bims-flamet 2025-02-09 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2025–02–09
34 papers selected by
Peio Azcoaga, Biodonostia HRI

Tumor microenvironment: obstacles and opportunities for T-cell based tumor immunotherapies.
Insights into IL-6/JAK/STAT3 signaling in the tumor microenvironment: Implications for cancer therapy.
Tumor cells escape immunosurveillance by hampering LFA-1.
Progress in immune microenvironment, immunotherapy and prognostic biomarkers in pediatric osteosarcoma.
Revisiting of Cancer Immunotherapy: Insight from the Dialogue between Glycolysis and PD-1/PD-L1 Axis in the Tumor Microenvironment.
Modulating lipid metabolism improves tumor immunotherapy.
High antigen-presenting CAF levels correlate with reduced glycosaminoglycan biosynthesis-heparan sulfate/heparin metabolism in immune cells and poor prognosis in esophageal squamous cell carcinoma: Insights from bulk and single-cell transcriptome profiling.
Targeting the kynurenine pathway: another therapeutic opportunity in the metabolic crosstalk between cancer and immune cells.
Anti-Tumor Strategies Targeting Nutritional Deprivation: Challenges and Opportunities.
Tumor-associated macrophages drive heterogenetic CD10High cancer stem cells to implement tumor-associated neutrophils reprogramming in oral squamous cell carcinoma.
Decoding multicellular interaction networks-a new horizon in tumor microenvironment research.
Effect of Extracellular Vesicles Derived From Tumor Cells on Immune Evasion.
CAR T cells, CAR NK cells, and CAR macrophages exhibit distinct traits in glioma models but are similarly enhanced when combined with cytokines.
Emerging insights into intravital imaging, unraveling its role in cancer immunotherapy.
Regulatory T cells converted from Th1 cells in tumors suppress cancer immunity via CD39.
Mechanistic insights into the role of traditional Chinese medicine in treating gastric cancer.
Harnessing amino acid pathways to influence myeloid cell function in tumor immunity.
Chemotherapy boosts anti-angiogenic and anti-PD-1 combination therapy through activation of cCAS-STING pathway in colon cancer.
Melanoma-derived cytokines and extracellular vesicles are interlinked with macrophage immunosuppression.
Redefining bladder cancer treatment: innovations in overcoming drug resistance and immune evasion.
Targeting secretory autophagy in solid cancers: mechanisms, immune regulation and clinical insights.
Immunometabolism of Tregs: mechanisms, adaptability, and therapeutic implications in diseases.
Mechanisms of T-cell Depletion in Tumors and Advances in Clinical Research.
Applications and enhancement strategies of ROS-based non-invasive therapies in cancer treatment.
The role of exosomal non-coding RNAs in the breast cancer tumor microenvironment.
Ribosomal RNA Biosynthesis Functionally Programs Tumor-Associated Macrophages to Support Breast Cancer Progression.
CCR8: a promising therapeutic target against tumor-infiltrating regulatory T cells.
Cell-associated galectin 9 interacts with cytotoxic T cells confers resistance to tumor killing in nasopharyngeal carcinoma through autophagy activation.
Role of bacteria in cancers and their therapeutic potential: Review of current knowledge.
Nanocarrier-mediated modulation of cGAS-STING signaling pathway to disrupt tumor microenvironment.
Tracking tumor-associated macrophages.
Predicting immunotherapy efficacy in endometrial cancer: focus on the tumor microenvironment.
Immunoglobulin-like transcript 5 polarizes M2-like tumor-associated macrophages for immunosuppression in non-small cell lung cancer.
HDAC1-3 inhibition triggers NEDD4-mediated CCR2 downregulation and attenuates immunosuppression in myeloid-derived suppressor cells.

Mol Cancer Res. 2025 Feb 03.

Tumor microenvironment: obstacles and opportunities for T-cell based tumor immunotherapies.

Miao-Miao Hu, Ying Zhao, Nan Zhang, Fang-Yuan Gong, Wei Zhang, Chun-Sheng Dong, Jian-Feng Dai, Jun Wang.

The complex composition and dynamic change of the tumor microenvironment (TME), mainly consisting of tumor cells, immune cells, stromal cells and extracellular components, significantly impedes the effector function of cytotoxic T cells (CTLs) and thus represents a major obstacle for tumor immunotherapies. In this review, we summarize and discuss the impacts and underlying mechanisms of major elements in the TME (different cell types, extracellular matrix, nutrients and metabolites, etc.) on the infiltration, survival and effector functions of T cells, mainly CD8+ CTLs. Moreover, we also highlight recent advances that may potentiate endogenous anti-tumor immunity and improve the efficacy of T-cell based immunotherapies in cancer patients by manipulating components inside/outside of the TME. A deeper understanding of the effects and action mechanisms of TME components on the tumor-eradicating ability of CTLs may pave the way for discovering new targets to augment endogenous anti-tumor immunity and for designing combinational therapeutic regimens to enhance the efficacy of tumor immunotherapies in clinic.

DOI: https://doi.org/10.1158/1541-7786.MCR-24-0747
Cytokine Growth Factor Rev. 2025 Jan 17. pii: S1359-6101(25)00003-6. [Epub ahead of print]

Insights into IL-6/JAK/STAT3 signaling in the tumor microenvironment: Implications for cancer therapy.

Win Lwin Thuya, Yang Cao, Paul Chi-Lui Ho, Andrea Li-Ann Wong, Lingzhi Wang, Jianbiao Zhou, Christophe Nicot, Boon Cher Goh.

  The IL-6/JAK/STAT3 signaling pathway is a key regulator of tumor progression, immune evasion, and therapy resistance in various cancers. Frequently dysregulated in malignancies, this pathway drives cancer cell growth, survival, angiogenesis, and metastasis by altering the tumor microenvironment (TME). IL-6 activates JAK kinases and STAT3 through its receptor complex, leading to the transcription of oncogenic genes and fostering an immunosuppressive TME. This environment recruits tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and regulatory T cells (Tregs), collectively supporting immune evasion and tumor growth. IL-6/JAK/STAT3 axis also contributes to metabolic reprogramming, such as enhanced glycolysis and glutathione metabolism, helping cancer cells adapt to environmental stresses. Therapeutic targeting of this pathway has gained significant interest. Strategies include monoclonal antibodies against IL-6 or its receptor (e.g., Tocilizumab, Siltuximab), JAK inhibitors (e.g., Ruxolitinib), and STAT3-specific inhibitors (e.g., Napabucasin), which have exhibited promise in preclinical and initial clinical studies. These inhibitors can suppress tumor growth, reverse immune suppression, and enhance the efficacy of immunotherapies like immune checkpoint inhibitors. Combination therapies that integrate IL-6 pathway inhibitors with conventional treatments are particularly promising, addressing resistance mechanisms and improving patient outcomes. Advances in biomarker-driven patient selection, RNA-based therapies, and isoform-specific inhibitors pave the way for more precise interventions. This review delves into the diverse roles of IL-6/JAK/STAT3 signaling in cancer progression, therapeutic strategies targeting this pathway, and the potential for integrating these approaches into personalized medicine to enhance treatment outcomes.

Keywords:  Cancer immunotherapy; Cytokine signaling; IL-6 signaling; JAK/STAT3 pathway; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1016/j.cytogfr.2025.01.003
Front Immunol. 2025 ;16 1519841

Tumor cells escape immunosurveillance by hampering LFA-1.

Shishir Upadhyay, Lewis Murugu, Lena Svensson.

  During tumor immunosurveillance, leukocytes play a crucial role in the cellular defense system, working collaboratively with other immune components to recognize and eliminate aberrant cells. Integral to this process is the integrin Lymphocyte Function-Associated Antigen 1 (LFA-1). LFA-1 facilitates adhesion during leukocyte migration and helps establish stable cell-to-cell contacts between leukocytes and their targets. Additionally, as a receptor, LFA-1 signaling activates leukocytes, promoting their differentiation and effector functions against cancer. However, tumors can develop mechanisms to evade immune clearance by disrupting LFA-1 functions or hijacking its pathways. In this review, we first detail how leukocytes utilize LFA-1 during immunosurveillance and then explore how tumors counteract this process in the tumor microenvironment (TME) by either altering LFA-1 functions or exploiting it to drive tumorigenesis. Moreover, we discuss therapeutic strategies targeting LFA-1, including inhibitors tested in laboratory studies and animal models, highlighting their potential as anticancer interventions and the need for further research to evaluate their clinical utility.

Keywords:  LFA-1; TME; cancer; immune escape; immunosurveillance; leukocytes

DOI:  https://doi.org/10.3389/fimmu.2025.1519841
Front Immunol. 2025 ;16 1548527

Progress in immune microenvironment, immunotherapy and prognostic biomarkers in pediatric osteosarcoma.

Lin Zhang, Haoming Jiang, Haichao Ma.

  Pediatric osteosarcoma, the most prevalent primary malignant bone tumor in children, is marked by aggressive progression and a generally poor prognosis. Despite advances in treatment, including multi-agent chemotherapy, survival rates remain suboptimal, with metastasis, particularly to the lungs, contributing significantly to mortality. The tumor microenvironment plays a crucial role in osteosarcoma progression, with immune cells such as tumor-associated macrophages and T lymphocytes significantly influencing tumor behavior. The immunosuppressive environment, dominated by M2 macrophages, contributes to immune evasion and poor therapeutic outcomes, though recent findings suggest the potential for reprogramming these cells to enhance immune responses. This review provides a comprehensive overview of the immune landscape in pediatric osteosarcoma, with a focus on the role of immune cells and their interactions within the tumor microenvironment (TME). It examines the impact of immune checkpoints, genetic mutations, and inflammatory pathways on osteosarcoma progression, highlighting their contribution to tumor immune evasion and disease advancement. Additionally, emerging immunotherapeutic strategies, such as immune checkpoint inhibitors, macrophage reprogramming, and antibody-based therapies, are summarized in detail, showcasing their potential to improve therapeutic outcomes.

Keywords:  ICB; PD-1; biomarkers; immunosuppressive environment; immunotherapy; pediatric osteosarcoma

DOI:  https://doi.org/10.3389/fimmu.2025.1548527
Int J Biol Sci. 2025 ;21(3): 1202-1221

Revisiting of Cancer Immunotherapy: Insight from the Dialogue between Glycolysis and PD-1/PD-L1 Axis in the Tumor Microenvironment.

Qiong Liu, Zihan Liu, Xi Zhang, Anqi Zeng, Linjiang Song.

  The interplay between metabolic pathways and immune escape has emerged as a captivating research area in oncobiology. Among these, the Warburg effect stands out as a hallmark metabolic reprogramming in cancer, characterized by elevated glucose utilization and excessive lactic acid production through anaerobic glycolysis. Key glycolytic enzymes not only fulfill the bioenergetic demands of cancer cells but also exhibit moonlighting roles, including regulation of epigenetic modifications, protein kinase activity, and immune escape mechanisms, thereby reshaping the tumor microenvironment. Tumor-specific vascular architecture facilitates lactate accumulation, which drives tumor progression by impairing immune cell function and acting as a signaling molecule to recruit immunosuppressive cells and modulate immune checkpoint pathways. The PD-1/PD-L1 co-stimulatory pathway plays a crucial role in negatively modulating the activation, proliferation, and cytokine secretion by T-lymphocytes. This review primarily focuses on elucidating the regulation and mechanisms underlying PD-1/PD-L1 signaling axis during glycolysis in tumor cells as well as surrounding cells. In the era of precision medicine, there is a particular interest in leveraging 18F-FDG PET/CT imaging as a valuable tool to assess PD-L1 expression status for more targeted therapeutic interventions. Additionally, the development of natural compounds capable of modulating metabolism opens new avenues for metabolism-based immunotherapy, though further studies are required to validate their in vivo efficacy.

Keywords:  Glycolysis; Lactate; PD-1/PD-L1; Tumor microenvironment; immunotherapy

DOI:  https://doi.org/10.7150/ijbs.104079
J Immunother Cancer. 2025 Feb 04. pii: e010824. [Epub ahead of print]13(2):

Modulating lipid metabolism improves tumor immunotherapy.

Yu Ping, Qiuqing Fan, Yi Zhang.

  Immunotherapy has progressed significantly in cancer treatment; however, several factors influence its outcomes. Abnormal lipid metabolism, which is frequently observed in cancers, promotes tumor proliferation, invasion, and metastasis. Li et al from the Medical Oncology Department of Chongqing University Cancer Hospital constructed a lipid metabolism scoring system and reported that MK1775 inhibited fatty acid oxidation in tumor-associated macrophages and reduced T-cell infiltration, further enhancing the efficacy of immunotherapy. This study demonstrated the critical role of lipid metabolism scoring system and lipid metabolism in immunotherapy. Currently, the metabolism of lipids, such as fatty acids, phospholipids, and cholesterol, has been reported to affect the tumor microenvironment by regulating immune cells, including T cells, natural killer cells, and macrophages. These metabolic changes can impair the efficacy of immunotherapy, resulting in tumor progression. Consequently, lipid metabolism emerges as an important immune regulator for improving immunotherapeutic outcomes and provides a novel and powerful strategy for tumor combination therapy.

Keywords:  Immunotherapy

DOI:  https://doi.org/10.1136/jitc-2024-010824
Int J Biol Macromol. 2025 Jan 29. pii: S0141-8130(25)00967-5. [Epub ahead of print]301 140418

High antigen-presenting CAF levels correlate with reduced glycosaminoglycan biosynthesis-heparan sulfate/heparin metabolism in immune cells and poor prognosis in esophageal squamous cell carcinoma: Insights from bulk and single-cell transcriptome profiling.

Siliang Wang, Kelly Van Van, Miaomiao Zheng, Wen-Lian Chen, Yu-Shui Ma.

  In esophageal squamous cell carcinoma (ESCC), the tumor microenvironment (TME) is characterized by a significant accumulation of cancer-associated fibroblasts (CAFs), which play a pivotal role in the host response against tumor cells. While fibroblasts are known to be crucial in the metabolic reprogramming of the TME, the specific metabolic alterations induced by these cells remain largely undefined. Utilizing single-cell RNA sequencing, we have identified a distinct subpopulation of antigen-presenting CAF (apCAF) within ESCC tumors. Our findings reveal that apCAF contribute to adverse patient outcomes by remodeling the tumor metabolic environment. Notably, apCAF modulate the glycosaminoglycan biosynthesis-heparan sulfate/heparin metabolism pathway in T cells, B cells, and macrophages. Disruption of this pathway may facilitate immune evasion by the tumor. These insights underscore the critical role of CAFs in shaping the metabolic landscape of the TME and lay the groundwork for developing therapeutic strategies aimed at enhancing anti-tumor immunity.

Keywords:  Antigen-presenting CAF; Esophageal squamous cell carcinoma; Glycosaminoglycan biosynthesis-heparan sulfate/heparin metabolism; Immune cell

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.140418
Front Oncol. 2024 ;14 1524651

Targeting the kynurenine pathway: another therapeutic opportunity in the metabolic crosstalk between cancer and immune cells.

Irene Kang, George Theodoropoulos, Medhi Wangpaichitr.

  The pivotal role of metabolic reprogramming in cancer-related drug resistance, through the tryptophan-catabolized kynurenine pathway (KP), has been particularly underscored in recent research. This pathway, driven by indoleamine 2,3-dioxygenase 1 (IDO1), facilitates immune evasion and promotes tumor progression by fostering an immunosuppressive environment. In Phase III investigation of the combination of IDO1 inhibition with immune checkpoint inhibitors (ICIs), the combination therapy was not efficacious. In this review, we revisit current advances, explore future directions, and emphasize the importance of dual inhibition of the KP rate-limiting enzymes IDO1 and tryptophan 2,3-dioxygenase-2 (TDO2) in appropriate patient populations. We propose that dual inhibition may maximize the therapeutic potential of KP inhibition. Additionally, we delve into the complex cellular interactions in cancer and metabolic dependencies within the tumor microenvironment (TME). Insights from preclinical studies, recent clinical trials, and promising therapeutic combinations will be discussed to elucidate and promote a clear path forward for the direction of KP research into cancer-related outcomes.

Keywords:  drug resistance; dual inhibitors; immunometabolism; kynurenine; lung cancer; metabolism

DOI:  https://doi.org/10.3389/fonc.2024.1524651
Adv Mater. 2025 Feb 02. e2415550

Anti-Tumor Strategies Targeting Nutritional Deprivation: Challenges and Opportunities.

Jinsheng Shi, Wei Han, Jie Wang, Xiaoying Kong.

  Higher and richer nutrient requirements are typical features that distinguish tumor cells from AU: cells, ensuring adequate substrates and energy sources for tumor cell proliferation and migration. Therefore, nutrient deprivation strategies based on targeted technologies can induce impaired cell viability in tumor cells, which are more sensitive than normal cells. In this review, nutrients that are required by tumor cells and related metabolic pathways are introduced, and anti-tumor strategies developed to target nutrient deprivation are described. In addition to tumor cells, the nutritional and metabolic characteristics of other cells in the tumor microenvironment (including macrophages, neutrophils, natural killer cells, T cells, and cancer-associated fibroblasts) and related new anti-tumor strategies are also summarized. In conclusion, recent advances in anti-tumor strategies targeting nutrient blockade are reviewed, and the challenges and prospects of these anti-tumor strategies are discussed, which are of theoretical significance for optimizing the clinical application of tumor nutrition deprivation strategies.

Keywords:  intelligent delivery systems; metabolic pathways; nutrients; nutritional deprivation; tumor cells

DOI:  https://doi.org/10.1002/adma.202415550
Int J Biol Sci. 2025 ;21(3): 1110-1126

Tumor-associated macrophages drive heterogenetic CD10High cancer stem cells to implement tumor-associated neutrophils reprogramming in oral squamous cell carcinoma.

Yuanhe You, Zhong Du, Zhuowei Tian, Shunshun Li, Fan Yu, Meng Xiao, Yue He, Yanan Wang.

  Tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) widely participate in the malignant progression in cancer. Previously, we have demonstrated that M1-like TAMs cascaded a stem-like phenotype of oral squamous cell carcinoma (OSCC). Yet, the underlying mechanisms still need to be demonstrated for the regulation of TAMs on cancer stem cells (CSCs) in OSCC. In this study, we investigated a group of CSCs with increased expression of cluster differentiation 10 (CD10), which acted as a mediator in the interaction network between TAMs and tumor-associated neutrophils (TANs) in OSCC. The results showed a significant association between TAMs infiltrations and increased expression of CD10 among all the CSCs-related molecules in OSCC. Then, we validated that OSCC cells with high CD10 expression possessed increased CSCs characteristics. TAMs could drive the heterogenetic CD10High CSCs by activating the IL6/STAT3/CD10 pathway. Furthermore, CD10High CSCs could recruit and reprogram tumor-associated neutrophils (TANs) in an immunosuppressive state by secreting S100A8/A9 in OSCC. These finding indicated that CD10High CSCs played great roles in signaling crosstalk between TAMs and TANs in OSCC, by which infiltrated TAMs drive CD 10High CSCs to recruit and reprogram TANs in an immunosuppressive state. Herein, we managed to demonstrate that TAMs could directly regulate a heterogenetic cluster of CSCs with high CD10 expression, and CD10High CSCs could recruit and reprogram TANs in OSCC. The novel crosstalk among OSCC-TAMs-CD10High CSCs-TANs might bring new prospects for improving the treatment strategies for OSCC patients.

Keywords:  CD10; cancer stem cells; immune reprogramming; tumor-associated macrophage; tumor-associated neutrophil

DOI:  https://doi.org/10.7150/ijbs.100611
Mol Oncol. 2025 Feb 05.

Decoding multicellular interaction networks-a new horizon in tumor microenvironment research.

Roi Balaban, Merav Cohen.

  The tumor microenvironment (TME) milieu directs a plethora of tumor-modulating functions. Recent years have seen pivotal breakthroughs in our understanding of the TME's role in tumor initiation and progression, with tangible clinical applications. Individual components of the TME exert their function predominantly by cell-cell crosstalk, both in the form of physical interaction and secreted factors. Notably, different spatial niches represent exclusive signaling hubs in the TME, propagating pro- or antitumoral functions. The exploration of these interactions has been vastly facilitated by novel molecular technologies, each of which provides a different perspective on this intricate intercellular communication network. Together, these complementary methods paint a detailed, high-resolution map of the TME's interaction landscape. In this viewpoint, we explore how cellular interactions can unlock a new level of understanding of TME complexity, and discuss the promises and challenges of characterizing tumors based on their cellular interaction footprint.

Keywords:  PIC‐seq; cell–cell communication; personalized medicine; scRNA‐seq; spatial niches; tumor microenvironment

DOI:  https://doi.org/10.1002/1878-0261.13810
Adv Sci (Weinh). 2025 Feb 03. e2417357

Effect of Extracellular Vesicles Derived From Tumor Cells on Immune Evasion.

Xuanfan Liu, Kenneth K W To, Qinsong Zeng, Liwu Fu.

  The crosstalk between immunity and cancer in the regulation of tumor growth is considered a hallmark of cancer. Antitumor immunity refers to the innate and adaptive immune responses that regulate cancer development and proliferation. Tumor immune evasion represents a major hindrance to effective anticancer treatment. Extracellular vesicles (EVs) are nano-sized and lipid-bilayer-enclosed particles that are secreted to the extracellular space by all cell types. They are critically involved in numerous biological functions including intercellular communication. Tumor-derived extracellular vesicles (TEVs) can transport a variety of cargo to modulate immune cells in the tumor microenvironment (TME). This review provides the latest update about how tumor cells evade immune surveillance by exploiting TEVs. First, the biogenesis of EVs and the cargo-sorting machinery are discussed. Second, how tumor cells modulate immune cell differentiation, activation, and function via TEVs to evade immune surveillance is illustrated. Last but not least, the novel antitumor strategies that can reverse immune escape are summarized.

Keywords:  extracellular vesicles; immune evasion; immunotherapy; targeted therapies; tumor microenvironment

DOI:  https://doi.org/10.1002/advs.202417357
Cell Rep Med. 2025 Jan 30. pii: S2666-3791(25)00004-7. [Epub ahead of print] 101931

CAR T cells, CAR NK cells, and CAR macrophages exhibit distinct traits in glioma models but are similarly enhanced when combined with cytokines.

Thomas Look, Roman Sankowski, Manon Bouzereau, Serena Fazio, Miaomiao Sun, Alicia Buck, Niklas Binder, Maximilian Mastall, Francesco Prisco, Frauke Seehusen, Julia Frei, Conrad Wyss, Berend Snijder, Cesar Nombela Arrieta, Michael Weller, Steve Pascolo, Tobias Weiss.

  Chimeric antigen receptor (CAR) T cell therapy is a promising immunotherapy against cancer. Although there is a growing interest in other cell types, a comparison of CAR immune effector cells in challenging solid tumor contexts is lacking. Here, we compare mouse and human NKG2D-CAR-expressing T cells, natural killer (NK) cells, and macrophages against glioblastoma, the most aggressive primary brain tumor. Invitro we show that T cell cancer killing is CAR dependent, whereas intrinsic cytotoxicity overrules CAR dependence for NK cells, and CAR macrophages reduce glioma cells in co-culture assays. In orthotopic immunocompetent glioma mouse models, systemically administered CAR T cells demonstrate superior accumulation in the tumor, and each immune cell type induces distinct changes in the tumor microenvironment. An otherwise low therapeutic efficacy is significantly enhanced by co-expression of pro-inflammatory cytokines in all CAR immune effector cells, underscoring the necessity for multifaceted cell engineering strategies to overcome the immunosuppressive solid tumor microenvironment.

Keywords:  CAR immune cells; glioblastoma; immune regulation; mRNA transfection; preclinical studies; single-cell sequencing; tumor homing

DOI:  https://doi.org/10.1016/j.xcrm.2025.101931
Cancer Immunol Immunother. 2025 Feb 04. 74(3): 100

Emerging insights into intravital imaging, unraveling its role in cancer immunotherapy.

Minfeng Yang, Shiqiang Hou, Yao Chen, Hongzhao Chen, Minjie Chu, Song-Bai Liu.

  Cancer immunotherapy has attracted great attention as a potential therapeutic approach for advanced malignancies due to its promising survival benefits. Comprehension of intricate interactions between the tumor microenvironment (TME) and immune checkpoint inhibitors (ICIs) is crucial for optimizing and improving immunotherapies. Currently, several experimental strategies are available to monitor this complexity but most of them fail to facilitate real-time monitoring of the immune response such as cellular phagocytosis and cytolysis. Consequently, the application of intravital imaging has been extensively studied in the domain of cancer immunotherapy. Intravital imaging has been proven to be a powerful real-time imaging modality that provides insights into intratumoral immune responses, cellular metabolic signatures, tumor vasculature, and cellular functions. This review aims to provide a comprehensive overview of the latest research on intravital imaging in cancer immunotherapy, especially addressing how intravital imaging sheds light on essential features of tumor immunity, immune infiltrations, tumor angiogenesis, and aids in the clarification of underlying immunotherapeutic mechanisms. Moreover, a variety of labeling tools, imaging windows and models for real-time visualizations of TME are also summarized. We will also investigate the full potential of using intravital imaging to circumvent the limitations of currently available imaging modalities, which hold promise to advent efficient immunotherapy for cancer patients.

Keywords:  Imaging windows; Immunotherapy; Intravital imaging; Tumor angiogenesis; Tumor immunity

DOI:  https://doi.org/10.1007/s00262-025-03944-1
J Exp Med. 2025 Apr 07. pii: e20240445. [Epub ahead of print]222(4):

Regulatory T cells converted from Th1 cells in tumors suppress cancer immunity via CD39.

Sang-Nee Tan, Jing Hao, Jing Ge, Yazheng Yang, Liguo Liu, Jia Huang, Meng Lin, Xiaohong Zhao, Genyu Wang, Zhiying Yang, Ling Ni, Chen Dong.

Regulatory T (Treg) cells are known to impede antitumor immunity, yet the regulatory mechanisms and functional roles of these cells remain poorly understood. In this study, through the characterization of multiple cancer models, we identified a substantial presence of peripherally induced Treg cells in the tumor microenvironment (TME). Depletion of these cells triggered antitumor responses and provided potent therapeutic effects by increasing functional CD8+ T cells. Fate-mapping and transfer experiments revealed that IFN-γ-expressing T helper (Th) 1 cells differentiated into Treg cells in response to TGF-β signaling in tumors. Pseudotime trajectory analysis further revealed the terminal differentiation of Th1-like Treg cells from Th1 cells in the TME. Tumor-resident Treg cells highly expressed T-bet, which was essential for their functions in the TME. Additionally, CD39 was highly expressed by T-bet+ Treg cells in both mouse and human tumors, and was necessary for Treg cell-mediated suppression of CD8+ T cell responses. Our study elucidated the developmental pathway of intratumoral Treg cells and highlighted novel strategies for targeting them in cancer patients.

DOI: https://doi.org/10.1084/jem.20240445
Front Oncol. 2024 ;14 1443686

Mechanistic insights into the role of traditional Chinese medicine in treating gastric cancer.

Ziqiang Chen, Ting Yu, Yunhe Wang, Jiaxin Li, Bo Zhang, Liya Zhou.

  Gastric cancer remains a leading cause of cancer-related mortality worldwide, with advanced stages presenting significant challenges due to metastasis and drug resistance. Traditional Chinese Medicine (TCM) offers a promising complementary approach characterized by holistic treatment principles and minimal side effects. This review comprehensively explores the multifaceted mechanisms by which TCM addresses gastric cancer. Specifically, we detail how TCM inhibits aerobic glycolysis by downregulating key glycolytic enzymes and metabolic pathways, thereby reducing the energy supply essential for cancer cell proliferation. We examine how TCM suppresses angiogenesis by targeting the vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) pathways, effectively starving tumors of nutrients and oxygen required for growth and metastasis. Furthermore, TCM modulates the immune microenvironment by enhancing the activity of effector immune cells such as CD4+ and CD8+ T cells and natural killer (NK) cells while reducing immunosuppressive cells like regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). These actions collectively contribute to slowing tumor progression, inhibiting metastasis, and enhancing the body's antitumor response. The insights presented underscore the significant potential of TCM as an integral component of comprehensive gastric cancer treatment strategies, highlighting avenues for future research and clinical application to improve patient outcomes.

Keywords:  aerobic glycolysis; anti-angiogenesis; gastric cancer; immunomodulation; immunotherapy; molecular markers; traditional Chinese medicine (TCM); tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2024.1443686
Mol Med. 2025 Feb 04. 31(1): 44

Harnessing amino acid pathways to influence myeloid cell function in tumor immunity.

Jiongli Pan, Yi Lin, Xinyuan Liu, Xiaozhen Zhang, Tingbo Liang, Xueli Bai.

  Amino acids are pivotal regulators of immune cell metabolism, signaling pathways, and gene expression. In myeloid cells, these processes underlie their functional plasticity, enabling shifts between pro-inflammatory, anti-inflammatory, pro-tumor, and anti-tumor activities. Within the tumor microenvironment, amino acid metabolism plays a crucial role in mediating the immunosuppressive functions of myeloid cells, contributing to tumor progression. This review delves into the mechanisms by which specific amino acids-glutamine, serine, arginine, and tryptophan-regulate myeloid cell function and polarization. Furthermore, we explore the therapeutic potential of targeting amino acid metabolism to enhance anti-tumor immunity, offering insights into novel strategies for cancer treatment.

Keywords:  Amino acid metabolism; Cancer immunotherapy; Immunometabolism; Metabolic reprogramming; Myeloid cells

DOI:  https://doi.org/10.1186/s10020-025-01099-4
Int Immunopharmacol. 2025 Feb 03. pii: S1567-5769(25)00202-4. [Epub ahead of print]149 114212

Chemotherapy boosts anti-angiogenic and anti-PD-1 combination therapy through activation of cCAS-STING pathway in colon cancer.

Xiaofei Li, Yuwen Dong, Tingyu Wang, Kai Huang, Wenjie Guo, Lingyan Xu, Yanhong Gu.

  Recent clinical trials have shown that combining chemotherapy with anti-angiogenic therapy and immunotherapy can enhance survival outcomes for patients with advanced colorectal cancer (CRC). However, the underlying mechanisms remain unclear. To address this knowledge gap, we investigated the effects and potential mechanisms of combining oxaliplatin with the anti-angiogenic drug fruquintinib and a PD-1 monoclonal antibody. Our findings indicate that this combination improves vascular conditions within the tumor microenvironment (TME), thereby downregulating the expression of hypoxia inducible factor-1α (HIF-1α), and alleviating tumor hypoxia. Moreover, the inclusion of oxaliplatin activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in the TME, and further increases the proportion of cytotoxic T cells, dendritic cells (DC) and natural killer (NK) cells in the TME without elevating immunosuppressive cells, such as regulatory T cells (Tregs) and M2-type macrophages, thus creating a more immunoreactive microenvironment that effectively inhibits colon tumor growth. Importantly, these results provide a theoretical basis for the clinical application of this three-agent regimen and offer new insights into combination therapy strategies for CRC treatment.

Keywords:  Anti-angiogenic therapy; Chemotherapy; Colorectal cancer; Immunotherapy; cGAS-STING

DOI:  https://doi.org/10.1016/j.intimp.2025.114212
Front Mol Biosci. 2024 ;11 1522717

Melanoma-derived cytokines and extracellular vesicles are interlinked with macrophage immunosuppression.

Shankar Suman, Wendy K Nevala, Alexey A Leontovich, James W Jakub, Liyi Geng, Sarah A McLaughlin, Svetomir N Markovic.

  Cytokines play a crucial role in mediating cell communication within the tumor microenvironment (TME). Tumor-associated macrophages are particularly influential in the regulation of immunosuppressive cytokines, thereby supporting tumor metastasis. The upregulation of Th2 cytokines in cancer cells is recognized for its involvement in suppressing anticancer immunity. However, the association between these cytokines and tumor-secreted extracellular vesicles (EVs) remains poorly understood. Therefore, our objective was to investigate the connection between tumor-promoting macrophages and melanoma-derived EVs. The analysis from altered cytokine profile data showed that melanoma-derived EVs upregulate Th2 cytokine expression in naïve macrophages, thereby contributing to the promotion of tumor-supporting functions. Notably, many of these cytokines were also found to be upregulated in metastatic melanoma patients (n = 30) compared to healthy controls (n = 33). Overall, our findings suggest a strong connection between melanoma secretory EVs and the induction of tumor-associated macrophages that facilitates the development of an immunosuppressive TME, supporting melanoma metastasis through regulation at both local and systemic levels.

Keywords:  cytokines; extracellular vesicles; immunosuppression; melanoma; tumor microenvironment; tumor-promoting macrophage

DOI:  https://doi.org/10.3389/fmolb.2024.1522717
Front Immunol. 2025 ;16 1537808

Redefining bladder cancer treatment: innovations in overcoming drug resistance and immune evasion.

Peng Huang, Jie Wang, Zongze Yu, Jiaan Lu, Zhou Sun, Zhigui Chen.

  Bladder cancer is one of the most common malignancies of the urinary system and has always presented great challenges in treatment due to its intricate biological features and high recurrence rates. Although great developments were achieved in immunotherapy and targeted therapies within the last decade, therapeutic outcomes for a great number of patients remain unsatisfactory, particularly as to long-term efficacy. Review discusses the molecular mechanisms developed during the process of bladder cancer progression: genetic and epigenetic alterations, dynamics of the tumor microenvironment (TME), and dysregulation and abnormal activation of various signaling pathways-all contributing to therapeutic resistance. It is genetic mutation, especially in both low- and high-grade tumors, that, alongside epigenetic modifications, plays a considerable role in tumor aggressiveness and drug resistance. TME, comprising cancer-associated fibroblasts (CAFs), immunosuppressive cells, and different components of the extracellular matrix (ECM), orchestrates a setting that fosters tumor growth and immune evasion and confers resistance on any therapeutic regime that might be used. The review also provides an overview of PI3K/AKT and MAPK signaling pathways in the progression of bladder cancer and the development of targeted therapies against them. Further, it discusses the challenges and mechanisms of resistance to immunotherapy, including those involving immune checkpoint inhibitors. Other promising approaches include the development of new therapeutic strategies that target not only the signaling pathways but also immune checkpoints in combination therapies. This review aims to contribute to the elaboration of more effective and personalized treatment strategies by fully understanding the underlying mechanisms involved in bladder cancer.

Keywords:  bladder cancer; combined therapy; drug resistance; precision therapy; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1537808
Exp Hematol Oncol. 2025 Feb 01. 14(1): 12

Targeting secretory autophagy in solid cancers: mechanisms, immune regulation and clinical insights.

Xinyu Li, Haiying Zhao.

Secretory autophagy is a classical form of unconventional secretion that integrates autophagy with the secretory process, relying on highly conserved autophagy-related molecules and playing a critical role in tumor progression and treatment resistance. Traditional autophagy is responsible for degrading intracellular substances by fusing autophagosomes with lysosomes. However, secretory autophagy uses autophagy signaling to mediate the secretion of specific substances and regulate the tumor microenvironment (TME). Cytoplasmic substances are preferentially secreted rather than directed toward lysosomal degradation, involving various selective mechanisms. Moreover, substances released by secretory autophagy convey biological signals to the TME, inducing immune dysregulation and contributing to drug resistance. Therefore, elucidating the mechanisms underlying secretory autophagy is essential for improving clinical treatments. This review systematically summarizes current knowledge of secretory autophagy, from initiation to secretion, considering inter-tumor heterogeneity, explores its role across different tumor types. Furthermore, it proposes future research directions and highlights unresolved clinical challenges.

DOI: https://doi.org/10.1186/s40164-025-00603-0
Front Immunol. 2025 ;16 1536020

Immunometabolism of Tregs: mechanisms, adaptability, and therapeutic implications in diseases.

Yuming Lu, Yifan Wang, Tiantian Ruan, Yihan Wang, Linling Ju, Mengya Zhou, Luyin Liu, Dengfu Yao, Min Yao.

  Immunometabolism is an emerging field that explores the intricate interplay between immune cells and metabolism. Regulatory T cells (Tregs), which maintain immune homeostasis in immunometabolism, play crucial regulatory roles. The activation, differentiation, and function of Tregs are influenced by various metabolic pathways, such as the Mammalian targets of rapamycin (mTOR) pathway and glycolysis. Correspondingly, activated Tregs can reciprocally impact these metabolic pathways. Tregs also possess robust adaptive capabilities, thus enabling them to adapt to various microenvironments, including the tumor microenvironment (TME). The complex mechanisms of Tregs in metabolic diseases are intriguing, particularly in conditions like MASLD, where Tregs are significantly upregulated and contribute to fibrosis, while in diabetes, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), they show downregulation and reduced anti-inflammatory capacity. These phenomena suggest that the differentiation and function of Tregs are influenced by the metabolic environment, and imbalances in either can lead to the development of metabolic diseases. Thus, moderate differentiation and inhibitory capacity of Tregs are critical for maintaining immune system balance. Given the unique immunoregulatory abilities of Tregs, the development of targeted therapeutic drugs may position them as novel targets in immunotherapy. This could contribute to restoring immune system balance, resolving metabolic dysregulation, and fostering innovation and progress in immunotherapy.

Keywords:  Tregs; immunometabolism; inflammation; metabolic diseases; metabolic pathways; microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1536020
Biol Proced Online. 2025 Feb 04. 27(1): 5

Mechanisms of T-cell Depletion in Tumors and Advances in Clinical Research.

Xiangfei Su, Mi Zhang, Hong Zhu, Jingwen Cai, Zhen Wang, Yuewei Xu, Li Wang, Chen Shen, Ming Cai.

  T lymphocytes (T cells) are essential components of the adaptive immune system that play a vital role in identifying and eliminating infected and tumor cells. In tumor immunotherapy, T cells have emerged as a promising therapeutic strategy due to their high specificity, potent cytotoxic capability, long-lasting immune memory, and adaptability within immunotherapeutic approaches. However, tumors can evade the immune system by depleting T cells through various mechanisms, such as inhibitory receptor signaling, metabolic exhaustion, and physical barriers within the tumor microenvironment. This review provided an overview of the mechanisms underlying T-cell depletion in tumors and discussed recent advances in clinical research related to T-cell immunotherapy for tumors. It highlighted the need for in-depth studies on key issues such as indications, dosage, and sequencing of combined therapeutic strategies tailored to different patients and tumor types, providing practical guidance for individualized treatment. Future research on T-cell depletion would be necessary to uncover the fundamental mechanisms and laws of T-cell depletion, offering both theoretical insights and practical guidance for the selection and optimization of tumor immunotherapy. Furthermore, interdisciplinary, cross-disciplinary, and international collaborative innovations are necessary for developing more effective and safer treatments for tumor patients.

Keywords:  T lymphocyte; T-cell depletion; Therapeutic strategy; Tumor immunotherapy

DOI:  https://doi.org/10.1186/s12575-025-00265-6
Redox Biol. 2025 Jan 28. pii: S2213-2317(25)00028-X. [Epub ahead of print]80 103515

Applications and enhancement strategies of ROS-based non-invasive therapies in cancer treatment.

Qiuyan Guo, Yingnan Tang, Shengmei Wang, Xinhua Xia.

  Reactive oxygen species (ROS) play a crucial role in the pathogenesis of cancer. Non-invasive therapies that promote intracellular ROS generation, including photodynamic therapy (PDT), sonodynamic therapy (SDT), and chemodynamic therapy (CDT), have emerged as novel approaches for cancer treatment. These therapies directly kill tumor cells by generating ROS, and although they show great promise in tumor treatment, many challenges remain to be addressed in practical applications. Firstly, the inherent complexity of the tumor microenvironment (TME), such as hypoxia and elevated glutathione (GSH) levels, hinders ROS generation, thereby significantly diminishing the efficacy of ROS-based therapies. In addition, these therapies are influenced by their intrinsic mechanisms. To overcome these limitations, various nanoparticle (NP) systems have been developed to improve the therapeutic efficacy of non-invasive therapies against tumors. This review first summarizes the mechanisms of ROS generation for each non-invasive therapy and their current limitations, with a particular focus on the enhancement strategies for each therapy based on NP systems. Additionally, various strategies to modulate the TME are highlighted. These strategies aim to amplify ROS generation in non-invasive therapies and enhance their anti-tumor efficiency. Finally, the current challenges and possible solutions for the clinical translation of ROS-based non-invasive therapies are also discussed.

Keywords:  Enhancement strategies; Nanoparticle; Non-invasive therapies; Reactive oxygen species; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.redox.2025.103515
Funct Integr Genomics. 2025 Feb 01. 25(1): 32

The role of exosomal non-coding RNAs in the breast cancer tumor microenvironment.

Mohamed J Saadh, Omer Qutaiba B Allela, Radhwan Abdul Kareem, Suhas Ballal, Mamata Chahar, Suman Saini, G V Siva Prasad, Hayder Naji Sameer, Atheer Khdyair Hamad, Zainab H Athab, Mohaned Adil.

  The leading form of cancer affecting females globally is breast cancer, characterized by an unregulated growth of cells within the breast. Therefore, examining breast tissue is crucial in accurately identifying and treating this disease. Exosomes are very small enclosures bounded by a layer of cells and produced by a variety of cells present in the cancerous tissue surroundings. They play a crucial role in several biological functions in cancerous tumors. These exosomes carry non-coding RNAs (ncRNAs) and are discharged into the TME, where they are instrumental in the development and advancement of tumors. Additionally, the ncRNAs enclosed in exosomes act as significant mediators of communication within cells. Consequently, there is limited comprehension regarding the precise roles and targets of exosomal RNA in regulation, as research in this area is still in its preliminary phases. This piece provides a comprehensive overview of the latest studies on exosomes, delving into their impact on the behavior of cancer cells and immune cells. Moreover, it presents a compilation of the diverse forms of non-coding RNA molecules found in exosomes released by both cancerous and supportive cells, including circular RNAs, microRNAs, and long non-coding RNAs. Current research has proven the noteworthy influence that non-coding RNA molecules have on the progression, proliferation, drug resistance, and immune responses of breast cancer cells.

Keywords:  Breast cancer; Exosome; Non-coding RNAs; Tumor microenvironment

DOI:  https://doi.org/10.1007/s10142-025-01531-2
Cancer Res. 2025 Feb 04.

Ribosomal RNA Biosynthesis Functionally Programs Tumor-Associated Macrophages to Support Breast Cancer Progression.

Brandon J Metge, Li'an Williams, Courtney A Swain, Dominique C Hinshaw, Amr R Elhamamsy, Dongquan Chen, Rajeev S Samant, Lalita A Shevde.

Macrophages are important cellular components of the innate immune system, serving as the first line of immune defense. They are also among the first immune cells to be reprogrammed by the evolving tumor milieu into tumor-supportive macrophages that facilitate tumor progression and promote therapeutic evasion. Here, we uncovered that macrophages from preneoplastic breast lesions were enriched for ribosome biosynthesis genes, indicating that this is an early event that is maintained in the tumor tissue. Furthermore, following treatment with irradiation or chemotherapy, breast tumors featured an abundance of tumor-supporting macrophages that displayed an enrichment of signatures of ribosomal RNA expression and ribosome biosynthesis. Consistently, rRNA synthesis was increased in tumor-supportive macrophages. In preclinical models of mammary cancer, a low dose of the RNA biogenesis inhibitor BMH-21 converted pro-tumor macrophages to tumor-suppressive macrophages and supported an inflammatory tumor microenvironment. Inhibition of rRNA transcription stimulated a nucleolar stress response that activated the p53 and NF-κB pathways, which orchestrated impaired ribosome biogenesis checkpoint signaling that induced an inflammatory program in macrophages. Finally, inhibiting ribosome biogenesis augmented the effectiveness of neoadjuvant therapy. Together, these findings provide evidence that ribosome biogenesis is a targetable dependency to reprogram the tumor immune microenvironment.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0707
Trends Immunol. 2025 Jan 30. pii: S1471-4906(25)00001-8. [Epub ahead of print]

CCR8: a promising therapeutic target against tumor-infiltrating regulatory T cells.

Yuanjia Wen, Yu Xia, Xiangping Yang, Huayi Li, Qinglei Gao.

  Tumor-infiltrating regulatory T (TI-Treg) cells constitute key components within the tumor microenvironment (TME) to suppress antitumor immunity and facilitate tumor progression. Although multiple therapies have been developed to eliminate TI-Treg cells, most of them exhibit only modest efficacy and harbor risks of inducing immune-related adverse events (irAEs). Recent studies demonstrate that CC chemokine receptor (CCR)8 is highly and specifically expressed on effector TI-Treg cells in mice and humans, highlighting CCR8 as a promising target for selective TI-Treg cell depletion in the treatment of various cancers. Here, we concentrate on the latest understanding of CCR8 regarding its expression, functions, and regulation, and summarize the current landscape of CCR8-targeted therapies. With favorable efficacy and safety, the latter represent an important class of next-generation putative cancer immunotherapies.

Keywords:  CCR8; cancer therapeutics; immunotherapy; regulatory T cells; tumor immunity

DOI:  https://doi.org/10.1016/j.it.2025.01.001
Cell Mol Immunol. 2025 Feb 05.

Cell-associated galectin 9 interacts with cytotoxic T cells confers resistance to tumor killing in nasopharyngeal carcinoma through autophagy activation.

Ngar-Woon Kam, Cho Yiu Lau, Jeffrey Yan Ho Lau, Xin Dai, Yusi Liang, Syrus Pak Hei Lai, Michael King Yung Chung, Valen Zhuoyou Yu, Wenting Qiu, Mengsu Yang, Corey Smith, Rajiv Khanna, Kwan Ming Ng, Wei Dai, Chi Ming Che, Victor Ho-Fun Lee, Dora L W Kwong.

  Immune effector cells, including cytotoxic T lymphocytes (CTLs) play essential roles in eliminating cancer cells. However, their functionality is often compromised, even when they infiltrate the tumor microenvironment (TME) or are transferred to cancer patients adoptively. In this study, we focused on galectin 9 (G9), an inhibitory ligand that we observed to be predominately positioned on the plasma membrane and readily interacts with CD8 + CTL in the TME of nasopharyngeal carcinoma (NPC). We discovered that cell-cell contact between activated effector CTLs and target tumor cells (TarTC) with G9 overexpression led to cellular death defects. Despite the formation of CTL-TarTC conjugates, there is no impact on the cell number nor viability of CTL, and the release of cytolytic content and associated activity were not completely abrogated. Instead, this interaction promoted autophagy and restricted necrosis in the TarTC. Furthermore, reducing G9 expression in tumor cells enhanced the suppressive effect on tumor growth upon adoptive transfer of activated effector CTL. Additionally, inhibiting autophagy effectively controlled tumor growth in cases of G9 overexpression. Therefore, we highlight the contribution of G9 in facilitating the resistance of NPC to CTL-mediated killing by inducing a selection-cell death state in tumor cells, characterized by increased autophagy and decreased necrosis.

Keywords:  Cell death; Cytotoxic T cells; Galectin 9; Immunotherapy; Nasopharyngeal carcinoma; Tumor microenvironment

DOI:  https://doi.org/10.1038/s41423-024-01253-8
Iran J Basic Med Sci. 2025 ;28(3): 273-282

Role of bacteria in cancers and their therapeutic potential: Review of current knowledge.

Wojciech Wawrety, Anna Kedziora.

  Cancers are extremely dynamic diseases that can actively cause refractorines to be gained from applied therapies, which is why they are at the forefront of deaths worldwide. In this literature review, we covered the most recent and important discoveries regarding the influence of human microbiota, including tumor bacteriome, on the development and treatment of cancer. Advances in research on microbial communities have enabled us to discover the role of the human microbiome in the development and course of this disease, helping us understand neoplasms better and design new potential therapies. As we show through our findings, by immunomodulation and the secretion of certain chemical substances, the correct bacteriome of the intestinal tract, respiratory system, or skin can protect humans against cancer development and help during the treatment process. Bacteria also reside inside tumors, forming part of the tumor microenvironment (TME), where they interact with immunological and cancer cells in many complex ways. Some bacteria, such as Pseudomonas aeruginosa or Akkermansia muciniphila, can stimulate anticancer cell-mediated immune responses or even directly lead to cancer cell death. We also present the clinical possibilities of using some live, usually modified bacteria to develop bacteriotherapies. Modifying the gut microbiome to stimulate standard treatment is also important. Research on the microbiome and cancer remains a challenging topic in microbiology, having a great potential for advancements in cancer therapy in the future, and is continuously becoming a more and more popular field of research, as shown by our statistical analysis of PubMed data.

Keywords:  Bacteria; Immunotherapy; Microbiota; Neoplasms; Tumor microenvironment

DOI:  https://doi.org/10.22038/ijbms.2024.77667.16798
Naunyn Schmiedebergs Arch Pharmacol. 2025 Feb 05.

Nanocarrier-mediated modulation of cGAS-STING signaling pathway to disrupt tumor microenvironment.

Sai Kiran S S Pindiprolu, Madhu Tanya Singh, Sai Varshini Magham, Chirravuri S Phani Kumar, Nagasen Dasari, Ramakrishna Gummadi, Praveen Thaggikuppe Krishnamurthy.

  The cGAS-STING signaling plays an important role in the immune response in a tumor microenvironment (TME) of triple-negative breast cancer (TNBC). The acute and controlled activation of cGAS-STING signaling results in tumor suppression, while chronic activation of cGAS-STING signaling results in immune-suppressive TME that could result in tumor survival. There is a need, therefore, to develop therapeutic strategies for harnessing tumor suppressive effects of cGAS-STING signaling while minimizing the risks associated with chronic activation. Combination therapies and nanocarriers-based delivery of cGAS-STING agonists have emerged as promising strategies in immunotherapy for controlled modulation of cGAS-STING signaling in cancer. These approaches aim to optimize the tumor suppressive effects of the cGAS-STING pathway while minimizing the challenges associated with modulators of cGAS-STING signaling. In the present review, we discuss recent advancements and strategies in combination therapies and nanocarrier-based delivery systems for effectively controlling cGAS-STING signaling in cancer immunotherapy. Further, we emphasized the significance of nanocarrier-based approaches for effective targeting of the cGAS-STING signaling, tackling resistance mechanisms, and overcoming key challenges like immune suppression, tumor heterogeneity, and off-target effects.

Keywords:  CGAS-STING pathway; Cancer advancement; Cancer microenvironment; Immune system activation; Immunotherapeutic interventions; Nanocarriers

DOI:  https://doi.org/10.1007/s00210-025-03835-3
Lab Anim (NY). 2025 Feb;54(2): 38

Tracking tumor-associated macrophages.

Alexandra Le Bras.

DOI: https://doi.org/10.1038/s41684-025-01511-w
Front Immunol. 2024 ;15 1523518

Predicting immunotherapy efficacy in endometrial cancer: focus on the tumor microenvironment.

Liubov A Tashireva, Irina V Larionova, Nikita A Ermak, Anastasia A Maltseva, Ekaterina I Livanos, Anna Yu Kalinchuk, Marina N Stakheyeva, Larisa A Kolomiets.

  Immunotherapy represents a groundbreaking therapeutic approach, based on the immune system's intrinsic capacity to interfere with tumor progression, that opens the horizons in the treatment of endometrial cancer. However, the clinical efficacy of immunotherapy is hampered by the development of resistance in patients. The resistance to immunotherapy is multifactorial mechanism, encompassed genetic and epigenetic alterations in tumor cells modulating immune checkpoint molecules, resulted in escaping immune surveillance. The tumor microenvironment can orchestrate an immunosuppressive milieu, attenuating the immune response and facilitating tumor progression. To overcome immunotherapeutic resistance in endometrial cancer we must bring to light the mechanisms of intricate interplay between neoplastic cells, the host immune system, and the tumor microenvironment. The identification of predictive biomarkers for immunotherapeutic response and the innovative agents capable of reversing resistance pathways must be developed. Our review summarizes accumulated data on the role of cells of the tumor microenvironment and their regulatory molecules in the mechanisms underlying therapeutic effects of immune checkpoint inhibitors, including resistance to therapy. Major question we raise here - which group of patients is the most favorable to achieve durable immunotherapy response in endometrial cancer?

Keywords:  endometrial cancer; immune checkpoint inhibitors; immunotherapy; predictive biomarkers; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1523518
Int J Cancer. 2025 Feb 05.

Immunoglobulin-like transcript 5 polarizes M2-like tumor-associated macrophages for immunosuppression in non-small cell lung cancer.

Huijun Xu, Xuebing Fu, Shuyun Wang, Yihui Ge, Lu Zhang, Juan Li, Fang Zhang, Yang Yang, Yifu He, Yuping Sun, Aiqin Gao.

  Immune checkpoint inhibitors (ICIs) have shifted the treatment paradigm of non-small cell lung cancer (NSCLC) over the last decade. Despite notable therapeutic advancements in responders, the response rate remains limited owing to the immunosuppressive tumor microenvironment (TME). Therefore, to improve the efficacy of ICIs, it is essential to explore alternative targets or signals that mediate immunosuppression. Immunoglobulin-like transcript (ILT) 5 is a negative regulator of immune activation in myeloid cells. However, the expression and function of ILT5 in NSCLC remain unknown. Here, we found that ILT5 was highly expressed in tumor-associated macrophages (TAMs) of NSCLC tissues and predicted poor patient survival. Functionally, ILT5 induces the M2-like polarization of TAMs, which subsequently decreases the density of T cells, and increases FOXP3+T cell accumulation, leading to an immunosuppressive TME. The combination of ILT5 expression with M2-like TAM density is a more reliable biomarker of patient survival than ILT5 expression alone. ILT5 knockout mitigates the reprogramming of TAM and T cell subsets toward immunosuppressive phenotypes and inhibits tumor growth in vivo. These findings highlight that ILT5 is a potential immunotherapeutic target and a promising prognostic biomarker for NSCLC.

Keywords:  M2‐like polarization; T cell immunity; immunoglobulin‐like transcript 5; non‐small cell lung cancer; tumor‐associated macrophages

DOI:  https://doi.org/10.1002/ijc.35360
Cancer Immunol Immunother. 2025 Feb 01. 74(3): 81

HDAC1-3 inhibition triggers NEDD4-mediated CCR2 downregulation and attenuates immunosuppression in myeloid-derived suppressor cells.

Zhiqi Xie, Jinjin Shao, Zeren Shen, Zhichao Ye, Yoshiaki Okada, Daisuke Okuzaki, Naoki Okada, Masashi Tachibana.

  Myeloid-derived suppressor cells (MDSCs) play a critical role in cancer progression and resistance, thus representing promising targets for immunotherapy. Despite the established role of histone deacetylases (HDACs) in epigenetic regulation of cell fate and function, their specific impact on MDSCs remains elusive. We sought to investigate the effects and underlying mechanisms of HDAC on MDSCs using various HDAC inhibitors. Our results indicate that HDAC1-3 inhibitors reduce CCR2 expression, a chemokine receptor that mediates the migration of monocytic (M-)MDSCs to tumors and attenuated the immunosuppressive activity of MDSCs. In an orthotropic hepatocellular carcinoma (HCC) murine model, HDAC1-3 inhibitors reduced the infiltration of M-MDSCs, increased the number of natural killer cells in tumors, and suppressed tumor growth. Our results also suggest that HDAC1-3 inhibitors potentiate the antitumor effects of anti-programmed cell death protein 1 antibodies. ATAC-seq and RNA-seq analyses revealed 115 genes epigenetically upregulated by HDAC1-3 inhibitors, primarily linked to transcriptional regulation and ubiquitination. We further elucidated that HDAC1-3 inhibitors facilitate CCR2 protein degradation through ubiquitination-mediated by NEDD4 E3 ligase. Our findings reveal a novel mechanism of action of HDAC1-3 inhibitors in MDSCs and suggest a potential synergistic immunotherapy strategy for clinical benefit in HCC.

Keywords:  CCR2; Hepatocellular carcinoma; Histone deacetylase; Myeloid-derived suppressor cells; NEDD4

DOI:  https://doi.org/10.1007/s00262-024-03931-y