bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2025–07–13
twenty-one papers selected by
Peio Azcoaga, Biodonostia HRI
  1. The role of the immune tumor microenvironment in shaping metastatic dissemination, dormancy, and outgrowth.
  2. Interactions between glioblastoma and myeloid cells.
  3. Tumor-associated macrophages and platelets in tumor microenvironment and its potential therapeutic role in ovarian cancer.
  4. Tumor-educated cells in tumor microenvironment: Key drivers of immunotherapy resistance.
  5. EV-mediated asymmetrical crosstalk between CAFs and cancer cells in the tumor microenvironment.
  6. Cancer associated fibroblasts in tumors: focusing on solid tumors and hematological malignancies.
  7. Microbial-induced trained immunity for cancer immunotherapy.
  8. Correction to "Atorvastatin Promotes the Expansion of Myeloid-Derived Suppressor Cells and Attenuates Murine Colitis".
  9. Effects of Mesenchymal Stem Cells on Functions of Chimeric Antigen Receptor-Expressing T Lymphocytes and Natural Killer Cells.
  10. Research Progress on the Combination of PARP Inhibitors (PARPi) and Immune Checkpoint Inhibitors (ICIs).
  11. LATS1/2-Integrin Axis Confers Tumor-Generated Forces That Activate Neighboring Fibroblasts.
  12. Unlocking Immunity Within: Inflammatory Monocytes Stimulate T Cells at Immune Hubs in the Tumor Microenvironment.
  13. Microbiome-mediated immune modulation in tumor microenvironment.
  14. Role of Innate Immunity in Cancer.
  15. The role of tumor-associated macrophages and PD-1/PD-L1 networking in colorectal cancer.
  16. The Multifaceted Role of the IL-2 Cytokine Family in Melanoma: Mechanisms, Therapeutic Implications, and Immune Modulation.
  17. Nanotechnology-enhanced immunotherapies for pancreatic ductal adenocarcinoma: challenges and opportunities.
  18. Preserved host immunity with intercellular adhesion molecule-1 (ICAM-1)-targeted near-infrared photoimmunotherapy (NIR-PIT) in the treatment of triple-negative breast cancer and other malignancies.
  19. ECM Mechanics Control Jamming-to-Unjamming Transition of Cancer Cells.
  20. Potential functions of TRPM2 and TRPM7 channels in the tumor microenvironment.
  21. Energy stress and adaptation strategy of tumor cells in different microenvironments: from primary tumors to distant metastases.
  1. Trends Cell Biol. 2025 Jul 04. pii: S0962-8924(25)00124-2. [Epub ahead of print]
    The role of the immune tumor microenvironment in shaping metastatic dissemination, dormancy, and outgrowth.
    Garis Grant, Christina M Ferrer.
      The tumor microenvironment (TME) is a dynamic and complex ecosystem composed of cancer cells and diverse non-malignant cell types, including immune cells, fibroblasts, and endothelial cells. Once viewed as passive bystanders, these host cells are now recognized as active participants in tumor progression, especially during metastasis. The TME varies by organ, cancer type, and disease stage, and shapes the trajectory of cancer progression. Among the immune cells in the TME, macrophages, neutrophils, and T cells play especially crucial and context-dependent roles - either promoting or inhibiting metastatic spread depending on the tumor stage, immune cell phenotypic states, and interactions. In this review we focus on the multifaceted contributions of these key immune populations across the major stages of the metastatic cascade: initiation, survival in the circulation, dissemination, dormancy, and reactivation. These insights highlight the heterogeneity of the metastatic immune microenvironment and underscore the therapeutic potential of targeting macrophages, neutrophils, and T cells to combat metastatic disease.
    Keywords:  circulating tumor cells (CTCs); disseminated tumor cells (DTCs); dormancy; immune tumor microenvironment; metastasis
    DOI:  https://doi.org/10.1016/j.tcb.2025.05.006
  2. Front Cell Dev Biol. 2025 ;13 1632122
    Interactions between glioblastoma and myeloid cells.
    Yuting Li, Yuhong Chen, Kai Cai, Yujuan Qin, Xi Wang, Bo Zhang, Lin Shi, Zonglin He, Jiasheng Wang, Jiecun Long, Yishun Zeng, Qiong Gong.
      Standing as the most aggressive form of primary malignant tumor, Glioblastoma (GBM) tumors with marked heterogeneity represents one of the enormous challenges in glioma treatment. Myeloid cells, which includes neutrophils, myeloid-derived suppressor cells, microglia, and macrophages, play a pivotal role in the tumor microenvironment of GBM. In the tumor microenvironment (TME), T cells and natural killer (NK) cells exert anti-tumor functions, whereas myeloid-derived suppressor cells (MDSCs) can promote tumor progression by suppressing these immune responses. Therefore, MDSCs play a critical role in shaping the effectiveness of immunotherapy. TME has constrained the ability of traditional GBM treatment approaches to significantly enhance prognostic outcomes for patients. This category encompasses conventional therapies like surgical resection and radiation therapy, along with cutting-edge methodologies such as immunotherapy. Through extensive investigations into the dynamic interactions between the GBM microenvironment and neoplastic cells, both targeted treatment strategies and innovative immunotherapeutic modalities have emerged, offering promising new directions for clinical intervention. This review focuses on the interactions between GBM and myeloid cells (MCs), providing novel insights into the oncogenesis and progression of GBM.
    Keywords:  GBM; MDSC; TAM; TME; myeloid cells
    DOI:  https://doi.org/10.3389/fcell.2025.1632122
  3. Clin Transl Oncol. 2025 Jul 07.
    Tumor-associated macrophages and platelets in tumor microenvironment and its potential therapeutic role in ovarian cancer.
    Jingwen Shi, Weiling Xiao, Yan Liu, Xiaoyan Fu, Meiyu Peng.
      Ovarian cancer is one of the most lethal cancers among gynecological tumors, with most cases diagnosed at an advanced stage. Despite advancements in medical science, current therapeutic options remain somewhat constrained, leading to a persistently high mortality among patients. The tumor microenvironment (TME) critically drives ovarian cancer progression by orchestrating tumorigenesis, metastasis, and chemoresistance via intercellular crosstalk, metabolic reprogramming, and immunosuppression. Tumor-associated macrophages (TAMs) and platelets are pivotal components of the ovarian cancer immune microenvironment. These components facilitate critical oncogenic processes, including tumor cell dissemination, immune evasion, and chemoresistance. Both TAMs and platelets have emerged as promising therapeutic targets. Furthermore, bidirectional crosstalk between platelets and TAMs dynamically shapes the immunosuppressive TME. This review synthesizes the roles and mechanisms of TAMs and platelets in ovarian cancer progression, discusses emerging therapeutic strategies targeting these components, and establishes a framework for advancing novel therapies in ovarian cancer treatment.
    Keywords:  Ovarian cancer; Platelet; TAMs; Targeted immunotherapy
    DOI:  https://doi.org/10.1007/s12094-025-03987-x
  4. Chin J Cancer Res. 2025 Jun 30. 37(3): 446-465
    Tumor-educated cells in tumor microenvironment: Key drivers of immunotherapy resistance.
    Ji'an Zou, Shuxing Wang, Yingzhe Zhang, Wentao Tian, Ge Mai, Yiting Xu, Wenjie Xiao, Edward E Graves, Fang Wu.
      In the past decade, immunotherapies targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed cell death 1 (PD-1), and PD-1 ligand (PD-L1) have been approved for solid tumors. However, some patients demonstrate suboptimal clinical outcomes due to resistance. The tumor microenvironment (TME) significantly affects the efficiency of immunotherapy by mediating interactions between tumor and non-tumor cells, including dendritic cells, T cells, B cells, macrophages, neutrophils, NK cells, and myeloid-derived suppressor cells (MDSCs). These non-tumor cells often exhibit two phenotypes with altered functions, and tumor cells drives their transition towards tumor promotion through tumor-education. Tumor-educated cells (TECs) are cells influenced by tumor cells, which acquire immune-suppressive phenotypes and promote tumor progression through resistance to anti-cancer therapies. These cells undergo modifications in response to signals from the tumor, which can influence their roles in tumor progression. Their dynamic interactions with tumor cells contribute to the reshaping of the TME, facilitating cancer growth and immune modulation. This review summarizes research on TECs in TME, explores mechanisms related to tumor education, and discusses their role in tumor progression and immunotherapy resistance. Additionally, potential therapeutic approaches targeting these cells are also reviewed, which may complement current treatment strategies.
    Keywords:  Tumor-educated cells; cancer immunotherapy; immune checkpoint blockade resistance; tumor microenvironment
    DOI:  https://doi.org/10.21147/j.issn.1000-9604.2025.03.12
  5. Biochim Biophys Acta Rev Cancer. 2025 Jul 03. pii: S0304-419X(25)00122-2. [Epub ahead of print]1880(4): 189380
    EV-mediated asymmetrical crosstalk between CAFs and cancer cells in the tumor microenvironment.
    Alice Santi, Annalisa Moccia, Anna Caselli, Paolo Cirri.
      Tumor is a complex tissue composed of both genetically transformed cancer cells and the cells of the tumor microenvironment, including connective cells, immune cells, and endothelial cells that actively contribute to the maintenance of the tumor and, consequently, to its progression. As for any other tissue, the communication between cells of the tumor microenvironment plays an essential role in determining the architecture and physiology of the tumor tissue. This intercellular communication is classically mediated by soluble factors (such as cytokines and growth factors) but it has been shown that the extracellular vesicle (EV) trafficking may also contribute to tumor growth and progression. In this paper, we discuss the EV-mediated transfer of proteins between cancer cells and cancer-associated fibroblasts (CAFs) in an attempt to propose an interpretation of the relationships between these two cell types within the tumor microenvironment. In particular, we propose that this type of crosstalk between cancer cells and CAFs is asymmetrical: on the one hand, cancer cells secrete signaling protein-bearing exosomes that induce the trans-differentiation of neighboring fibroblasts into CAFs; on the other hand, CAFs transfer biomass to cancer cells through ectosome trafficking, thus supporting cancer cell proliferation.
    Keywords:  CAFs; Cellular crosstalk; Ectosome; Exosome; Extracellular vesicles; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189380
  6. Front Oncol. 2025 ;15 1596947
    Cancer associated fibroblasts in tumors: focusing on solid tumors and hematological malignancies.
    Chengyun Pan, Lin Zheng, Jishi Wang.
      The co evolution of tumor cells and microenvironmental matrix components almost determines the series of processes involved in cancer occurrence and progression. However, many anti-cancer treatments are designed around tumor cells, neglecting the supportive role of stromal cells. Cancer-associated fibroblasts (CAFs), as the main stromal cells in tumor microenvironment, are currently considered as a key component promoting tumorigenesis, development, and regulating the transfer of tumor cells to distant locations through secretion of different growth factors, cytokines, chemokines, and the degradation of extracellular matrix. Therefore, the strategy of targeting both cancer cells and CAFs shows great potential in cancer treatment. In hematological malignancies, the role of CAFs in the progression of tumors has gradually been recently tapped. This review describes the role and functional characteristics of CAFs in tumors, mainly concentrates on the potential role of CAFs in the disease progression of hematological malignancies according to recent findings, and emphasizes the importance of CAFs as a key target to overcome tumor progression and improve treatment efficacy.
    Keywords:  cancer associated fibroblasts; hematological malignancies; heterogeneity; microenvironment; tumor progression
    DOI:  https://doi.org/10.3389/fonc.2025.1596947
  7. Pharmacol Rev. 2025 Jun 12. pii: S0031-6997(25)07482-4. [Epub ahead of print]77(5): 100074
    Microbial-induced trained immunity for cancer immunotherapy.
    Patricia Vuscan, Brenda Kischkel, Leo A B Joosten, Mihai G Netea.
      Myeloid innate immune cells, including macrophages, neutrophils, myeloid-derived suppressor cells, and dendritic cells, represent major components of the tumor microenvironment (TME), exhibiting remarkable plasticity and dual roles in cancer progression and immune regulation. In recent years, microbial-induced innate immune memory, also termed "trained immunity" (TRIM), has emerged as a novel strategy to reprogram myeloid cells into an immunostimulatory, antitumor state. In this review, we explore the intricate landscape of myeloid cells in cancer and examine how microbial ligands, such as the Bacillus Calmette-Guérin vaccine and β-glucan, reprogram both bone marrow progenitors and tissue-resident myeloid cells to enhance inflammatory and antitumor responses. Notable findings include the hematopoietic stem and progenitor cell reprogramming by Bacillus Calmette-Guérin for sustained anticancer immunity, and the enhanced granulopoiesis and neutrophil-mediated tumor killing mediated by β-glucan-induced TRIM. These mechanisms synergize with immunotherapies, such as immune checkpoint inhibitors, by reshaping the immunosuppressive TME and enhancing adaptive immunity. However, challenges remain, including the structural complexity of microbial products, the lack of predictive biomarkers, and the need for optimized dosing and delivery strategies. Addressing these gaps by introducing precise characterization of microbial-derived ligands, biomarker-driven patient selection through large-scale clinical trials, as well as the development of novel approaches for targeted therapy will be essential to harness the full potential of microbial-induced TRIM, ultimately paving the way for more effective and durable cancer immunotherapies. SIGNIFICANCE STATEMENT: Tumor-promoting myeloid cells within the tumor microenvironment remain a major barrier to effective cancer immunotherapy. Microbial-induced trained immunity offers a novel strategy to reprogram myeloid cells into an antitumor state. This review provides a comprehensive overview of myeloid cell populations in cancer and the mechanisms underlying microbial-induced trained immunity. It also highlights preclinical and clinical evidence demonstrating the efficacy of microbial-based strategies in overcoming immunosuppression and synergizing with existing immunotherapies, offering a promising approach to improve cancer treatment outcomes.
    DOI:  https://doi.org/10.1016/j.pharmr.2025.100074
  8. Immunology. 2025 Jul 10.
    Correction to "Atorvastatin Promotes the Expansion of Myeloid-Derived Suppressor Cells and Attenuates Murine Colitis".
      
    DOI:  https://doi.org/10.1111/imm.70009
  9. Cells. 2025 Jun 25. pii: 978. [Epub ahead of print]14(13):
    Effects of Mesenchymal Stem Cells on Functions of Chimeric Antigen Receptor-Expressing T Lymphocytes and Natural Killer Cells.
    Vladislav Volarevic, Carl Randall Harrell, Aleksandar Arsenijevic, Valentin Djonov, Ana Volarevic.
      Chimeric antigen receptor (CAR)-engineered immune cells, particularly CAR T lymphocytes and CAR natural killer (NK) cells, have revolutionized cancer immunotherapy. However, their therapeutic efficacy and safety can be influenced by the tumor microenvironment, particularly the presence of mesenchymal stem cells (MSCs). MSCs are immunomodulatory cells which can alter the function of tumor-infiltrated immune cells in both supportive and suppressive ways. Results obtained in recently conducted experimental studies demonstrate that MSCs modulate proliferation, cytotoxicity, cytokine production and anti-tumor activity in CAR-expressing immune cells in both a juxtacrine and a paracrine manner. While MSCs can enhance CAR cell viability and persistence through trophic support, they may also impair cytotoxic function and promote an immunosuppressive phenotype under certain conditions. Understanding the dualistic nature of MSCs in CAR-based immunotherapy for malignant diseases is critical for optimizing clinical outcomes. Additionally, MSCs may serve as vehicles for targeted delivery of immunomodulatory agents, and should be considered as active components in the design of next-generation CAR-based immunotherapies. Accordingly, in this review article we emphasize molecular and cellular mechanisms involved in MSC-dependent modulation of CAR-expressing immune cells, paving the way for more efficient CAR-based immunotherapy for malignant diseases.
    Keywords:  chimeric antigen receptor; immune cells; immunotherapy; malignant diseases; mesenchymal stem cells
    DOI:  https://doi.org/10.3390/cells14130978
  10. Adv Biol (Weinh). 2025 Jul 09. e2400720
    Research Progress on the Combination of PARP Inhibitors (PARPi) and Immune Checkpoint Inhibitors (ICIs).
    Qi Liu, Chunmei Zhang, Yixuan Gao, Dongmei Feng, Duo Deng, Yun Pan.
      Deficiencies in DNA damage repair (DDR), such as poly (ADP-ribose) polymerase (PARP) deficient, cause cancer development by promoting DNA mutations while also exposing the specificity and vulnerability of cancer to afford a treatment option. PARP inhibitor (PARPi) has shown great prospects in the treatment of tumors carrying homologous recombination (HR) deficiencies, such as germline BRCA1/2 mutations. PARPi leads to an increase in the expression of tumor neoantigen, interferon (IFN), and programmed cell death 1/programmed death-ligand 1 (PD-1/PD-L1), which also regulate the tumor microenvironment (TME), promoting a deeper anti-tumor immunotherapy. ICIs targeting PD-1/PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have achieved impressive success in the treatment of malignancies. Considering PARPi do enhance the anti-tumor response of ICIs, the combination of PARPi and ICIs has gradually become an alternative treatment option for individuals not receiving apparent efficacy from ICI monotherapy. In this review, the emphasis will be on the mechanisms and immune responses associated with PARPi, profess the principle, then count the clinical studies of this combination therapy.
    Keywords:  CTLA‐4; DNA damage response; PARP inhibitor; PD‐1/PD‐L1; immune checkpoint inhibitors
    DOI:  https://doi.org/10.1002/adbi.202400720
  11. Cancer Sci. 2025 Jul 07.
    LATS1/2-Integrin Axis Confers Tumor-Generated Forces That Activate Neighboring Fibroblasts.
    Yanliang Liu, Saisai Liu, Yasuhisa Sakamoto, Paweenapon Chunthaboon, Chanida Thinyakul, Ryunosuke Mori, Shuran Li, Takahiro Watanabe-Nakayama, Seiji Omata, Yasuyuki Morita, Toshiro Moroishi.
      Tumors generate various forces during growth and progression, which in turn promote tumor development. Although fibroblasts are considered the primary force generators in the tumor microenvironment, recent studies have shown that cancer cells also generate considerable tensile forces. However, the roles that these forces play in the tumor microenvironment and the pathways regulating this process remain largely unknown. Here, we demonstrated that the Hippo pathway-associated kinases, LATS1/2, in cancer cells are essential for collective force generation and fibroblast activation via extracellular matrix-mediated cell-cell interactions. In murine breast cancer 4 T1 spheroids, the deletion of LATS1/2 dampened force generation and disrupted reorganization of the surrounding collagen matrix. LATS1/2-mediated mechanical forces of tumors are required for fibroblast activation and differentiation into mechanoresponsive fibroblasts. Mechanistically, LATS1/2 regulate tumor force generation through the expression of collagen receptor integrins. Our findings not only identify the Hippo pathway as a critical regulator of tumor force generation but also suggest potential strategies for targeting it in cancer therapy from a mechanobiological perspective, offering new avenues in the fight against cancer.
    Keywords:  cancer‐associated fibroblast; hippo pathway; integrins; mechanobiology; tumor microenvironment
    DOI:  https://doi.org/10.1111/cas.70137
  12. J Invest Dermatol. 2025 Jul 09. pii: S0022-202X(25)01855-X. [Epub ahead of print]
    Unlocking Immunity Within: Inflammatory Monocytes Stimulate T Cells at Immune Hubs in the Tumor Microenvironment.
    Guillem Estivill, Anais Elewaut, Anna C Obenauf.
      
    Keywords:  Immunotherapy resistance; Inflammatory monocytes; PGE(2)/IFN-I axis; T-cell restimulation; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.jid.2025.05.037
  13. Int Rev Cell Mol Biol. 2025 ;pii: S1937-6448(24)00171-0. [Epub ahead of print]394 107-145
    Microbiome-mediated immune modulation in tumor microenvironment.
    John Richards, Eleanor L Davis, L Shakila, Janani Narayanan, Sadhna Aggarwal, Anshuman Mishra, Kranthi Kumar Madamchetty Venkata, Brandon K Walther, Abishai Dominic.
      This chapter explores the complex interplay between the tumor microenvironment (TME), the microbiome, and the immune system. It focuses on how microbes and their metabolites influence tumor development, progression, and the subsequent immune responses. The TME is a highly complex environment made up of cancer cells, immune cells, and the extracellular matrix, where immune cells can either inhibit or promote tumor growth depending on the context. The chapter highlights several key mechanisms of interaction, including microbial metabolites, the presentation of microbial antigens by tumor or immune cells, and the role of immune checkpoints, such as PD-L1, in modulating immune responses. Certain bacteria, viruses, and fungi can trigger immune responses that lead to the destruction of cancer cells, often through processes such as immunogenic cell death (ICD). Conversely, dysbiosis, or an imbalance in microbial communities, can create a pro-tumorigenic environment, aiding in tumor progression through chronic inflammation, immune suppression, and metabolic alterations. The chapter categorizes microbial interactions with cancer into three areas: microbes directly causing cancer (e.g., Epstein-Barr virus and HPV), cancers that induce infections (e.g., obstructing the respiratory or digestive systems), and tumors located in organs with natural microbiomes, such as the gastrointestinal tract. In addition to these mechanisms, the chapter also illuminates how microbial antigens can serve as potential identifiers and tools for cancer diagnosis and treatment, offering new avenues for personalized medicine. The insights gained from this exploration are important for advancing microbial-based therapies and improving the effectiveness of immunotherapies in cancer treatment.
    Keywords:  Cancer prevention; Immune check point therapy; Immunotherapy; Metabolites; Microbe-induced immunogenic cell death; Microbiome; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/bs.ircmb.2024.12.012
  14. Adv Exp Med Biol. 2025 ;1476 309-337
    Role of Innate Immunity in Cancer.
    Ann Mary Joseph, Ahmad Al Aiyan, Rekha Kumari, Andrew J T George, Uday Kishore.
      The cancer-immune interaction is a dynamic sequence of actions carried out by cellular and soluble factors that either promote or suppress tumor development, proliferation, and metastasis. The immune system may be stimulated or suppressed as a result of the interaction between tumors and immune cells. Understanding this complex interplay will allow us to use the immune system for long-term management of cancer. Innate immune cells are capable of detecting the molecular alterations caused by changes in the local environment and then mount and modulate effector responses. The effect that the innate immune system has on neoplastic disease depends on the balance of signals within the tumor microenvironment. Even though there has been a lot of focus on the adaptive immune system's functions, there is mounting evidence that the innate immune system's effector cells play an important role in tumor surveillance. We discuss the innate immune cells, soluble factors, signaling pathways, and their role in tumor immune surveillance.
    Keywords:  Immune signaling; Inflammation; Innate immunity; TME
    DOI:  https://doi.org/10.1007/978-3-031-85340-1_13
  15. Contemp Oncol (Pozn). 2025 ;29(2): 123-130
    The role of tumor-associated macrophages and PD-1/PD-L1 networking in colorectal cancer.
    Melina Yerolatsite, Nanteznta Torounidou, Anna-Lea Amylidi, George Zarkavelis, Loizos Hadjigeorgiou, Evangeli Lampri, Christina Bali, Vaia Georvasili, Eleftherios Kampletsas, Davide Mauri.
      Colorectal cancer (CRC) is the fourth most common cancer worldwide and a leading cause of cancer-related mortality. Despite improvements in cancer prevention, early diagnosis, and therapeutic options, metastatic CRC (mCRC) remains a major challenge, with a significantly lower 5-year survival rate compared to localized CRC. The heterogeneity of CRC, both localized and metastatic, necessitates a thorough molecular characterization to guide treatment strategies. A significant aspect of CRC progression involves the tumor microenvironment, particularly tumor-associated macrophages (TAMs), which are abundant and exhibit high plasticity. Tumor-associated macrophages, especially those polarized into the M2 phenotype, support various aspects of tumor progression, including angiogenesis, metastasis, and immune evasion. The PD-1/PD-L1 immune checkpoint axis, overexpres-sed in M2 TAMs, contributes to immune suppression, facilitating tumor growth. While some studies suggest that TAMs may have a positive role in CRC prognosis, others associate TAM infiltration with poor outcomes, particularly in metastatic disease. The relationship between TAMs and the PD-1/PD-L1 axis in CRC is still not fully understood, though emerging data highlight their potential to shape the immune resistance environment. Further research is needed to clarify the role of TAMs and the PD-1/PD-L1 network in CRC progression and to develop more effective immunotherapies targeting these pathways. This review systematically explores the current literature on TAMs and their interaction with the PD-1/PD-L1 axis in CRC, emphasizing the need for continued investigation to improve patient outcomes.
    Keywords:  PD-1/PD-L1 network; colorectal cancer; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.5114/wo.2025.150448
  16. J Immunol Res. 2025 ;2025 8890939
    The Multifaceted Role of the IL-2 Cytokine Family in Melanoma: Mechanisms, Therapeutic Implications, and Immune Modulation.
    Mona Daghaighei, Samaneh Dodge, Soheil Bolandi, Boutros Youssef, Niket Attarde, Moein Maddahi, Maryam Mostofi, Reza Morovatshoar, Mehrnaz Mostafavi, Dejbakht Majid, Mohammadamin Joulani, Pegah Tamimi, Malihe Sharafi, Qumars Behfar, Yasaman Ghodsi Boushehri, Alireza Azani.
      Background and Objective: Melanoma is a complex malignancy where the interplay between immune cells, cytokines, and the tumor microenvironment (TME) significantly influences disease progression and patient outcomes. This review explores the involvement of the interleukin-2 (IL-2) cytokine family in both the development and therapeutic approaches for melanoma. Methods: A narrative literature review was conducted, synthesizing findings from studies on immune cell behavior, cytokine functions, and their implications in melanoma and other cancers. This narrative review emphasizes the roles of immune cells and cytokines in both promoting and inhibiting tumor growth. Results: Neutrophils, influenced by tumor-derived cytokines, can adopt phenotypes that either inhibit or promote tumor growth. B cells in the TME often correlate with better survival, although their regulatory forms can suppress immune responses. Tissue-resident memory T cells (TRM cells) are crucial for antitumor immunity, particularly in response to immune checkpoint inhibitors (ICIs). Dendritic cells (DCs) are vital for antigen presentation, yet their function can be compromised in melanoma. Macrophages frequently support tumor growth through immunosuppressive actions. The IL-2 cytokine family, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, plays diverse roles in immune regulation. These cytokines are involved in T-cell proliferation, B-cell differentiation, and modulation of other immune responses, influencing both tumor progression and the effectiveness of immunotherapies. Conclusions: Immune cells and cytokines are pivotal in the pathogenesis, progression, and immunotherapy of melanoma. Understanding their complex roles offers insights into potential therapeutic strategies, highlighting the importance of targeted immunotherapies in treating melanoma and possibly other cancers. Additional studies are required to clarify the precise mechanisms and interactions occurring within the TME to enhance treatment strategies.
    Keywords:  cytokines; immunotherapy; interleukin; interleukin-2 family; melanoma
    DOI:  https://doi.org/10.1155/jimr/8890939
  17. Drug Deliv Transl Res. 2025 Jul 08.
    Nanotechnology-enhanced immunotherapies for pancreatic ductal adenocarcinoma: challenges and opportunities.
    Sheng Yang, Yen-Nhi Ngoc Ta, Yunching Chen.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a dismal five-year survival rate. The tumor microenvironment, characterized by dense stroma and immunosuppression, significantly limits the effectiveness of current treatments, including immunotherapy. Nanotechnology offers a promising solution by enabling precise drug delivery, enhancing immune activation, and overcoming physical barriers within the tumor microenvironment. In this review, we explore the mechanisms of PDAC development and the immunosuppressive nature of its tumor microenvironment, emphasizing the challenges faced by immunotherapy. We also examine the role of nanotechnology in modulating the tumor microenvironment, enhancing cancer vaccine efficacy, and stimulating immune cells within the PDAC tumor microenvironment. Current clinical trials employing nanotechnology-based strategies are discussed, providing insight into their potential for improving therapeutic outcomes. While significant challenges remain in translating nanomedicine into clinical success, the integration of nanotechnology with immunotherapy holds promise for overcoming the limitations of conventional treatments and improving survival in PDAC patients.
    Keywords:  Cancer vaccine; Desmoplasia; Pancreatic ductal adenocarcinoma (PDAC); Tumor microenvironment; Vessel normalization
    DOI:  https://doi.org/10.1007/s13346-025-01908-7
  18. Cancer Lett. 2025 Jul 07. pii: S0304-3835(25)00474-4. [Epub ahead of print]630 217906
    Preserved host immunity with intercellular adhesion molecule-1 (ICAM-1)-targeted near-infrared photoimmunotherapy (NIR-PIT) in the treatment of triple-negative breast cancer and other malignancies.
    Seiichiro Takao, Hideyuki Furumoto, Aki Furusawa, Makoto Kano, Hiroshi Yamamoto, Motofumi Suzuki, Miyu Kano, Peter L Choyke, Hisataka Kobayashi.
      Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that combines an antibody photoabsorber-conjugate (APC) with NIR light to induce direct cytotoxicity and immunogenic cell death. Intercellular Adhesion Molecule 1 (ICAM-1), a cell surface protein overexpressed in various cancers, is a promising target for cancer therapy. We previously reported that ICAM-1-targeted NIR-PIT could be used in the treatment of ICAM-1 expressing triple-negative breast cancer (TNBC); however, ICAM-1 is also expressed on immune cells within the tumor microenvironment (TME). Therefore, the net impact of ICAM-1-targeted NIR-PIT on the tumor vs. antitumor host immunity remains unclear, posing a significant challenge to its clinical advancement. In this study, we investigated the antitumor effect of ICAM-1-targeted NIR-PIT including its influence on host immunity following NIR light irradiation, using immunocompetent mouse models. In vitro, ICAM-1-targeted NIR-PIT caused immunogenic cell death in EO771 (breast cancer) and SP2/0 (myeloma) models expressing ICAM-1. Ex vivo, ICAM-1-targeted NIR-PIT effectively eliminated ICAM-1-expressing cancer cells and immune cells within the TME. However, the net effect was to suppress tumor progression and prolong survival in EO771, MOC1 (oral carcinoma), and SP2/0 models in vivo. Enhanced antitumor host immunity was observed after ICAM-1-targeted NIR-PIT in the MOC1 model. In conclusion, ICAM-1-targeted NIR-PIT holds promise as a treatment for various cancer models expressing ICAM-1 beyond TNBC by directly killing cancer cells and enhancing host immune response.
    Keywords:  ICAM-1; Intercellular adhesion molecule-1; Near-infrared photoimmunotherapy (NIR-PIT); Preclinical model
    DOI:  https://doi.org/10.1016/j.canlet.2025.217906
  19. Cells. 2025 Jun 20. pii: 943. [Epub ahead of print]14(13):
    ECM Mechanics Control Jamming-to-Unjamming Transition of Cancer Cells.
    Claudia Tanja Mierke.
      Cancer metastasis constitutes a multifactorial phenomenon that continues to confound therapeutic strategies. The biochemical signals governing motile phenotypes have been extensively characterized, but mechanobiological interactions have only recently been integrated into cancer cell motility models and remain less well elucidated. The identification of the biochemically and mechanically controlled epithelial-mesenchymal transition (EMT) of cancer cells, which occurs either completely or partially, has led to a major breakthrough and a universal phenomenon in cancers. In addition, a relatively new theory based on mechanobiological aspects called "jamming-to-unjamming transition" is being proposed to explain the transition of cancer cells to an invasive phenotype. The latter transition may help to better understand the different types of 3D migration and invasion of cancer cells. Similarly to EMT, the transition from jamming to unjamming seems to be controlled by molecular and physical factors, including cell mechanics and mechanical cues from the extracellular matrix (ECM) of the tumor microenvironment (TME). It is challenging to grasp the distinctions between the transition from jamming to unjamming and EMT, as they appear to be the same at first glance. However, upon closer examination, the two transitions are quite separate. Moreover, it is still unclear whether both transitions may act synergistically. This review highlights the most important breakthroughs in the transition from jamming to unjamming, with a focus on mechanobiology and extracellular environmental aspects, and it compares them with those of EMT. In addition, the impact of the TME, such as ECM scaffold and cancer-associated fibroblasts (CAFs) on the jamming-to-unjamming transition is discussed. Finally, the research frontiers and future directions in the field of mechanobiological research in cancer metastasis are outlined.
    Keywords:  EMT; cell and tissue mechanics; extracellular matrix confinement; individual and collective migration and invasion; jamming-to-unjamming transition; mechanobiology; stiffness; viscoelasticity
    DOI:  https://doi.org/10.3390/cells14130943
  20. J Leukoc Biol. 2025 Jul 09. pii: qiaf098. [Epub ahead of print]
    Potential functions of TRPM2 and TRPM7 channels in the tumor microenvironment.
    Irma Yadira Izaguirre-Hernández, Adriana Sumoza-Toledo.
      The tumor microenvironment (TME) is a complex and dynamic ecosystem consisting of both cellular and non-cellular components that collectively modulate the anti-tumor immune response, as well as cancer growth, invasion, metastasis, immune evasion, and resistance to therapy. Calcium (Ca2+) and magnesium (Mg2+) are two essential ions for a wide range of cellular processes including proliferation, differentiation, migration and protein secretion. The intracellular homeostasis and spatio-temporal distribution of these two ions are tightly regulated by ion channels, notably members of the transient receptor potential melastatin (TRPM) subfamily such as TRPM2 and TRPM7. TRPM2 is a Ca2+-permeable channel activated by ADP-ribose (ADPR) and reactive oxygen species (ROS), whereas TRPM7 permeates both Ca2+ and Mg2+ ions and exhibit constitutive activity. Both channels have been involved in redox-sensitive signaling and function as temperature sensors across various physiological and pathological context, such as cancer. Here we provide an overview of the potential roles of TRPM2 and TRPM7 in regulating cellular dynamics within the TME, with a focus on their contributions to immune modulation.
    Keywords:  TRPM2; TRPM7; calcium; ion channels; magnesium; tumor microenvironment
    DOI:  https://doi.org/10.1093/jleuko/qiaf098
  21. Acta Biochim Biophys Sin (Shanghai). 2025 Jul 04.
    Energy stress and adaptation strategy of tumor cells in different microenvironments: from primary tumors to distant metastases.
    Mingzhe Xu, Junjie Fei, Zhi-Xiong Xiao, Yong Yi.
      Since the Warburg effect was first described in the 1920s, tumor energy metabolism has been a central focus of cancer research, emerging as a potential therapeutic target. The tumor microenvironment-including blood vessels, immune cells, stromal components, and other cell types-profoundly influences tumor cell metabolism. Variations in energy supply, oxygen availability, nutrient composition, and the accumulation of metabolic waste across different microenvironments challenge tumor cell survival and progression. In response, tumor cells adapt through flexible regulation and reprogramming of metabolic pathways. Although recent studies have explored metabolic adaptation mechanisms in various tumor microenvironments, the full spectrum from primary tumors to distant metastases remains unexplored. This review summarizes energy stress and adaptation maneuvers in tumor cells across different stages of tumor progression and offers a new perspective for comprehensive research to explore therapeutic strategies targeting tumor metabolism.
    Keywords:  energy stress; metabolic reprogramming; tumor cell survival; tumor microenvironment
    DOI:  https://doi.org/10.3724/abbs.2025106
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