bims-flamet 2025-09-07 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2025–09–07
twenty-two papers selected by
Peio Azcoaga, Biodonostia HRI

N1 and N2 neutrophil subtypes in breast cancer: functional implications and clinical perspectives: a narrative review.
Polarization of Tumor Cells and Tumor-Associated Macrophages: Molecular Mechanisms and Therapeutic Targets.
Perineural invasion and the "cold" tumor microenvironment in pancreatic cancer: mechanisms of crosstalk and therapeutic opportunities.
Metabolic reprogramming and immunosenescence in colorectal cancer: mechanisms and therapeutic implications.
Antigen escape in CAR-T therapy: A tumor microenvironment perspective from hematological to solid tumors.
The impact of aberrant lipid metabolism on the immune microenvironment of gastric cancer: a mini review.
The tumor-microbe connection.
Role of metabolic reprogramming of cancer‑associated fibroblasts in tumor development and progression (Review).
Crosstalk between heterogeneous cancer-associated fibroblast subpopulations and the immune system in breast cancer: key players and promising therapeutic targets.
Insights into the Mechanisms of Immune-Checkpoint Inhibitors Gained from Spatiotemporal Dynamics of the Tumor Microenvironment.
Deciphering the secrets of tumor-initiating cells in pancreatic ductal adenocarcinoma microenvironment: mechanisms and therapeutic opportunities.
Genetic Engineering in CAR T Cells for Solid Tumors: Current State, Barriers and Future Developments.
Role of mesenchymal stem cells in modulating cytokine networks and immune checkpoints in gastric cancer therapy.
Unlocking the power of innate lymphoid cell plasticity in the tumor microenvironment: A revolutionary pathway for cancer immunotherapy.
Development of combinatorial immunotherapy for patients with advanced gastric cancer from the perspective of immunosuppressive mechanisms in the tumor microenvironment.
Synthetic Biology and Biomaterials Strategies to Deceive the Tumor Microenvironment in CAR-T Immunotherapy.
Physiologically-based pharmacokinetic model for CAR-T cells delivery and efficacy in solid tumors.
ECM-Induced IL-23 Drives Immune Suppression in Breast Cancer via Regulating PD-1 on Tregs.
Melanoma and its fibroblastic allies: the emerging importance of CAFs in immune suppression, ECM modulation, and therapy resistance.
ChREBP-Mediated Choline Deprivation and Chemokine Secretion Shape Tumor-Associated Macrophages to Promote Immune Evasion.
Moxibustion Enhances Chemotherapy of Breast Cancer by Affecting Tumor Microenvironment [Retraction].
The association between periostin and tumor microenvironment: a promising cancer prognostic biomarker and therapeutic target to combat tumor progression and chemoresistance.

Ann Med Surg (Lond). 2025 Sep;87(9): 5762-5769

N1 and N2 neutrophil subtypes in breast cancer: functional implications and clinical perspectives: a narrative review.

Emmanuel Ifeanyi Obeagu.

  Breast cancer (BC) remains a leading cause of cancer-related deaths globally, with the tumor microenvironment (TME) playing a pivotal role in disease progression. Neutrophils, the most abundant white blood cells, have gained attention for their dualistic role in cancer immunity. Two major neutrophil subtypes, N1 and N2, have been identified, each exhibiting distinct functions in the TME. N1 neutrophils are typically associated with anti-tumor immunity, promoting tumor cell clearance through mechanisms such as reactive oxygen species production, cytokine release, and the activation of cytotoxic immune cells. In contrast, N2 neutrophils promote tumor progression, metastasis, and immune suppression by secreting pro-angiogenic factors and recruiting regulatory immune cells like Tregs and myeloid-derived suppressor cells. The polarization of neutrophils into N1 or N2 subtypes is regulated by the dynamic interactions within the TME, including cytokines, hypoxic conditions, and signals from tumor cells. In BC, factors such as IL-8, transforming growth factor-beta, and granulocyte-macrophage colony-stimulating factor drive N2 polarization, contributing to tumor evasion of immune surveillance. Conversely, pro-inflammatory signals can induce N1 polarization, which is often linked to favorable clinical outcomes. However, in aggressive breast cancer subtypes such as triple-negative breast cancer, the TME is more conducive to N2 polarization, resulting in poor prognosis and resistance to treatment.

Keywords:  N1 neutrophils; N2 neutrophils; breast cancer; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.1097/MS9.0000000000003609
MedComm (2020). 2025 Sep;6(9): e70372

Polarization of Tumor Cells and Tumor-Associated Macrophages: Molecular Mechanisms and Therapeutic Targets.

Guohao Wei, Bin Li, Mengyang Huang, Mengyao Lv, Zihui Liang, Chuandong Zhu, Lilin Ge, Jing Chen.

  Tumor-associated macrophages (TAMs) are prominent constituents of solid tumors, and their prevalence is often associated with poor clinical outcomes. These highly adaptable immune cells undergo dynamic functional changes within the immunosuppressive tumor microenvironment (TME), engaging in reciprocal interactions with malignant cells. This bidirectional communication facilitates concurrent phenotypic transformation: tumor cells shift toward invasive mesenchymal states, whereas TAMs develop immunosuppressive, pro-tumorigenic traits. Increasing evidence highlights metabolic reprogramming, characterized by dysregulation of lipid metabolism, amino acid utilization, and glycolytic activity, as the fundamental molecular basis orchestrating this pathological symbiosis. However, a comprehensive understanding of how metabolic reprogramming specifically coordinates the mutual polarization of tumor cells and TAMs is lacking. This review thoroughly examines the molecular mechanisms governing this co-polarization process, detailing critical transcriptional regulators, essential signaling pathways, and the maintenance of adaptive phenotypes within the TME. Furthermore, this review critically assesses promising therapeutic strategies aimed at disrupting this alliance, including the use of metabolically targeted agents, engineered chimeric antigen receptor macrophages, and TAM-selective nanoparticle delivery systems. These insights provide a crucial foundation for the development of next-generation cancer immunotherapies focused on reprogramming pathological polarization dynamics to overcome treatment resistance and improve clinical outcomes.

Keywords:  TAMs; TME; metabolism reprogramming; tumor cell

DOI:  https://doi.org/10.1002/mco2.70372
Front Immunol. 2025 ;16 1650117

Perineural invasion and the "cold" tumor microenvironment in pancreatic cancer: mechanisms of crosstalk and therapeutic opportunities.

Jianbiao Xu, Hong Yao, Junfeng Wang, Yun Jin, Wei Chang, Lanjiang Li, Lei Zou.

  Pancreatic ductal adenocarcinoma (PDAC) remains a devastating malignancy characterized by profound lethality, aggressive local invasion, dismal prognosis, and significant resistance to existing therapies. Two critical biological features underpin the challenges in treating PDAC: extensive perineural invasion (PNI), the process by which cancer cells infiltrate and migrate along nerves, and a profoundly immunosuppressive, or "cold," tumor microenvironment (TME). PNI is not only a primary route for local tumor dissemination and recurrence but also a major contributor to the severe pain often experienced by patients. Concurrently, the PDAC TME is typified by a dense desmoplastic stroma, hypoxia, and an abundance of immunosuppressive cells-including cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs)-while lacking sufficient infiltration of effector T cells, rendering it largely unresponsive to immunotherapies like checkpoint inhibitors. Although historically studied as separate entities, accumulating evidence reveals a deep-seated and complex bidirectional crosstalk between the neural components involved in PNI and the immune and stromal cells constituting the TME. Key cellular mediators, such as CAFs and TAMs, and shared signaling pathways, including the CXCL12/CXCR4 axis, TGF-β signaling, and neurotrophin pathways (e.g., NGF/TrkA), appear to act as critical nodes, coordinating the progression of PNI while simultaneously shaping and maintaining the immunosuppressive TME. This review synthesizes the current understanding of these intricate neuro-immune interactions in PDAC. We delineate the molecular and cellular mechanisms governing this crosstalk and explore how targeting these shared regulatory networks presents novel therapeutic opportunities, potentially disrupting PNI while concurrently "heating" the cold TME to overcome immunotherapy resistance. Elucidating this interplay is crucial not only for a deeper comprehension of PDAC's invasive and metastatic mechanisms but also for uncovering new therapeutic vulnerabilities to improve patient outcomes.

Keywords:  CXCL12/CXCR4; cancer-associated fibroblasts; immunosuppression; neuro-immune crosstalk; pancreatic ductal adenocarcinoma; perineural invasion; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2025.1650117
Front Cell Dev Biol. 2025 ;13 1662464

Metabolic reprogramming and immunosenescence in colorectal cancer: mechanisms and therapeutic implications.

Jun Zhu, Kuan Shen, Qiang Su, Guozhong Yao, Xiaochen Chen.

  Colorectal cancer (CRC), as a highly prevalent malignant tumor worldwide, has a persistently high incidence and mortality rate. In recent years, metabolic reprogramming and immunosenescence have received extensive attention as key mechanisms for tumorigenesis, development and treatment resistance. Metabolic reprogramming not only provides energy and biosynthetic precursors for tumor cells, but also regulates immune responses by reconstructing the tumor microenvironment (TME). Immunosenescence is characterized by the depletion of effector immune cell function and the increase in the proportion of immunosuppressive cells. The two jointly promote the immune escape and therapeutic resistance of CRC. This article systematically reviews the research progress of metabolic reprogramming and immunosenescence in colorectal cancer and explores the related targeted therapeutic strategies, aiming to provide a new theoretical perspective for the precise treatment of CRC.

Keywords:  colorectal cancer; immunosenescence; immunotherapy; metabolic reprogramming; tumor microenvironment

DOI:  https://doi.org/10.3389/fcell.2025.1662464
Int J Cancer. 2025 Aug 29.

Antigen escape in CAR-T therapy: A tumor microenvironment perspective from hematological to solid tumors.

Shuai Wang, Wenying Li, Jiayi Li, Zhigang Guo, Jiannan Chen, Zhigang Hu.

  Chimeric antigen receptor T-cell (CAR-T) therapy has shown remarkable efficacy in hematologic malignancies, but antigen escape remains a major challenge, especially in solid tumors, where the tumor microenvironment (TME) exacerbates the problem. Mechanisms of antigen escape include antigen loss, epitope masking, lineage switching, and trogocytosis-mediated CAR dysfunction. The TME promotes immune evasion through physical barriers, immunosuppressive cells, and metabolic competition. To overcome these challenges, multi-targeted CAR-Ts, gene editing, epigenetic interventions, and combination therapies have been developed to enhance CAR-T efficacy. Emerging strategies-such as microbial-guided antigen labeling, nanotechnology for metabolic normalization, armored CAR-T secreting TME-modulating agents, and adaptive CAR systems responsive to TME signals-offer new solutions to target "cold" tumors. Future breakthroughs will rely on synergizing dynamic CAR systems for broad antigen coverage, achieved via multi-targeting and non-canonical antigen recognition, with engineered TME remodeling driven by microbial, viral, and immune cell allies, as well as armored CAR-T cells secreting immunomodulators. Combined with metabolic engineering and interdisciplinary innovation, this integrated approach will effectively enable CAR-T cells to orchestrate a multi-faceted anti-tumor ecosystem rather than functioning in isolation.

Keywords:  CAR‐T optimization; CAR‐T therapy; antigen escape; trogocytosis; tumor microenvironment

DOI:  https://doi.org/10.1002/ijc.70117
Front Immunol. 2025 ;16 1639823

The impact of aberrant lipid metabolism on the immune microenvironment of gastric cancer: a mini review.

Shuangyu Chen, Wenqian Chen, Tinghui Xu, Jiayang Li, Jianghao Yu, Yibo He, Shengliang Qiu.

  Gastric cancer (GC) remains one of the leading causes of cancer-related mortality worldwide, with limited responses to immune checkpoint blockade (ICB) therapies in most patients. Increasing evidence indicates that the tumor immune microenvironment (TIME) plays a crucial role in immunotherapy outcomes. Among various metabolic abnormalities in the TIME, dysregulated lipid metabolism has emerged as a critical determinant of immune cell fate, differentiation, and function. In this review, we comprehensively summarize the current understanding of the immune landscape in GC, focusing on how altered lipid metabolism reshapes immune cell populations-including tumor-associated macrophages (TAMs), dendritic cells (DCs), regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and cytotoxic CD8+ T cells. We highlight key metabolic pathways such as fatty acid oxidation(FAO), cholesterol homeostasis, and lipid uptake that impact immune cell activity, contributing to immune evasion and therapeutic resistance. Importantly, we explore emerging therapeutic strategies targeting lipid metabolism, including inhibitors of cluster of differentiation 36 (CD36), fatty acid synthase (FASN), and sterol regulatory element-binding protein 1 (SREBP1) and discuss their synergistic potential when combined with ICB therapies. In conclusion, lipid metabolic reprogramming represents a promising yet underexplored axis in modulating antitumor immunity in GC. Integrating metabolic intervention with immunotherapy holds potential to overcome current treatment limitations and improve clinical outcomes. Future studies incorporating spatial omics and single-cell profiling will be essential to elucidate cell-type specific metabolic dependencies and foster translational breakthroughs.

Keywords:  CD8+ T cells; fatty acid oxidation; gastric cancer; immune checkpoint blockade; immunotherapy resistance; lipid metabolism; tumor immune microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2025.1639823
Mol Oncol. 2025 Sep 03.

The tumor-microbe connection.

Gerlanda Vella, Maria Rescigno.

  The discovery of tumor-associated bacteria (TAB) challenges the traditional view of tumors as sterile environments. These microbes are engaged in a complex dialog with the other components of the tumor microenvironment (TME), influencing immunity, metastasis, and treatment response. Yet the precise mechanisms by which TAB influence tumor biology remains incompletely understood. Deciphering the complex host-microbe interactions could unlock novel therapeutic strategies to reshape the TME and improve treatment outcomes. Here we summarize the key findings in the field, highlighting the most outstanding questions regarding bacterial sources, the roles of TAB in cancer, and their interactions with the other cellular components of the TME.

Keywords:  intratumoral microbiota; metastasis; therapy efficacy; tumor microenvironment

DOI:  https://doi.org/10.1002/1878-0261.70115
Int J Oncol. 2025 Nov;pii: 90. [Epub ahead of print]67(5):

Role of metabolic reprogramming of cancer‑associated fibroblasts in tumor development and progression (Review).

Ruyue Li, Yintao Li.

  The occurrence and development of tumors is affected by tumor cells themselves and various components of the tumor microenvironment (TME). Among these, cancer‑associated fibroblasts (CAFs), the main stromal component, can differentiate from different cell types and play an important role in the TME. The present review summarized the role of the metabolic reprogramming of CAFs in tumor development and progression. As the rapid growth of tumors is a process inseparable from energy supply and the TME is characterized by hypoxia and nutrient deficiencies, metabolic reprogramming can reverse the effects of a lack of energy supply in the TME. Studies have found that CAFs can affect tumor proliferation, migration, invasion, metastasis and drug resistance by changing metabolic patterns. The present review promoted research on the metabolic reprogramming of CAFs and emphasized the importance of considering the heterogeneity and plasticity of CAFs in the TME, which will lead to the development of more effective therapeutic strategies that target specific metabolic pathways in CAFs, potentially improving the efficacy of cancer treatments and overcoming drug resistance.

Keywords:  amino acid; cancer‑associated fibroblasts; glycolysis; lipid; metabolic reprogramming; tumor

DOI:  https://doi.org/10.3892/ijo.2025.5796
J Exp Clin Cancer Res. 2025 Sep 01. 44(1): 263

Crosstalk between heterogeneous cancer-associated fibroblast subpopulations and the immune system in breast cancer: key players and promising therapeutic targets.

Lu Liu, Weijun Wan, Yilin Chang, Luoquan Ao, Yan Xu, Xiang Xu.

  The tumor microenvironment (TME) of breast cancer is a complex ecosystem, in which cancer-associated fibroblasts (CAFs), as the most abundant stromal cell type, meticulously construct an ecological niche that supports tumor growth through mechanisms including extracellular matrix (ECM) remodeling, secretion of bioactive factors, and interactions with neighboring cells. High-resolution technologies, including single-cell sequencing and spatial transcriptomics, have revealed the high heterogeneity, functional diversity, and spatial distribution within the CAF population. Significant differences exist in the interactions between distinct CAF subpopulations and immune cells. Through complex crosstalk with the immune system, they collaboratively establish an immunosuppressive network, becoming a core driving force for tumor immune escape. This review focuses on the latest research advances in heterogeneous subpopulations of CAFs within the breast cancer microenvironment, delves into how the complex bidirectional crosstalk between different CAF subpopulations and immune cells collaboratively shapes the tumor immune microenvironment (TIME), and summarizes various CAF-based therapeutic strategies for breast cancer, aiming to provide critical theoretical basis and novel therapeutic perspectives for the clinical translation of CAF heterogeneity research.

Keywords:  Breast cancer; Cancer-associated fibroblasts; Heterogeneity; Therapeutic strategies; Tumor microenvironment

DOI:  https://doi.org/10.1186/s13046-025-03527-z
Adv Sci (Weinh). 2025 Aug 28. e08692

Insights into the Mechanisms of Immune-Checkpoint Inhibitors Gained from Spatiotemporal Dynamics of the Tumor Microenvironment.

Yuanyuan Zhang, Zhihua Liu.

  Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has revolutionized cancer treatment, yet durable responses are achieved in only a subset of patients. The tumor microenvironment (TME) plays a key role in cancer progression and immune modulation, critically influencing the efficacy of ICIs. Recent advances in single-cell technologies have enabled high-resolution profiling of the TME, particularly tumor-infiltrating immune cells, across diverse cancer types. However, our understanding of how immune cells shape ICI responses and how they are dynamically altered during treatment remains incomplete. In this review, we summarize recent progress in characterizing TME features associated with ICI responsiveness, highlighting key immune cell subsets involved in ICI therapy and emphasizing their phenotypic plasticity and functional adaptability following ICIs. Additionally, we outline the spatial architecture of the TME in terms of its effects on immune cell behavior and interactions, and discuss the critical role of stromal components and the microbiota in modulating the immune landscape and influencing ICI responsiveness. By integrating these insights, we aim to deepen our understanding of the cellular and molecular mechanisms underlying ICI responses, elucidate determinants of therapeutic sensitivity and resistance, and inform the development of more effective immunotherapeutic strategies.

Keywords:  immune checkpoint inhibitors; immunotherapy response; spatial architecture; spatiotemporal dynamics; tumor microenvironment

DOI:  https://doi.org/10.1002/advs.202508692
Front Immunol. 2025 ;16 1614707

Deciphering the secrets of tumor-initiating cells in pancreatic ductal adenocarcinoma microenvironment: mechanisms and therapeutic opportunities.

Jun Zhou, Jiajun Li, Haoyi Lu, Yanggang Hong.

  Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by poor prognosis, strong resistance to therapy, and a dense immunosuppressive tumor microenvironment (TME). A small subset of cells known as cancer stem cells (CSCs), or tumor-initiating cells (TICs), are increasingly recognized as key contributors to tumor initiation, metastasis, immune evasion, and treatment failure. These cells are defined by their self-renewal capacity, plasticity, and resistance to chemotherapeutic and targeted therapies. Pancreatic cancer stem cells (PaCSCs) are maintained by specific surface markers (CD44, CD133, EpCAM, ALDH1A1) and regulated by stemness-associated signaling pathways such as Wnt/β-catenin, Notch, Hedgehog, and TGF-β. Their survival is further enhanced by metabolic reprogramming, including shifts between glycolysis and oxidative phosphorylation and the activation of ROS-detoxifying enzymes. Importantly, PaCSCs reside in specialized niches formed by hypoxia, cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and extracellular matrix (ECM) components that together shield them from immune clearance and promote therapeutic resistance. This review outlines the molecular features and functional roles of PaCSCs, their interaction with the TME, and recent advances in targeting this CSC-stroma network. Promising therapeutic strategies, such as CAR-T/NK cell therapies, epigenetic inhibitors, and combination regimens with checkpoint blockade or stromal modulators, are discussed in the context of ongoing clinical trials. Targeting both CSCs and their supportive microenvironment is emerging as a necessary strategy to overcome resistance and improve clinical outcomes in PDAC.

Keywords:  cancer stem cell; immune evasion; pancreatic ductal adenocarcinoma; tumor microenvironment; tumor-initiating cell

DOI:  https://doi.org/10.3389/fimmu.2025.1614707
Hum Gene Ther. 2025 Aug 29. 0

Genetic Engineering in CAR T Cells for Solid Tumors: Current State, Barriers and Future Developments.

Rodrigo A Redondo-Frutos, Pedro Justicia-Lirio, Carmen Barbero-Jimenez, Maider Garnica, Lucia Trudu, Paula Rodriguez-Marquez, Juan J Lasarte, Felipe Prosper, Juan R Rodriguez-Madoz.

  Chimeric antigen receptor (CAR) T cell therapy has revolutionized treatment for hematological malignancies, yet translating this success to solid tumors remains challenging. Major obstacles include antigen heterogeneity, on-target off-tumor toxicity, limited infiltration and persistence, and the immunosuppressive tumor microenvironment (TME). The present review discusses recent engineering strategies designed to overcome these barriers. Innovations such as affinity-tuned and logic-gated CARs improve specificity and safety, while multi-antigen targeting helps address tumor heterogeneity by avoiding antigen escape. Gene-editing approaches enhance CAR T cell fitness by promoting memory phenotypes, metabolic resilience, and resistance to inhibitory signals imposed by the immunosuppressive TME. Additional modifications improve trafficking, enable extracellular matrix degradation, and reprogram CAR T cells to withstand the hostile conditions of the TME. Together, these advances reflect a growing shift toward rational CAR design and synthetic immunology, with the goal of achieving durable and safe responses in solid tumors. Early clinical trials show promise, and continued translational efforts will be key to unlocking the full therapeutic potential of CAR T cells in this setting.

Keywords:  CAR T; TME; genetic engineering; solid tumors

DOI:  https://doi.org/10.1177/10430342251372041
Biochim Biophys Acta Rev Cancer. 2025 Aug 29. pii: S0304-419X(25)00175-1. [Epub ahead of print]1880(5): 189433

Role of mesenchymal stem cells in modulating cytokine networks and immune checkpoints in gastric cancer therapy.

Zakari Shaibu, Isah Adamu Danbala, Zhihong Chen, Wei Zhu.

  Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, driven by a complex tumor microenvironment (TME) that promotes disease progression and therapeutic resistance. This review explores the pivotal roles of mesenchymal stem cells (MSCs), cytokines, and immune checkpoint inhibitors (ICIs) in shaping the immunosuppressive GC TME, with emphasis on their interaction and implications for immunotherapy. MSCs secrete cytokines such as IL-6, TGF-β, and IL-10, fostering an immunosuppressive milieu that enables tumor growth, immune evasion, and resistance to ICIs. We synthesize current knowledge on how MSC-derived cytokines regulate immune checkpoint expression, suppress anti-tumor immunity, and contribute to TME heterogeneity. Additionally, we discuss therapeutic strategies targeting MSC-cytokine-immune checkpoint interactions to enhance ICI efficacy and improve clinical outcomes. Emerging approaches including MSC reprogramming, exosome-based therapies, and multi-omics technologies are highlighted as promising avenues to decipher TME complexity and develop personalized immunotherapies. By elucidating mechanisms of MSC-mediated immune modulation in GC, this review aims to inspire novel strategies to overcome therapeutic resistance in this challenging disease.

Keywords:  Cytokines; Gastric cancer; Immune checkpoints; Immunotherapy; Mesenchymal stem cells; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2025.189433
Biochim Biophys Acta Rev Cancer. 2025 Aug 26. pii: S0304-419X(25)00172-6. [Epub ahead of print]1880(5): 189430

Unlocking the power of innate lymphoid cell plasticity in the tumor microenvironment: A revolutionary pathway for cancer immunotherapy.

Peng Yin, Pei Cao, Yu Liang, Chao Wang, Yu Tian.

  Innate lymphoid cells (ILCs) are emerging as powerful players in the immune system, capable of dramatically influencing tumor immunity. Their extraordinary plasticity, which allows them to adapt to dynamic changes in the tumor microenvironment, positions them as a double-edged sword in cancer immunotherapy. While they can drive anti-tumor immune responses, they can also promote tumor progression under certain conditions. In this review, we delve into the multifaceted roles of ILCs-focusing on ILC1, ILC2, and ILC3-and explore how their functional plasticity can be harnessed to shift their activities from immune suppression to potent anti-tumor actions. We highlight groundbreaking therapeutic strategies aimed at modulating ILC plasticity, such as metabolic reprogramming, cytokine therapy, and CAR-ILC1 therapy, each designed to enhance the anti-tumor potential of these cells. Despite the immense promise, challenges remain, including immune suppression within the TME and the short-lived efficacy of cytokines. However, targeting ILC plasticity offers a transformative approach to overcome these hurdles, presenting an opportunity to personalize cancer treatment and create tailored immunotherapies that dynamically modulate the immune response. This review underscores the game-changing potential of ILC-based therapies and provides insights into the next generation of cancer immunotherapies that could revolutionize the fight against cancer.

Keywords:  Cancer immunotherapy; Innate lymphoid cells (ILCs); Metabolic reprogramming; Plasticity; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1016/j.bbcan.2025.189430
Fukushima J Med Sci. 2025 Sep 02.

Development of combinatorial immunotherapy for patients with advanced gastric cancer from the perspective of immunosuppressive mechanisms in the tumor microenvironment.

Kosaku Mimura, Koji Kono.

Combinatorial immunotherapy using anti-programmed cell death 1 (PD-1) monoclonal antibody (mAb) is being developed to overcome the limited efficacy of monotherapy with anti-PD-1 mAb for patients with advanced gastric cancer (GC). Anti-PD-1 mAb exhibits clinical efficacy by enhancing the function of cytotoxic T lymphocyte (CTL) through the inhibition of the PD-1 pathway;however, there are various immunosuppressive mechanisms that inhibit CTL function, as well as the PD-1 pathway in the tumor microenvironment (TME). Immune suppressive cells and expression of the inhibitory immune checkpoint molecules are included as main inhibitory mechanisms against CTL in the TME. On the other hand, increasing the number of CTLs enhances the efficacy of anti-PD-1 mAb, and immunogenic tumor cell death (ICD) is crucial to induce CTL through the activation of the cancer immunity cycle. In the present review, we discuss the therapeutic potential of developing combinatorial immunotherapy focusing on the inhibitory immune checkpoint molecules and immune suppressive cells in the TME, as well as on the ICD induced by radiotherapy for patients with advanced GC.

DOI: https://doi.org/10.5387/fms.25-00009
Small. 2025 Sep 01. e06429

Synthetic Biology and Biomaterials Strategies to Deceive the Tumor Microenvironment in CAR-T Immunotherapy.

Grazia Marsico, Sudarshan Gc, Velia Siciliano.

  Chimeric antigen receptor (CAR)-T cell immunotherapy has emerged as a groundbreaking approach in cancer treatment, offering new hope across various malignancies. However, its success against solid tumors remains limited due to critical challenges, including off-tumor, on-target toxicity, immune resistance, poor T cell infiltration into the tumor microenvironment (TME), and T cell exhaustion. In response, interdisciplinary innovations in synthetic biology and biomaterials are redefining how can be engineer smarter, more responsive CAR-T cells. Recent advances have introduced biomaterials not only as precision delivery vehicles but also as artificial antigen-presenting cells (APCs), high-throughput screening platforms, and tools to replicate the complex biomechanical landscape of the TME. This review highlights these cutting-edge strategies, emphasizing how biomaterials and synthetic circuits can aid studies and strategies to enhance CAR-T cell efficacy in solid tumors while minimizing adverse effects. Future directions at the intersection of tumor-inspired biomaterials and T cell engineering, envisioning a new generation of CAR-T therapies tailored to overcome the formidable barriers of the TME are also explored.

Keywords:  CAR‐T; biomaterials; delivery systems; ex vivo mechanical models; immunotherapy; solid tumor microenvironment; synthetic biology

DOI:  https://doi.org/10.1002/smll.202506429
bioRxiv. 2025 Aug 21. pii: 2025.08.20.671229. [Epub ahead of print]

Physiologically-based pharmacokinetic model for CAR-T cells 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 the 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-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 an order of magnitude. 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 FAP-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. Significance Statement Preclinical studies and early clinical trials of CAR-T therapy show encouraging responses in glioblastoma, diffuse midline gliomas, and neuroblastoma, yet substantial obstacles remain for effective CAR-T therapy for solid tumors. Building on our discovery that judicious VEGF blockade normalizes tumor vessels and enhances CD8⁺T-cell infiltration, we developed a mathematical model to optimize CAR-T therapy for solid tumors. Simulations predict that vascular normalization can render the TME immunosupportive and decrease CAR-T doses tenfold. In desmoplastic tumors, FAP-CAR-T efficacy is improved by combining anti-VEGF and stromal normalizing agents. Optimal scheduling and direct intratumoral delivery can mitigate T-cell exhaustion and improve tumor control further. Thus, our model serves as a strategic roadmap for optimal CAR-T deployment in solid tumors.

DOI: https://doi.org/10.1101/2025.08.20.671229
J Exp Clin Cancer Res. 2025 Sep 01. 44(1): 264

ECM-Induced IL-23 Drives Immune Suppression in Breast Cancer via Regulating PD-1 on Tregs.

Giovanna Talarico, Mara Lecchi, Anna Zanichelli, Paola Portararo, Laura Botti, Vera Cappelletti, Massimo Costanza, Annamaria Piva, Pietro Pratesi, Francesco Bertolini, Massimo Di Nicola, Claudio Tripodo, Valeria Cancila, Serenella Maria Pupa, Mario Paolo Colombo, Claudia Chiodoni, Paolo Verderio, Sabina Sangaletti.

   BACKGROUND: High-grade breast cancer (HGBC) is an aggressive disease with poor prognosis, underscoring the need for new treatment strategies. The tumor microenvironment (TME), particularly the extracellular matrix (ECM), plays a pivotal role in tumor progression, therapy resistance, and immune regulation. An ECM-related gene signature (defined ECM3), found in approximately 35% of HGBC cases, is associated with aggressive tumors, epithelial-to-mesenchymal transition (EMT), poor clinical outcome and increased infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs).
METHODS: In this study, we investigated the impact of the ECM on T cell regulation in HGBC patients, focusing on the relationship between ECM3 + tumors and T cell phenotypes. We employed mouse models to dissect the molecular mechanisms linking ECM components to T cell regulation, with particular attention to the role of the matricellular protein SPARC, a key component of the ECM3 signature.
RESULTS: We revealed a significant correlation between highly suppressive programmed cell death-1 (PD-1) negative regulatory T cells (Tregs) and ECM3 + tumors. In mouse models, SPARC was found to down-regulate PD-1 on Tregs by promoting IL-23 release, which in turn induced SATB1 expression, a repressor of the pdcd1 gene. The selective expression of the IL-23 receptor on Tregs accounted for the targeted effect of IL-23 on these cells. Notably, blocking IL-23 with monoclonal antibodies restored PD-1 expression on Tregs and activated T effector cells.
CONCLUSION: These findings extend the immune-regulatory role of the ECM to include regulatory T cells and identify potential new therapeutic targets for high-grade breast cancers. Moreover, they highlight ECM3 as a potential biomarker of resistance to PD-1/PD-L1 immune checkpoint blockade (ICB), suggesting that ECM3⁺ patients may benefit from alternative checkpoint inhibitor therapies beyond PD-1/PD-L1.

Keywords:  Breast cancer; ECM3 signature; Extracellular matrix; IL-23; Immune suppression; PD-1; SPARC; T cells; Tregs

DOI:  https://doi.org/10.1186/s13046-025-03518-0
Naunyn Schmiedebergs Arch Pharmacol. 2025 Aug 28.

Melanoma and its fibroblastic allies: the emerging importance of CAFs in immune suppression, ECM modulation, and therapy resistance.

Chou-Yi Hsu, Raed Obaid Saleh, Jaafaru Sani Mohammed, Nasrin Mansuri, Rekha M M, Mayank Kundlas, Alex Anand, Samir Sahoo, Ahmed Hussein Zwamel, Hanen Mahmod Hulail.

  Melanoma, a heterogeneous and malignant skin tumor, carries disparate prognoses based on the original site of origin, cutaneous, ocular, or mucosal. Advanced and metastatic disease continues to be difficult due to resistance to existing treatments. In the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) have multifunctional roles in tumor growth, immune escape, and drug resistance. These heterogeneous stromal cells remodel the extracellular matrix and are angiogenic and immunomodulatory with high concurrence with poor clinical outcomes. It further addresses the role of CAFs in the formation of immunosuppressive niches and BRAF/MEK inhibitor resistance, primarily through mechanisms such as POSTN and β-catenin signaling. Key findings identify CAF-derived exosomes and signaling factors (e.g., TGF-β, IL-6, FGF2, PDPN) as central to melanoma development. Emerging therapy modalities for targeting these stromal elements, such as POSTN inhibition, PEDF restoration, and CAR-T cell treatments, are reviewed. CAFs have long been recognized as pivotal components within melanoma's TME, originating from various sources and manifesting considerable heterogeneity. These cells play an active role in remodeling the extracellular matrix (ECM), stimulating angiogenesis, supporting tumor metabolism, and promoting drug resistance, thereby facilitating tumor growth and metastasis. Through the secretion of various cytokines and growth factors, such as TGF-β and IL-6, they contribute to immune evasion by attracting immunosuppressive cells and impairing the function of cytotoxic T lymphocytes. In this context, we also highlight recent therapeutic strategies aimed at targeting CAFs to enhance treatment efficacy. By examining the diverse functions of CAF subtypes in modulating immune responses and influencing therapeutic outcomes, this review provides deeper insight into CAF-targeted interventions that can disrupt their tumor-supportive roles in melanoma.

Keywords:  Cancer-associated fibroblasts; Extracellular matrix; Melanoma; Metastasis; Tumor microenvironment

DOI:  https://doi.org/10.1007/s00210-025-04565-2
Cancer Res. 2025 Sep 05.

ChREBP-Mediated Choline Deprivation and Chemokine Secretion Shape Tumor-Associated Macrophages to Promote Immune Evasion.

Jianhong Zhao, Baoxiang Chen, Yanrong Deng, Lifang Fan, Siyuan Yin, Haisheng Yu, Yongchang Wei, Jing Dai, Qun Qian, Quanjiao Chen, Xianghai Ren, Xiaoyu Xie, Wenyi Wei, Jinfang Zhang, Congqing Jiang.

Tumor metabolic reprogramming has been recognized as a critical determinant in tumor development and cancer immunotherapy response. Aberrant choline metabolism is emerging as a defining hallmark of cancer. Here, we found that carbohydrate responsive element binding protein (ChREBP)-mediated choline deprivation induced tumor-associated macrophage (TAM) reprogramming and maintained an immunosuppressive tumor microenvironment (TME). Mechanistically, ChREBP interacted with SP1 to increase the expression of immunosuppressive chemokines CCL2 and CCL7 and choline transporter SLC44A1. As such, high CCL2 and CCL7 expression promoted recruitment of TAMs. Tumor cells with high SLC44A1 levels competed with M1-like TAMs for choline, inhibiting cGAS-STING signaling and promoting the repolarization of M1-like to M2-like macrophages. Clinically, ChREBP-SP1-choline metabolism axis expression was associated with poor clinical outcome in colorectal cancer. Thus, the study identified the interplay between tumors and TAMs via choline competition as a previously unknown immune evasion mechanism in the TME and propose ChREBP as a potential immunotherapeutic target in cancer.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0235
Cancer Manag Res. 2025 ;17 1801-1802

Moxibustion Enhances Chemotherapy of Breast Cancer by Affecting Tumor Microenvironment [Retraction].

[This retracts the article DOI: 10.2147/CMAR.S249797.].

DOI: https://doi.org/10.2147/CMAR.S563254
Cancer Cell Int. 2025 Sep 03. 25(1): 320

The association between periostin and tumor microenvironment: a promising cancer prognostic biomarker and therapeutic target to combat tumor progression and chemoresistance.

Mohsen Nabi-Afjadi, Farnoosh Farzam, Sina Soltani, Nafiseh Golestani, Shiva Sarani Asl, Fatemeh Aziziyan, Hamidreza Zalpoor, Fatemeh Ghasemi, Bahareh Dabirmanesh, Khosro Khajeh.

  Over the past few decades, cancer research has increasingly focused on tumor microenvironment (TME). The TME contains diverse cellular components and secreted factors, including leukocytes, endothelial cells, cancer-associated fibroblasts, and other non-cancerous cells and extracellular matrix proteins. The interactions between tumor cells and microenvironment elements are complex and unpredictable. Nonetheless, these relationships govern and control several cancer traits, including immune response, metastasis, differentiation status, cell proliferation, and resistance to cell death. In this line, Matricellular proteins, including periostin (POSTN), are increasingly recognized for their regulatory roles in the TME and cancer progression. Periostin is involved in tumor biology through matrix remodeling, invasion, and proliferation. In this review, we focused on the role of periostin as a biomarker for cancer growth and treatment resistance and a potential prognostic and therapeutic factor in cancer patients. In addition, we will discuss the periostin's dual role as both a promoter and inhibitor of tumor growth, depending on its concentration and cellular context. Key findings indicate that low periostin levels may suppress cancer progression by preventing epithelial-to-mesenchymal transition (EMT). In contrast, high levels can enhance migration and metastasis through the activation of integrin signaling pathways. Furthermore, we will discuss the implications of targeting periostin in therapeutic strategies, particularly in light of its complex functions within the TME.

Keywords:  Biomarker; Chemoresistance; Metastasis; Periostin; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12935-025-03959-9