bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2025–11–16
twenty-one papers selected by
Peio Azcoaga, Biodonostia HRI
  1. The immune microenvironment in tumors: focus on canine and feline spontaneous neoplasms.
  2. Metabolism in the tumor microenvironment: implications for pathogenesis and therapeutics.
  3. Editorial: Community series in the immunosuppressive tumor microenvironment and strategies to revert its immune regulatory milieu for cancer immunotherapy, volume II.
  4. Therapeutic Strategies Targeting CD163 and CD169 in Macrophages for Cancer.
  5. Guardians of the tumor microenvironment: the neutrophil saga.
  6. Overcoming Immune Evasion in the Prostate Tumor Microenvironment: Novel Targeted Strategies to Improve Treatment Outcomes.
  7. Unlocking IL-33: New Insights into Tumor Immunity.
  8. Pan-cancer single-cell RNA sequencing analysis refines multi-origin monocyte and macrophage lineages.
  9. IFN-gamma in the tumor microenvironment: dual roles in cancer progression and therapy.
  10. Decoding the mechanisms underlying breast cancer brain metastasis: paving the way for precision therapeutics.
  11. A global bibliometric perspective on autophagy and tumor microenvironment in cancer research.
  12. A bispecific antibody targeting PD-L1/TNFR2 increases tumor targeting and enhances antitumor efficacy in colorectal cancer.
  13. The PI3K/Akt/mTOR Pathway: Immuno-Metabolic Orchestration in IR/MASH-Associated Hepatocellular Carcinoma.
  14. The emerging role of cancer-associated fibroblasts in hematological malignancies: from their influence on tumor progression and drug resistance to novel therapeutic opportunities.
  15. CAR-T cell therapy in hepatocellular carcinoma: from mechanistic insights to clinical translation.
  16. Macrophage polarization in tumors: The impact of efferocytosis.
  17. Physiologically based pharmacokinetic model for CAR-T cell delivery and efficacy in solid tumors.
  18. Soil and Seed: Tumor Microenvironment Nurtures Immunotherapy Resistance and Renewal.
  19. Emerging insights into the immunosuppressive tumor microenvironment and its implications for glioblastoma immunotherapy.
  20. Reprogramming the tumor microenvironment to boost adoptive T cell therapy.
  21. shRNA-based PD-1 suppression preserves memory phenotype and function of CD19-targeted CAR-T cell.
  1. Front Vet Sci. 2025 ;12 1674694
    The immune microenvironment in tumors: focus on canine and feline spontaneous neoplasms.
    Maddalena Rizzi, Giulia D'Annunzio, Chiara Tugnoli, Giuseppe Sarli, Luisa Vera Muscatello.
      Companion animals develop spontaneous tumors with biological and immunological features closely resembling human cancers. The tumor microenvironment (TME), particularly its immune infiltrates, plays a pivotal role in tumor progression and immune evasion. This review summarizes current knowledge on the composition and function of immune cells (including T cells, B cells, macrophages, dendritic cells, neutrophils, and mast cells) in the TME of canine and feline tumors. A better understanding of these mechanisms may aid in identifying prognostic biomarkers and novel immunotherapeutic targets in both veterinary and human oncology.
    Keywords:  TAMs; TILs; immune checkpoints; spontaneous neoplasms; tumor microenvironment
    DOI:  https://doi.org/10.3389/fvets.2025.1674694
  2. Front Immunol. 2025 ;16 1610255
    Metabolism in the tumor microenvironment: implications for pathogenesis and therapeutics.
    Jonas Aakre Wik, Emma Riiser Berge, Kristine Stromsnes, Bjørn Steen Skålhegg.
      The immune system protects the body against dangers that include pathogens, damage and cancer. Modern cancer therapies have sought to bolster immune responses against cancer using immunotherapy, which may include various forms of immune checkpoint therapy (ICT) in addition to methods of adoptive cell transfer (ACT), which is often associated with transfer of chimeric antigen receptor (CAR) T cells. Despite favorable outcomes in some patients and some cancers, as many as 60-80% of patients fail to benefit from ICT due to primary or adaptive resistance. This highlights the need for deeper understanding of how cancers suppress the immune system. Solid tumors, which make up approximately 90% of all cancers, are characterized by an immunosuppressive tumor microenvironment (TME). A hallmark of the TME is dysfunctional vascularization and impaired perfusion, which hinder effective drug delivery and promote hypoxia-induced metabolic reprograming in both cancer and immune cells. As the TME imposes intense metabolic stress through nutrient competition and lactate-driven acidification - both of which activates immunosuppressive pathways, targeting the TME itself may be beneficial in enhancing the efficacy of immunotherapy. Here we will briefly discuss the potential of targeting the metabolism of the TME as a means to promote normalized tumor vascularization and/or enhance anti-tumor immune responses.
    Keywords:  T cells; angiogenesis; cancer; immunotherapy; macrophages; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1610255
  3. Front Immunol. 2025 ;16 1724894
    Editorial: Community series in the immunosuppressive tumor microenvironment and strategies to revert its immune regulatory milieu for cancer immunotherapy, volume II.
    Mazdak Ganjalikhani Hakemi, Nair Jayakumar.
      
    Keywords:  cancer; immune regulation; immunometabolism; immunosuppression; immunotherapy; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fimmu.2025.1724894
  4. Pathol Int. 2025 Nov 12.
    Therapeutic Strategies Targeting CD163 and CD169 in Macrophages for Cancer.
    Yukio Fujiwara, Yoshihiro Komohara.
      Macrophage activation markers, specifically CD163 and CD169, play pivotal roles in the modulation of immune responses within the tumor microenvironment (TME), influencing the outcome of various cancers. These markers delineate the activation states of macrophages, with CD163 associated with the protumoral phenotype and CD169 with activation of tumor immunity. This review comprehensively explores the dualistic roles of these markers in cancer progression and immune suppression, and discusses the mechanisms through which these markers influence macrophage behavior, the impact of their expression on cancer progression, and the therapeutic potential of targeting these pathways to reprogram the TME toward enhancing antitumor immunity. This review aims to underscore the therapeutic potential of macrophage activation markers as targets for cancer treatment, highlighting emerging strategies and future directions in cancer immunotherapy.
    Keywords:  CD163; CD169; macrophages; tumor microenvironment
    DOI:  https://doi.org/10.1111/pin.70062
  5. Blood. 2025 Nov 13. 146(20): 2373-2374
    Guardians of the tumor microenvironment: the neutrophil saga.
    Samir Parekh.
      
    DOI:  https://doi.org/10.1182/blood.2025030664
  6. Cancers (Basel). 2025 Oct 27. pii: 3441. [Epub ahead of print]17(21):
    Overcoming Immune Evasion in the Prostate Tumor Microenvironment: Novel Targeted Strategies to Improve Treatment Outcomes.
    Jing Huang, Ademola Ojo, Serena Tsao, Amir Horowitz, Natasha Kyprianou, Che-Kai Tsao.
      Despite advances in diagnostic and therapeutic technology, prostate cancer remains a leading cause of morbidity and mortality among men. While androgen deprivation therapy and next-generation androgen receptor pathway inhibitors offer durable responses, the emergence of the lethal phenotype, metastatic castration-resistant prostate cancer (mCRPC) eventually develops for most. A growing body of evidence points to the tumor microenvironment (TME) as a key driver of immune evasion and therapeutic failure. This review focuses on the current knowledge of immune suppression in the prostate TME, including cancer-associated fibroblasts, myeloid-derived suppressor cells, tumor-associated macrophages, immune checkpoint pathways, and several associated key metabolic alterations. These cellular and molecular networks contribute to therapeutic resistance and disease progression and may be used as therapeutic targets. We will also examine emerging treatment strategies aimed at reprogramming the TME, as well as combination approaches incorporating immunotherapies with other signaling inhibitors. Future success in clinical therapeutic development for mCRPC will depend on rational combinations that address both tumor-intrinsic resistance and extrinsic immune suppression, with emphasis on biomarker-driven patient and treatment selection.
    Keywords:  biomarker-driven treatment; immune evasion; metastatic castration-resistant prostate cancer; prostate cancer; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers17213441
  7. Immune Netw. 2025 Oct;25(5): e36
    Unlocking IL-33: New Insights into Tumor Immunity.
    Byeong Hoon Kang, Heung Kyu Lee.
      IL-33, a member of the IL-1 cytokine family, is constitutively expressed in the nucleus of various cell types. As an alarmin, IL-33 is released upon tissue damage and activates immune cell populations through its receptor, suppression of tumorigenicity 2 (ST2). Given that ST2 is expressed on diverse immune cells involved in both type 1 and type 2 immunity, IL-33 exerts pleiotropic effects on immune responses. In the tumor microenvironment (TME), IL-33 plays a dual role, promoting both protumor and antitumor TME. In this review, we summarize general characteristics of IL-33 and its immunological functions, with particular emphasis on its role in tumor immunity. Furthermore, we discuss recent advances in utilizing IL-33 in cancer immunotherapies and propose IL-33 as a potential candidate for the development of new cancer therapies.
    Keywords:  Cancer immunotherapy; IL-33; Tumor microenvironment; Type 1 immunity; Type 2 immunity
    DOI:  https://doi.org/10.4110/in.2025.25.e36
  8. Cancer Immunol Res. 2025 Nov 13.
    Pan-cancer single-cell RNA sequencing analysis refines multi-origin monocyte and macrophage lineages.
    Truc Do Thanh Nguyen, Andrew J Lee, Hyun Jung Park, Nameeta Shah, Bayrta Mandzhieva, Dong-Sup Lee, Inkyung Jung, Woong-Yang Park.
      Tumor-associated macrophages (TAMs) play crucial and important role in cancer dynamics by affecting homeostasis, immunosuppression, and angiogenesis within the tumor microenvironment. Using single-cell transcriptomics, we constructed a comprehensive atlas of myeloid cell populations across healthy and pan-cancer tissues that revealed heterogeneity. Our analysis suggested that TAMs may arise from two distinct origins: C1QC+ TAMs, which likely are derived from resident tissue macrophages, SPP1+ TAMs and ISG15+ TAMs, which appear to originate from circulating monocytes. Regarding immature myeloid-derived suppressor cells (MDSCs), we highlighted THBS1+ MDSCs and their descendants, SPP1+ TAMs, as key contributors to tumor progression, immunosuppression, and angiogenesis. We proposed a dichotomous model for TAMs, in which C1QC+ TAMs are associated with better patient outcomes, whereas the THBS1+ MDSCs - SPP1+ TAMs lineage correlates with poorer survival and unfavorable response to immunotherapy. This study offers insight into the complex interactions among monocyte-macrophage subtypes and sheds light on TAM heterogeneity and its implications for cancer progression and therapeutic strategies.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-24-1255
  9. EXCLI J. 2025 ;24 1352-1371
    IFN-gamma in the tumor microenvironment: dual roles in cancer progression and therapy.
    Jiahui Cui, Yi Zhang, Li Yang.
      Interferon-gamma (IFN-γ), as a pleiotropic cytokine, plays a pivotal role in antitumor immunity. Its remarkable immunostimulatory, antiproliferative, and pro-apoptotic effects make it a promising candidate for tumor immunotherapy. Here, we highlight the dual role of IFN-γ in the tumor microenvironment during tumor development and treatment. IFN-γ can enhance antigen presentation, boost cytotoxic T cell and natural killer cell activity, and inhibit angiogenesis, promoting tumor regression and correlating with favorable therapeutic outcomes. However, prolonged exposure may induce the upregulation of immune checkpoint molecules such as programmed death-ligand 1, trigger T cell exhaustion, and recruit regulatory T cells, phenomena associated with the development of treatment resistance in cancer therapy. This dual nature poses significant challenges for harnessing IFN-γ in tumor treatment, necessitating an in-depth understanding of its mechanisms within specific microenvironments. Although numerous studies have explored IFN-γ-based tumor therapies, their outcomes have been inconsistent. Thus, although IFN-γ-based therapeutic strategies hold considerable promise, their clinical translation requires precise modulation to fully exploit its antitumor effects while mitigating potential protumor risks. See also the graphical abstract(Fig. 1).
    Keywords:  IFN-gamma; immunoregulation; immunotherapy; tumor progression; tumor regression
    DOI:  https://doi.org/10.17179/excli2025-8617
  10. Biomark Res. 2025 Nov 11. 13(1): 144
    Decoding the mechanisms underlying breast cancer brain metastasis: paving the way for precision therapeutics.
    Xuanhe Zhang, Xiang Wang, Saimeng Shi, Duancheng Guo.
      The development of brain metastasis is a major cause of significantly reduced survival in breast cancer patients. The initiation and progression of breast cancer brain metastasis (BCBM) involve multiple distinct molecular pathways and reprogramming of the tumor microenvironment (TME). This review systematically summarizes key mechanisms underlying BCBM, including epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) remodeling, and the spatiotemporal dynamics of metabolic reprogramming regulated by critical signaling pathways during brain colonization. In particular, we highlight emerging mechanisms of breaching the specialized brain multifunctional barriers. Furthermore, this review provides an in-depth analysis of the cooperative immune-suppressive network within the BCBM TME, emphasizing the crosstalk among various immune cell components (such as T cells, B cells, macrophages, neutrophils, NK cells, MDSCs) and intracranial-specific cellular elements (including astrocytes, microglia, brain metastasis-associated fibroblasts). Through the complex interplay, these cells collectively facilitate immune evasion and metastatic outgrowth. Accordingly, we discuss the current clinical management of BCBM and potential future directions. Deeper mechanistic insights are expected to offer novel biomarkers and reveal new targets for developing precision therapeutic strategies against BCBM.
    Keywords:  Brain metastasis; Breast cancer; Clinical therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s40364-025-00854-3
  11. Discov Oncol. 2025 Nov 10. 16(1): 2065
    A global bibliometric perspective on autophagy and tumor microenvironment in cancer research.
    Ishita Debnath, Moumita Kundu.
       BACKGROUND: Autophagy plays a key role in cell recycling and also has a double-edged sword role in cancer. It serves as a tumor suppressor in the initial phases but eventually maintains stress resistance in cancer cells. Autophagy plays a role in immune cell interactions and cancer-associated fibroblasts within the tumor microenvironment, managing metabolism, immune evasion, and angiogenesis that enable tumor development and drug resistance. Autophagy is, therefore, a major target for cancer therapy.
    METHOD: To investigate the function of autophagy and tumor microenvironment (TME) in cancer progression, we performed a comprehensive search of Scopus and PubMed. We mapped the collaboration network between different journals, countries, institutions, journals, and keywords using VOSviewer (version 1.6.20) and extracted relevant quantitative information.
    RESULT: There is increasing research into autophagy and the TME in cancer, with 3,002 articles showing a consistent annual increase. China and the United States have the highest outputs. "Cancer" is a leading journal in the topic, and "Frontiers in Oncology" is the most cited. Four primary research themes have been highlighted through keyword analysis. Autophagy and the TME play central roles in the diagnosis, prognosis, and treatment of cancer, and natural products and drugs targeting the TME are promising. Nevertheless, manipulating autophagy can result in greater resistance to cancer.
    CONCLUSION: In conclusion, our study utilized bibliometric tools to investigate the emerging trend of autophagy and TME in cancer. It is the first extensive bibliometric study to comprehensively map the overlap of autophagy and tumor microenvironment in cancer biology. Our results indicate leading authors, collaborative communities, knowledge gaps, and promising subfields like immunotherapy and hypoxia. The findings provide a strategic guide for future directions in research and therapeutic development in cancer biology.
    Keywords:  Autophagy; Bibliometric analysis; Cancer; Trends; Tumor microenvironment; VOSviewer
    DOI:  https://doi.org/10.1007/s12672-025-03831-2
  12. J Immunother Cancer. 2025 Nov 13. pii: e013001. [Epub ahead of print]13(11):
    A bispecific antibody targeting PD-L1/TNFR2 increases tumor targeting and enhances antitumor efficacy in colorectal cancer.
    Xiaozhen Kang, Peng Qian, Yifeng Han, Mengdi Wu, Yuxin Li, Chun Xu, Jiwu Wei.
       BACKGROUND: Immune checkpoint inhibitors (ICIs) have shown limited efficacy in colorectal cancer (CRC), largely due to immunosuppressive tumor microenvironment (TME) including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Additionally, the off-target effects of ICIs can reduce drug accumulation in tumor tissues and lead to immune-related adverse events, further compromising their clinical utility.
    METHODS: Using knob-into-hole technology, we developed ATAPL1, a bispecific antibody targeting both programmed death-ligand 1 (PD-L1) and tumor necrosis factor receptor 2 (TNFR2). In multiple subcutaneous and orthotopic CRC mouse models, ATAPL1 was evaluated for its tumor targeting, antitumor efficacy, immunomodulatory effects within the TME, and potential combinations with standard chemotherapies.
    RESULTS: Compared with αPD-L1 or αTNFR2 monotherapy, ATAPL1 showed enhanced tumor accumulation and significantly improved antitumor efficacy, with no significant toxicity. It effectively modulated the TME by decreasing immunosuppressive Tregs and monocytic MDSCs (M-MDSCs), while promoting CD8+ T-cell activation and macrophage function. ATAPL1 also primed long-term immune surveillance, suggesting durable antitumor activity. Furthermore, ATAPL1 overcame chemotherapy resistance and exhibited superior therapeutic effects when combined with FOLFOX or FOLFIRI, compared with either treatment alone.
    CONCLUSION: These findings support ATAPL1 as a promising dual-targeted therapeutic strategy for CRC. It offers the potential to overcome immune and chemotherapy resistance, reduce off-target effects, and improve treatment outcomes through enhanced immune activation and tumor targeting.
    Keywords:  Antibody; Colorectal Cancer; Immune Checkpoint Inhibitor; Immunotherapy
    DOI:  https://doi.org/10.1136/jitc-2025-013001
  13. Int J Biol Sci. 2025 ;21(14): 6025-6041
    The PI3K/Akt/mTOR Pathway: Immuno-Metabolic Orchestration in IR/MASH-Associated Hepatocellular Carcinoma.
    Jian Zhao, Yuehua Zhang, Zhigong Wei, Kai Li, Lei Sun, Dan Li, Yongsheng Wang.
      Insulin resistance (IR) and Metabolic Dysfunction-Associated Steatohepatitis (MASH) are key drivers of hepatocellular carcinoma (HCC), yet the mechanisms underlying their induction of an immunosuppressive tumor microenvironment (TME) require elucidation. This review posits that the PI3K/Akt/mTOR signaling pathway acts as the central integrator of this process, becoming fundamentally rewired-or "imprinted"-by the unique pathological context of IR/MASH-HCC. We highlight how this "imprinted" pathway integrates disparate pathological signals to precisely direct tumor metabolic reprogramming, TME immune landscape remodeling, and the metabolic-dependent regulation of immune cells. We particularly dissect the synergistic amplification of pathway-mediated immune evasion (including PD-L1 upregulation and EMT) by the IR/MASH microenvironment. This integrated framework, which conceptualizes the pathway as the central processing unit of a uniquely aggressive immuno-metabolic phenotype, not only illuminates the unique biology of IR/MASH-HCC but also provides new insights and a theoretical basis for the clinical translation of targeting the PI3K/Akt/mTOR pathway-encompassing novel combination strategies and biomarker development-to foster more effective clinical interventions.
    Keywords:  Hepatocellular Carcinoma; Insulin Resistance; MASH; Metabolic Reprogramming; PI3K/Akt/mTOR Signaling Pathway; Tumor Immune Microenvironment
    DOI:  https://doi.org/10.7150/ijbs.120657
  14. Clin Exp Med. 2025 Nov 11. 25(1): 367
    The emerging role of cancer-associated fibroblasts in hematological malignancies: from their influence on tumor progression and drug resistance to novel therapeutic opportunities.
    Sahar Jalilivand, Somayeh Yazdanparast, Mehdi Bakhtiyaridovvombaygi, Mehrdad Izadirad, Fatemeh Mikanik, Ahmad Gharehbaghian.
      The tumor microenvironment (TME) plays a critical role at all stages of tumor progression. Cancer-associated fibroblasts (CAFs), as the main components of this environment, display diversities in origin, phenotype, and function, which contribute to cancer progression by regulating the tumor cell biology via cell-cell contact, releasing numerous regulatory elements such as growth factors (GFs), cytokines, and chemokines, and even remodeling the extracellular matrix (ECM). In this Review, we discuss the current understanding of CAFs' pro- or anti-tumor functions in various hematological malignancies, including acute and chronic leukemia, lymphoma, and multiple myeloma (MM). The accumulating evidence highlighted that CAFs not only are implicated in these neoplasms' initiation, development, and metastasis but also are involved in chemoresistance to various chemotherapy drugs such as daunorubicin and bortezomib. Intriguingly, cell culture-based methods' results outlined that targeting signaling pathways that are used by CAFs to exert their pro-tumorigenic effects could be exploited in favor of tumor inhibition, which requires more investigation. Therefore, this therapeutic approach should be considered in future studies to develop a novel targeted therapy in hematological malignancies.
    Keywords:  Cancer-associated fibroblast; Hematological malignancies; Progression; Treatment; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s10238-025-01908-4
  15. Cancer Treat Rev. 2025 Nov 10. pii: S0305-7372(25)00168-9. [Epub ahead of print]141 103046
    CAR-T cell therapy in hepatocellular carcinoma: from mechanistic insights to clinical translation.
    Reza Elahi, Yassine Alami Idrissi, Anwaar Saeed.
      Chimeric antigen receptor (CAR)-T cell therapy has transformed cancer immunotherapy, achieving durable complete remissions in hematologic cancers. Yet its translation to solid tumors like hepatocellular carcinoma (HCC), a leading cause of cancer-related deaths worldwide, faces formidable barriers, including immunosuppressive tumor microenvironments (TMEs), antigen heterogeneity, and risks of on-target/off-tumor toxicity. This review discusses the evolving role of CAR-T therapy in HCC across three domains: (1) foundational concepts in CAR-T design, mechanistic action, and antigen-targeting strategies; (2) breakthroughs from preclinical studies and early-phase clinical trials, such as glypican-3 (GPC3) and alpha-fetoprotein (AFP) directed CAR-T cells that have demonstrated preliminary safety and anti-tumor activity; and (3) innovative strategies to overcome TME-driven resistance, including metabolic reprogramming and stromal modulation. We highlight cutting-edge engineering solutions such as armored CAR-T cells engineered for cytokine support, dual-targeting constructs to mitigate antigen escape, and hypoxia-resistant designs alongside synergistic approaches combining CAR-T with immune checkpoint inhibitors or tyrosine kinase inhibitors. Furthermore, we dissect emerging tactics to disrupt TME immunosuppression. While CAR-T therapy holds promise for redefining HCC management, its success will depend on overcoming biological and logistical barriers through patient-tailored designs and robust translational pipelines. Future directions should prioritize biomarker-driven clinical trials, scalable manufacturing platforms, and integration with existing multimodal HCC therapies to maximize durable responses.
    Keywords:  Immunotherapy; chimeric antigen receptor (CAR); hepatocellular carcinoma (HCC); tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.ctrv.2025.103046
  16. Int Immunopharmacol. 2025 Nov 11. pii: S1567-5769(25)01795-3. [Epub ahead of print]168(Pt 1): 115807
    Macrophage polarization in tumors: The impact of efferocytosis.
    YuLing Zhang, Hongjing Zang, Qiuyuan Wen.
      Efferocytosis is an indispensable process for maintaining tissue homeostasis, in which apoptotic cells (ACs) are cleared by professional and non-professional phagocytes. Impaired efferocytosis has been linked to various pathological conditions, ranging from inflammatory disorders to tumors. Mounting evidence suggests that efferocytosis plays a critical role in tumors initiation and progression through multiple molecules and their associated signaling pathways. By fostering an immunosuppressive microenvironment and enabling cancer cell to evade immune surveillance, efferocytosis promotes tumor growth. These findings highlight novel directions for cancer treatment by targeting efferocytosis. This article reviews the process of efferocytosis and its role in the tumor microenvironment, elucidating key signaling pathways that drive M2 macrophage polarization. It also discusses emerging anti-tumor therapeutic strategies based on these mechanisms.
    Keywords:  Efferocytosis; Macrophage; Tumor; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.intimp.2025.115807
  17. Proc Natl Acad Sci U S A. 2025 Nov 18. 122(46): e2522634122
    Physiologically based pharmacokinetic model for CAR-T cell delivery and efficacy in solid tumors.
    Andreas G Hadjigeorgiou, Lance L Munn, Triantafyllos Stylianopoulos, Rakesh K Jain.
      Abnormal blood vessels limit the delivery and function of endogenous T cells as well as adoptively transferred Chimeric Antigen Receptor (CAR)-T cells in tumor microenvironment (TME). We recently showed that vascular normalization using anti-VEGF therapy can overcome these challenges and improve the outcome of CAR-T therapy in glioblastoma models in mice. Here, we developed a physiologically based pharmacokinetic model to simulate the dynamics of both adoptively transferred CAR-T cells and endogenous immune cells in solid tumors following vascular normalization. Similar to our data, our model simulations show that vascular normalization reprograms the TME from immunosuppressive to immunosupportive by enhancing infiltration of endogenous CD8+ T cells and CAR-T cells, increasing M1 macrophages, and reducing M2 macrophages and regulatory T cells, thereby improving efficacy. Strikingly, vascular normalization reduces the number of infused CAR-T cells needed for tumor control by approximately fivefold. Moreover, synchronizing a second CAR-T infusion at their peak proliferative phase maximizes antitumor function. Furthermore, the efficacy of CAR-T cells engineered to secrete anti-VEGF antibody depends on the ability of CAR-T cells to induce vascular normalization. Additionally, combining vascular and stromal normalization can improve the efficacy of anti-VEGF antibody-producing Fibroblast Activated Protein-CAR-T cells for the treatment of desmoplastic tumors such as pancreatic ductal adenocarcinoma. Finally, the model predicts that local CAR-T delivery can sustain high concentrations within the TME and induce recruitment of other antitumor immune cells, improving outcomes. Our model provides a versatile framework to optimize dosing strategies, treatment sequencing, and delivery routes for improving CAR-T therapies for solid tumors.
    Keywords:  CAR-T cells; mathematical model; stroma normalization; vascular normalization
    DOI:  https://doi.org/10.1073/pnas.2522634122
  18. Int J Mol Sci. 2025 Oct 30. pii: 10547. [Epub ahead of print]26(21):
    Soil and Seed: Tumor Microenvironment Nurtures Immunotherapy Resistance and Renewal.
    Yiya Li, Qiushi Feng, Yangyang Xia, Lingzi Liao, Shang Xie.
      Cancer immunotherapy has become a powerful clinical strategy for cancer management, while its efficacy is frequently limited by primary and acquired resistance. The tumor microenvironment (TME) plays a pivotal role in mediating such resistance through multifaceted mechanisms involving cellular, metabolic, mechanical, and microbial components. This review systematically examines how the TME contributes to immunotherapy failure. We compare resistance mechanisms common to both immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell (CAR-T) therapies, two cornerstone modalities in clinical practice. Furthermore, we discuss emerging strategies designed to overcome these barriers, including immune microenvironment, stromal normalization, metabolic modulation, and microbiota engineering. By integrating recent preclinical and clinical insights, this review aims to provide a comprehensive framework for understanding and targeting microenvironmental resistance, ultimately facilitating the translation of novel combination therapies into improved patient outcomes.
    Keywords:  chimeric antigen receptor T-cell; immune checkpoint inhibitors; immunotherapy resistance; overcoming strategies; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms262110547
  19. Front Immunol. 2025 ;16 1665742
    Emerging insights into the immunosuppressive tumor microenvironment and its implications for glioblastoma immunotherapy.
    Niovi Nicolaou, Maria S Andreou, Christiana M Neophytou, Panagiotis Papageorgis.
      Glioblastoma is considered the most common and lethal form of brain cancer. Despite tremendous progress in glioblastoma therapeutics, the profound intra- and inter-tumoral heterogeneity of glioblastoma tumors, the difficulty of agents to cross the blood-brain barrier (BBB), the development of drug resistance as well as the immunosuppressive tumor microenvironment (TME) predominantly account for the failure of existing conventional and targeted therapies. Therefore, there is a growing necessity to decipher the complexity of the TME that promotes immunosuppression and to discover innovative strategies targeting both the tumor and its TME to improve patient treatment outcomes. In this comprehensive review, we present the latest evidence implicating various components of the TME in regulating the efficacy of immunotherapies. We also discuss the current challenges and opportunities of immunotherapy in treating glioblastoma, including ongoing clinical trials using immune checkpoints inhibitors (ICIs), CAR-T cell therapy, vaccines, cytokine therapy and oncolytic viruses.
    Keywords:  drug resistance; glioblastoma; immune checkpoint inhibitors; immunosuppressive tumor microenvironment; immunotherapy
    DOI:  https://doi.org/10.3389/fimmu.2025.1665742
  20. Front Immunol. 2025 ;16 1677548
    Reprogramming the tumor microenvironment to boost adoptive T cell therapy.
    Maria Fernanda Meza Pacheco, Lee-Hwa Tai.
      Adoptive T cell therapies (ACT) have revolutionized the management of hematologic malignancies; however, their efficacy in solid tumors remains limited. Accumulating evidence implicates the tumor microenvironment (TME) - a highly complex and immunosuppressive niche as a major barrier to their effectiveness. In this review, we propose that the next generation of ACT will require a fundamental shift from a reductionist focus on T cell engineering alone to an integrated approach that considers the interactions between immune cells and the TME. A comprehensive literature review identified several emerging strategies to enhance the efficacy of ACT, including reprogramming tumor vasculature, repolarizing immunosuppressive myeloid and stromal cells, leveraging oncolytic viruses to remodel antigen presentation, inducing acute sterile inflammation, and targeting the physical properties of the extracellular matrix. While many of these approaches remain in early-stage development, some have already progressed to clinical trials, indicating their potential for clinical translation. Additionally, we found that conventional therapies, such as surgery, chemotherapy, and radiotherapy, can be strategically integrated with ACT to improve therapeutic outcomes. These findings highlight a shift in the field toward more integrative approaches. Future advances will likely depend on reprogramming the TME to support T cell persistence and functions. Addressing these interconnected challenges will require closer collaboration between immunology, oncology, and bioengineering disciplines.
    Keywords:  CAR (chimeric antigen receptor) T-cell therapy; adoptive T cell immunotherapy; immunomodulation; immunotherapy; oncology; tumor infiltrating lymphocyte; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1677548
  21. Transl Cancer Res. 2025 Oct 31. 14(10): 6454-6468
    shRNA-based PD-1 suppression preserves memory phenotype and function of CD19-targeted CAR-T cell.
    Jiaxuan Zhao, Han Wu, Zhe Sun, Yeting Cui, Nan Liu, Yixuan Wang, Youyong Wang, Jiangzhou Shi, Tongcun Zhang.
       Background: Chimeric antigen receptor T cell (CAR-T) therapy targeting cluster of differentiation 19 (CD19) has shown promise in treating B-cell acute lymphoblastic leukemia (B-ALL), but the long-term efficacy of CD19-targeted CAR-T therapy remains limited. Programmed cell death protein 1 (PD-1), an inhibitory receptor on activated T cells, engages programmed death ligand 1 (PD-L1) in the tumor microenvironment, suppressing CAR-T cell function by impairing key signaling pathways. To address this limitation, we investigated the effect of short hairpin RNA (shRNA)-mediated PD-1 knockdown on alleviating CAR-T cell exhaustion, preserving memory phenotype, and enhancing the long-term efficacy of CD19-targeted CAR-T cells.
    Methods: To overcome this limitation, we employed shRNA to achieve PD-1 knockdown in CD19-targeting CAR-T cells. Following screening multiple shRNA candidates, we assessed the cytotoxicity, cytokine secretion, and proliferation of PD-1 knockdown CAR-T cells. Their memory phenotype, exhaustion marker, and cytolytic function were further evaluated after repeated antigen stimulation. Therapeutic efficacy and safety were validated in NOD.Cg-PrkdCscid Il2rgtm1/Vst (NPG) mice.
    Results: PD-1 knockdown significantly enhanced CAR-T cell cytotoxicity and persistence against PD-L1+ RAJI (human Burkitt's lymphoma cell line) cells. After three rounds of antigen stimulation, PD-1 knockdown CAR-T cells sustained cytotoxic activity, retained a memory-like phenotype, and displayed attenuated exhaustion markers. In vivo, they prolonged survival without inducing cytokine release syndrome (CRS), indicating improved efficacy and safety.
    Conclusions: PD-1 knockdown mitigates tumor-induced T-cell exhaustion and represents a promising strategy to enhance the durability and potency of CAR-T cell therapy in cancer treatment.
    Keywords:  Chimeric antigen receptor T cell (CAR-T); anti-tumor efficiency; exhaustion; programmed cell death protein 1 (PD-1)
    DOI:  https://doi.org/10.21037/tcr-2025-938
This page is being maintained by Thomas Krichel. It was last updated on 2025‒11‒16 at 15:56.