cells, such as dendritic cells, macrophages, T cells, and fibroblasts, in addition to tumor cells. The induction of CD8+ T cells allows inflammasomes to commence an immunological response against the tumor, successfully inhibiting its growth and progression. The inflammasome comprises four main types: NLRP1, NLRP3, NLRC4, and AIM2. Nevertheless, the inflammasomes are activated by infection, injury, or stimulation of host cells, thus triggering the inflammatory response. The essential roles of the NLRP1, NLRP3, NLRC4, and AIM2 inflammasomes are emphasized in both tumors and immune cells. Furthermore, the article provides an overview of inhibitors targeting various tumor inflammasome pathways currently in clinical trials. Here, in this review, we underscore the role of the inflammatory response in cancer progression and highlight the significance of inflammasomes in regulating immune cells within the tumor microenvironment. Targeting these inflammasomes offers novel strategies for cancers.
    Keywords:  Immune cells; Immunotherapy; Inflammasome; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12967-025-06665-2
  19. bioRxiv. 2025 Jun 03. pii: 2025.05.30.657094. [Epub ahead of print]
    Klf4 -dependent pivotal role of smooth muscle-derived Gli1 + lineage progenitor cells in lung cancer progression.
    Sizhao Lu, Andre C Navarro, Amber M Johnson, Tysen Noble, Austin J Jolly, Allison M Dubner, Karen S Moulton, Raphael A Nemenoff, Mary Cm Weiser-Evans.
      Lung cancer remains the leading cause of cancer-related deaths worldwide. Despite the remarkable efficacy of immune checkpoint inhibitors, only a subset of lung adenocarcinoma (LUAD) patients respond and many eventually progress, underscoring the need to develop novel combination therapies. The interaction between cancer cells and the tumor microenvironment (TME), a complex niche including cells of the innate and adaptive immune system, cancer-associated fibroblasts (CAFs), vascular cells, and extracellular matrix (ECM) plays a vital role in tumorigenesis and cancer progression. Using fate mapping, we previously identified a novel subpopulation of resident vascular stem cells derived from vascular smooth muscle cells, designated AdvSca1-SM (vascular Adventitial location, Stem cell antigen-1 expression, SMooth muscle origin) cells. AdvSca1-SM cells are the predominant cell type responding to vessel wall dysfunction and their selective differentiation to myofibroblasts promotes vascular fibrosis. SMC-to-AdvSca1-SM cell reprogramming is dependent on SMC induction of the transcription factor KLF4, and KLF4 is essential for maintenance of the stem cell phenotype. The function of AdvSca1-SM cells in LUAD tumorigenesis has not been explored. Using an orthotopic immunocompetent mouse model of LUAD, we demonstrate that AdvSca1-SM cells are a major component of lung tumors, significantly contributing to cancer associated fibroblasts (CAFs). Compared to AdvSca1-SM cells, CAFs have altered ECM gene expression with a reduction of a stemness signature. AdvSca1-SM-specific genetic ablation of Klf4 altered their phenotype resulting in inhibition of communication between cancer cells and CAFs, decreases in innate immunosuppressive populations, and increased T cell infiltration into the tumor. Targeting this population may represent a novel strategy to improve the response to immunotherapy.
    DOI:  https://doi.org/10.1101/2025.05.30.657094
  20. Ann Med Surg (Lond). 2025 Jun;87(6): 3464-3488
    Inflammatory signaling pathways in neutrophils: implications for breast cancer therapy.
    Emmanuel Ifeanyi Obeagu, Syed A A Rizvi.
      Neutrophils, key components of the innate immune system, have emerged as pivotal players in the tumor microenvironment (TME), particularly in breast cancer. These versatile cells contribute to both pro-tumorigenic and anti-tumorigenic processes through inflammatory signaling pathways that influence tumor progression, immune evasion, and therapeutic responses. Their recruitment to the TME, mediated by chemokines such as CXCL1 and CXCL8, and their subsequent activation underscore their complex role in breast cancer biology. Neutrophil extracellular traps, cytokine secretion, and reactive oxygen species production further highlight their dualistic nature in cancer pathophysiology. Critical inflammatory signaling pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K)/AKT, regulate neutrophil activity in breast cancer. Dysregulation of these pathways can lead to the promotion of angiogenesis, immune suppression, and metastasis. For example, the NF-κB pathway fosters the secretion of pro-inflammatory cytokines, while JAK/STAT signaling drives the differentiation of tumor-associated neutrophils. The MAPK and PI3K/AKT pathways influence neutrophil survival and chemotactic responses, further enhancing their contribution to the tumor-supportive microenvironment. Understanding these mechanisms provides a framework for therapeutic intervention.
    Keywords:  breast cancer; inflammatory signaling pathways; neutrophils; therapeutic targeting; tumor microenvironment
    DOI:  https://doi.org/10.1097/MS9.0000000000003251
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