bims-flamet 2025-08-17 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2025–08–17
25 papers selected by
Peio Azcoaga, Biodonostia HRI

Harnessing innate immunity against glioblastoma microenvironment.
Lipid metabolic reprogramming in tumor-associated macrophages: A key driver of functional polarization and tumor immunomodulation.
Targeting lipid metabolism to enhance cancer immunotherapy.
HPV infection and the immune microenvironment in cervical cancer.
Targeting glycosylation to enhance tumor immunotherapy.
Immune Evasion in Head and Neck Squamous Cell Carcinoma: Roles of Cancer-Associated Fibroblasts, Immune Checkpoints, and TP53 Mutations in the Tumor Microenvironment.
Macrophages at the crossroads of cellular senescence and cancer development and progression: Therapeutic opportunities and challenges.
Classic versus innovative strategies for immuno-therapy in pancreatic cancer.
Therapeutic potential of targeting macrophages and microglia in glioblastoma.
Targeting RARγ Decreases Immunosuppressive Macrophage Polarization and Reduces Tumor Growth.
Harnessing intratumoral microbiota: new horizons in immune microenvironment and immunotherapy.
Metabolic Interactions in the Tumor Microenvironment of Classical Hodgkin Lymphoma: Implications for Targeted Therapy.
Endogenous macrophages as "Trojan horses" for targeted oral delivery of mRNA-encoded cytokines in tumor microenvironment immunotherapy.
Cancer-Associated Fibroblasts: Immunosuppressive Crosstalk with Tumor-Infiltrating Immune Cells and Implications for Therapeutic Resistance.
Neurotransmitters: an emerging target for therapeutic resistance to tumor immune checkpoint inhibitors.
CD24a knockout results in an enhanced macrophage- and CD8⁺ T cell-mediated anti-tumor immune responses in tumor microenvironment in a murine triple-negative breast cancer model.
Targeting LAG-3: Relatlimab, Fianlimab, and ieramilimab reshape the landscape of cancer combination immunotherapy.
Neutrophil Dynamics in Response to Cancer Therapies.
Exploring the Neurobiological Mechanisms of Cancer Growth.
In-depth insight into tumor-infiltrating stromal cells linked to tertiary lymphoid structures and their prospective function in cancer immunotherapy.
GABAergic signaling in colorectal cancer: Mechanistic insights, tumor microenvironment crosstalk, and therapeutic opportunities.
Transcriptional Repression of CCL2 by KCa3.1 K+ Channel Activation and LRRC8A Anion Channel Inhibition in THP-1-Differentiated M2 Macrophages.
Tumor-Immune Cell Interactions in Cancer Progression.
IL-20 Subfamily Biological Effects: Mechanistic Insights and Therapeutic Perspectives in Cancer.
Dendritic cells function beyond antigen presentation.

Front Immunol. 2025 ;16 1648601

Harnessing innate immunity against glioblastoma microenvironment.

Wenbo Zhang, Wanhong Zhang, Henghao Wu, Xinsheng Han.

  Glioblastoma (GBM) possesses a profoundly immunosuppressive tumor microenvironment (TME) dominated by innate immune mechanisms. Tumor-associated macrophages (TAMs), microglia, and myeloid-derived suppressor cells (MDSCs) constitute the major immunosuppressive axis, promoting tumor progression through cytokine secretion (IL-10, TGF-β), metabolic reprogramming, and inhibition of cytotoxic immunity. These innate immune cells not only facilitate immune evasion but also impair adaptive T-cell responses, limiting the efficacy of current immunotherapies. Emerging evidence highlights the therapeutic potential of targeting innate immunity via TAM repolarization, MDSC depletion, and NK cell activation to reshape the immunosuppressive TME. This review summarizes the pivotal role of innate immunity in GBM pathogenesis and explores novel combinatorial strategies that integrate innate immune modulation with checkpoint blockade, oncolytic virotherapy, and metabolic interventions to overcome therapeutic resistance in this lethal malignancy.

Keywords:  NK cell; glioblastoma; immunotherapy; innate immunity; microglia; myeloidderived suppressor cells; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2025.1648601
Crit Rev Oncol Hematol. 2025 Aug 07. pii: S1040-8428(25)00269-0. [Epub ahead of print]215 104881

Lipid metabolic reprogramming in tumor-associated macrophages: A key driver of functional polarization and tumor immunomodulation.

Xianglong Feng, Jiahao Zhang, Boyi Yu, Weimiao An, Xiaodong Jin.

  Tumor-associated macrophages (TAMs) are pivotal immunoregulatory cells in the tumor microenvironment (TME). They play a central role in tumor progression through dynamic regulation of metabolic reprogramming, especially lipid metabolism. TAMs switch between pro-tumor (M2) and anti-tumor (M1) phenotypes through a high degree of plasticity. This process is regulated by fatty acid oxidation (FAO), cholesterol homeostasis and phospholipid metabolism. Targeting TAMs lipid metabolism provides a new strategy for remodeling the anti-tumor tumor microenvironment, and its synergistic effect with tumor immunotherapy such as immune checkpoint inhibitors is expected to be a new direction for precision tumor therapy.

Keywords:  Cholesterol metabolism; FAO; Lipid metabolic; TAMs

DOI:  https://doi.org/10.1016/j.critrevonc.2025.104881
Biochim Biophys Acta Rev Cancer. 2025 Aug 11. pii: S0304-419X(25)00158-1. [Epub ahead of print] 189416

Targeting lipid metabolism to enhance cancer immunotherapy.

Dan Zhao, Lei Wu, Yongsheng Li.

  In recent years, the interaction between lipid metabolism and immune checkpoint inhibitors (ICIs) has become a key area of research in cancer treatment. Tumor cells utilize lipid metabolism reprogramming to promote rapid proliferation, evade immune surveillance, and develop resistance to treatment, highlighting the significant role of lipid metabolism in cancer progression and immune regulation. This review analyzes the mechanisms by which lipid metabolism reshapes the tumor microenvironment (TME) and collaborates with ICIs to enhance therapeutic effects. We discussed how lipid metabolism regulates tumor phenotypes and summarized the impact of dysregulated lipid metabolism on infiltrating immune cells in the TME. We propose that targeting lipid metabolism may be a promising strategy for improving immunotherapy. Furthermore, we suggest that lipid metabolism can serve as a predictive biomarker for the response to immunotherapy and guide the immunotherapy process. Finally, we outline future research directions, including the development of innovative drugs targeting lipid metabolism to enhance the effectiveness of immunotherapy.

Keywords:  Combination therapy; Immune checkpoint inhibitors; Immune evasion; Lipid metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2025.189416
Front Immunol. 2025 ;16 1645019

HPV infection and the immune microenvironment in cervical cancer.

Yibo Li, Jingui Deng, Yayong Liu, Shuangfeng Yu.

  Cervical cancer remains a leading cause of cancer-related mortality in women, particularly in low-resource settings, despite advances in treatment modalities. The tumor immune microenvironment (TME) plays a pivotal role in cervical cancer pathogenesis, progression, and therapeutic response, driven largely by persistent HPV infection and subsequent immune evasion mechanisms. Clinical evidence supports the efficacy of pembrolizumab in PD-L1-positive recurrent/metastatic disease, while combinatorial strategies show promise in overcoming resistance. However, challenges persist, including biomarker identification and management of immune-related adverse events. This review elucidates the dynamic interplay between HPV-mediated immune suppression and the TME, highlighting the roles of tumor-associated macrophages (TAMs), regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and exhausted lymphocyte subsets in fostering an immunosuppressive milieu. Overall, this review integrates current advances in tumor immunology and immunotherapy, providing a comprehensive framework for developing precision-based strategies to improve outcomes in cervical cancer.

Keywords:  cervical cancer; human papillomavirus; immune checkpoint inhibitors; immune microenvironment; immune pathway; immunotherapy

DOI:  https://doi.org/10.3389/fimmu.2025.1645019
Trends Pharmacol Sci. 2025 Aug 14. pii: S0165-6147(25)00156-7. [Epub ahead of print]

Targeting glycosylation to enhance tumor immunotherapy.

Qiang Zhu, Xiaoming Chen, Xiaotao Duan, Jianwei Sun, Wen Yi.

  Glycans are complex sugar modifications found on cell surfaces that play crucial roles in biological processes. Glycosylation patterns are aberrantly altered in the tumor microenvironment (TME), which helps cancer cells escape immune surveillance by creating a tumor-specific 'glyco-code' that weakens immune responses and reduces immunotherapy effectiveness. Recent studies have illustrated the potential to improve antitumor immune responses by manipulating glycosylation in the TME. We review the effects of aberrant glycosylation on the regulation of tumor immunity and the corresponding strategies for manipulating glycosylation to enhance antitumor immunity. These strategies include inhibiting glycan-receptor interactions, engineering cell-surface glycans, and remodeling the extracellular matrix. This Review highlights the importance of glycosylation in designing effective and personalized cancer treatments.

Keywords:  glycoengineering; glycosylation; immunotherapy; lectins; tumor immunity; tumor microenvironment

DOI:  https://doi.org/10.1016/j.tips.2025.07.013
Cancers (Basel). 2025 Aug 07. pii: 2590. [Epub ahead of print]17(15):

Immune Evasion in Head and Neck Squamous Cell Carcinoma: Roles of Cancer-Associated Fibroblasts, Immune Checkpoints, and TP53 Mutations in the Tumor Microenvironment.

Chung-Che Tsai, Yi-Chiung Hsu, Tin-Yi Chu, Po-Chih Hsu, Chan-Yen Kuo.

  Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy characterized by complex interactions within the tumor microenvironment (TME) that facilitate immune evasion and tumor progression. The TME consists of diverse cellular components, including cancer-associated fibroblasts, immune and endothelial cells, and extracellular matrix elements, that collectively modulate tumor growth, metastasis, and resistance to therapy. Immune evasion in HNSCC is orchestrated through multiple mechanisms, including the suppression of cytotoxic T lymphocytes, recruitment of immunosuppressive cells, such as regulatory T and myeloid-derived suppressor cells, and upregulation of immune checkpoint molecules (e.g., PD-1/PD-L1 and CTLA-4). Natural killer (NK) cells, which play a crucial role in anti-tumor immunity, are often dysfunctional within the HNSCC TME due to inhibitory signaling and metabolic constraints. Additionally, endothelial cells contribute to tumor angiogenesis and immune suppression, further exacerbating disease progression. Recent advancements in immunotherapy, particularly immune checkpoint inhibitors and NK cell-based strategies, have shown promise in restoring anti-tumor immunity. Moreover, TP53 mutations, frequently observed in HNSCC, influence tumor behavior and therapeutic responses, highlighting the need for personalized treatment approaches. This review provides a comprehensive analysis of the molecular and cellular mechanisms governing immune evasion in HNSCC with a focus on novel therapeutic strategies aimed at improving patient outcomes.

Keywords:  CTLA-4; PD-1/PD-L1; cancer-associated fibroblasts; head and neck squamous cell carcinoma; immune evasion; immunotherapy; myeloid-derived suppressor cells; natural killer cells; regulatory T cells; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers17152590
Pharmacol Ther. 2025 Aug 07. pii: S0163-7258(25)00118-4. [Epub ahead of print]274 108906

Macrophages at the crossroads of cellular senescence and cancer development and progression: Therapeutic opportunities and challenges.

Shi-Long Jiang, Dong Wang, Chan Zou, Ze-Wu Zhu, Chao Luo, Zhi-Bin Wang.

  Macrophages are pleiotropic immune cells essential for maintaining tissue homeostasis and modulating immune responses. Their inherent plasticity enables polarization into distinct functional phenotypes: M1 (pro-inflammatory) and M2 (anti-inflammatory), which critically influence the progression of various diseases, including cancer. Cellular senescence, a state characterized by irreversible cell cycle arrest and the secretion of pro-inflammatory factors (SASP), substantially contributes to aging and disease pathogenesis. The interaction between macrophages and senescent cells is complex: macrophages contribute to tissue integrity by clearing senescent cells to prevent tissue dysfunction, while senescent cells can alter macrophage function, influencing inflammation and cancer development. This review examines the dual roles of macrophages in cellular senescence and cancer, focusing on their capacity to both protect against and promote tumor progression. It examines how macrophages recognize and phagocytose senescent cells, the impact of macrophage dysfunction on senescence-associated pathologies, and the role of tumor-associated macrophages (TAMs) in shaping the tumor microenvironment. Key concepts to be addressed include macrophage plasticity, SASP-mediated modulation of macrophage function, and the dual role of macrophages in cancer, where they can either suppress tumor growth or promote progression via angiogenesis, immune evasion, and metastasis. The mutual interplay between macrophages and senescent cells highlights the therapeutic potential of targeting this interaction for managing age-related diseases and cancer.

Keywords:  Cancer; Cellular senescence; Immune evasion; Macrophages; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.pharmthera.2025.108906
Adv Drug Deliv Rev. 2025 Aug 07. pii: S0169-409X(25)00156-5. [Epub ahead of print]225 115671

Classic versus innovative strategies for immuno-therapy in pancreatic cancer.

Maria Giovanna Formelli, Andrea Palloni, Simona Tavolari, Chiara Deiana, Elisa Andrini, Mariacristina Di Marco, Davide Campana, Giuseppe Lamberti, Giovanni Brandi.

  Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a dismal prognosis. Immunotherapy with immune checkpoint inhibitors (ICIs), either as monotherapy, in combination with other ICIs, or alongside chemotherapy, has significantly improved outcomes in several solid tumors. However, its efficacy in PDAC remains limited due to multiple resistance mechanisms. Key determinants of immunotherapy resistance in PDAC include physical barriers that hinder immune cells infiltration, such as aberrant vasculature, cancer-associated fibroblasts (CAFs), and excessive hyaluronic acid deposition in the tumor microenvironment (TME). Additionally, PDAC is characterized by an immunosuppressive TME enriched with regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and by low immunogenicity of tumor cells due to KRAS mutations, MYC overexpression, and a low tumor mutational burden, further impairing antitumor immunity. This review discusses advanced drug delivery systems to overcome determinants of immunotherapy resistance and to improve outcomes, explores emerging immunotherapy strategies, including adoptive cell therapies, cancer vaccines, and the potential role of microbiota as modulator of TME through fecal microbiota transplantation or intratumoral bacterial inoculation. Given the ambivalent role of microbiota in PDAC, the need for a clear definition of favorable strains and their selection is highlighted. Emerging approaches involving engineered bacteria and artificial intelligence applications are also explored. Finally, we propose a hypothetical conceptual framework for an innovative multimodal immunotherapy approach to overcome resistance and improve clinical outcomes in PDAC.

Keywords:  Adoptive cell therapy; Immune checkpoint inhibitors; Immunotherapy; Microbiota; Pancreatic ductal adenocarcinoma; Tumor microenvironment; Vaccine

DOI:  https://doi.org/10.1016/j.addr.2025.115671
Trends Pharmacol Sci. 2025 Aug 09. pii: S0165-6147(25)00149-X. [Epub ahead of print]

Therapeutic potential of targeting macrophages and microglia in glioblastoma.

Fei Zhou, Pritha Mukherjee, Jinming Mu, Peiwen Chen.

  Glioblastoma (GBM) is a highly aggressive and lethal form of brain tumor in human adults that resists standard of care (SOC) and immunotherapy. Tumor-associated macrophages and microglia (TAMs) represent the most abundant cell population within the GBM tumor microenvironment (TME), comprising up to 50% of the whole tumor mass. TAMs play a pivotal role in promoting tumor progression, driving immunosuppression and inducing therapy resistance. Recent advances have revealed TAM heterogeneity - including their cellular identity (e.g., bone marrow-derived macrophages versus microglia) and the presence of distinct activation/function states and subpopulations within each subtype - in GBM tumors. Targeting the context-dependent TAM infiltration, reprogramming, new subpopulations, survival, phagocytosis, and their interactions with GBM cells in the TME has emerged as a promising therapeutic strategy. Herein we review recent advances in pharmacological targeting of the TAM biology and highlight how these strategies may enhance the effectiveness of SOC and immunotherapies in GBM.

Keywords:  glioblastoma; immunotherapy; tumor microenvironment (TME); tumor-associated macrophages and microglia (TAMs)

DOI:  https://doi.org/10.1016/j.tips.2025.07.006
Molecules. 2025 Jul 24. pii: 3099. [Epub ahead of print]30(15):

Targeting RARγ Decreases Immunosuppressive Macrophage Polarization and Reduces Tumor Growth.

Jihyeon Park, Jisun Oh, Sang-Hyun Min, Ji Hoon Yu, Jong-Sup Bae, Hui-Jeon Jeon.

  Tumor-associated macrophages (TAMs) play a critical role in the tumor microenvironment (TME), interacting with cancer cells and other components to promote tumor growth. Given the influence of TAMs on tumor progression and resistance to therapy, regulating the activity of these macrophages is crucial for improving cancer treatment outcomes. TAMs often exhibit immunosuppressive phenotypes (commonly referred to as M2-like macrophages), which suppress immune responses and contribute to drug resistance. Therefore, inhibiting immunosuppressive polarization offers a promising strategy to impede tumor growth. This study revealed retinoic acid receptor gamma (RARγ), a nuclear receptor, as a key regulator of immunosuppressive polarization in THP-1 macrophages. Indeed, the inhibition of RARγ, either by a small molecule or gene silencing, significantly reduced the expression of immunosuppressive macrophage markers. In a three-dimensional tumor spheroid model, immunosuppressive macrophages enhanced the proliferation of HCT116 colorectal cancer cells, which was significantly hindered by RARγ inhibition. These findings suggest that targeting RARγ reprograms immunosuppressive macrophages and mitigates the tumor-promoting effects of TAMs, highlighting RARγ as a promising therapeutic target for developing novel anti-cancer strategies.

Keywords:  M2 polarization; retinoic acid receptor gamma; therapeutic target; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3390/molecules30153099
J Transl Med. 2025 Aug 12. 23(1): 897

Harnessing intratumoral microbiota: new horizons in immune microenvironment and immunotherapy.

Jinhe Zhang, Zinan You, Xinqiao Li, Jinpeng Hu, Jiamu Li, Zhitao Jing.

  Microorganisms are ubiquitous in the human body, including within tumor tissues. Recent studies have demonstrated that intratumoral microbiota serve as critical regulators of the tumor microenvironment (TME), promoting the progression of solid tumors (e.g., gastric, lung, and breast cancers). These microbes modulate immune factors (such as IFN-γ and TNF-α), thereby influencing the activation and infiltration of immune cells, including T cells and macrophage. Additionally, by reshaping the immune landscape, intratumoral microbiota can dysregulate immune checkpoint expression, ultimately affecting the efficacy of cancer immunotherapy. This review synthesizes the current understanding of the origins of intratumoral microbiota, their heterogeneity across cancer types, and their intricate roles in modulating immune responses and tumor metastasis. We further discuss innovative therapeutic strategies leveraging the intratumoral microbiota, including engineered bacteria, oncolytic viruses, and nanoparticles, and address existing challenges and potential future research directions. A deeper understanding of these microbial‒host interactions may open new avenues for precise microbiota-based cancer diagnostics and personalized immunotherapeutic strategies.

Keywords:  Immune microenvironment; Immune response; Immunotherapy; Tumor metastasis; intratumoral microbiota

DOI:  https://doi.org/10.1186/s12967-025-06916-2
Int J Mol Sci. 2025 Aug 04. pii: 7508. [Epub ahead of print]26(15):

Metabolic Interactions in the Tumor Microenvironment of Classical Hodgkin Lymphoma: Implications for Targeted Therapy.

Michał Kurlapski, Alicja Braczko, Paweł Dubiela, Iga Walczak, Barbara Kutryb-Zając, Jan Maciej Zaucha.

  Classical Hodgkin lymphoma (cHL) is a biologically and clinically unique malignancy characterized by rare Hodgkin and Reed-Sternberg (HRS) cells surrounded by a dense and diverse inflammatory infiltrate. These malignant cells actively reshape the tumor microenvironment (TME) through metabolic reprogramming and immune evasion strategies. This review synthesizes current knowledge on how metabolic alterations contribute to tumor survival, immune dysfunction, and therapeutic resistance in cHL. We discuss novel therapeutic approaches aimed at disrupting these processes and examine the potential of combining metabolic interventions with immune-based strategies-such as immune checkpoint inhibitors (CPIs), epigenetic modulators, bispecific antibodies, and CAR-T/CAR-NK cell therapies-which may help overcome resistance and enhance anti-tumor responses. Several agents are currently under investigation for their ability to modulate immune cell metabolism and restore effective immune surveillance. Altogether, targeting metabolic vulnerabilities within both tumor and immune compartments offers a promising, multifaceted strategy to improve clinical outcomes in patients with relapsed or refractory cHL.

Keywords:  Hodgkin lymphoma; cell metabolism; therapeutic strategies; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms26157508
Biomaterials. 2025 Aug 11. pii: S0142-9612(25)00539-3. [Epub ahead of print]325 123620

Endogenous macrophages as "Trojan horses" for targeted oral delivery of mRNA-encoded cytokines in tumor microenvironment immunotherapy.

Po-Kai Luo, Wan-An Chang, Sheng-Yao Peng, Li-An Chu, Ya-Han Chuang, Lam-Duc-Huy Nguyen, Jhih-Syuan Guo, Hao-Chi Wei, Po-Liang Lai, Hsiao-Huang Chang, Kuan-Lin Wang, Yin-Hsu Chen, Hsing-Wen Sung.

  Macrophages (MΦ) in the tumor microenvironment (TME) are often skewed toward the M2 phenotype, which suppresses immune responses and supports tumor progression. Interferon-γ (IFN-γ) plays a pivotal role in reprogramming MΦ toward a pro-inflammatory M1-like phenotype, thereby enhancing anti-tumor immunity. This study introduces a targeted oral immunotherapy strategy using IFN-γ mRNA-loaded lipid nanoparticles conjugated with β-glucans (IFN-γ mRNA@βGlus-LNPs), evaluated in a mouse model of triple-negative breast cancer. Following oral administration, the nanoparticles target transcytotic M cells in Peyer's patches, are taken up by endogenous MΦ in intestinal lymphoid tissues, and transported via lymphatic and systemic circulation to the tumor site. In the TME, the nanoparticles induce transient, localized IFN-γ expression, reprogramming both infiltrating and resident MΦ toward an M1-like phenotype and activating cytotoxic T cell responses. By harnessing the natural tumor-homing ability and biocompatibility of MΦ, this "Trojan horse" approach offers a promising platform for effective, safe mRNA-based cancer immunotherapy.

Keywords:  Cellular carriers; Macrophage polarization; Oral delivery; Targeted cancer therapy; Tumor immunotherapy

DOI:  https://doi.org/10.1016/j.biomaterials.2025.123620
Cancers (Basel). 2025 Jul 28. pii: 2484. [Epub ahead of print]17(15):

Cancer-Associated Fibroblasts: Immunosuppressive Crosstalk with Tumor-Infiltrating Immune Cells and Implications for Therapeutic Resistance.

Jogendra Singh Pawar, Md Abdus Salam, Md Shalman Uddin Dipto, Md Yusuf Al-Amin, Moushumi Tabassoom Salam, Sagnik Sengupta, Smita Kumari, Lohitha Gujjari, Ganesh Yadagiri.

  Cancer is no longer considered as an isolated event. Rather, it occurs because of a complex biological drive orchestrating different cell types, growth factors, cytokines, and signaling pathways within the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are the most populous stromal cells within the complex ecosystem of TME, with significant heterogeneity and plasticity in origin and functional phenotypes. Very enigmatic cells, CAFs determine the progress and outcomes of tumors through extensive reciprocal signaling with different tumors infiltrating immune cells in the TME. In their biological drive, CAFs release numerous chemical mediators and utilize various signaling pathways to recruit and modulate tumor-infiltrating immune cells. The CAF-induced secretome and exosomes render immune cells ineffective for their antitumor activities. Moreover, by upregulating immune inhibitory checkpoints, CAFs create an immunosuppressive TME that impedes the susceptibility of tumor cells to tumor-infiltrating lymphocytes (TILs). Further, by depositing and remodeling extracellular matrix (ECM), CAFs reshape the TME, which enhances tumor growth, invasion, metastasis, and chemoresistance. Understanding of CAF biology and its crosstalk with tumor-infiltrating immune cells is crucial not only to gain insight in tumorigenesis but to optimize the potential of novel targeted immunotherapies for cancers. The complex relationships between CAFs and tumor-infiltrating immune cells remain unclear and need further study. Herein, in this narrative review we have focused on updates of CAF biology and its interactions with tumor-infiltrating immune cells in generating immunosuppressive TME and resistance to cell death.

Keywords:  CAF-induced immunosuppression; biological crosstalk; cancer-associated fibroblasts; tumor cell resistance; tumor microenvironment; tumor-infiltrating immune cells

DOI:  https://doi.org/10.3390/cancers17152484
Mol Cancer. 2025 Aug 11. 24(1): 216

Neurotransmitters: an emerging target for therapeutic resistance to tumor immune checkpoint inhibitors.

Jiyuan Yang, Yu Wu, Xinhui Lv, Sicong Liu, Ziwen Yuan, Yafang Chen, Xiangyu Ding, Zhong Li, Xudong Wang.

  The critical role of neurotransmitters in the resistance to tumor immune checkpoint inhibitor (ICI) is becoming increasingly significant in therapeutic contexts. ICIs work by enhancing antitumor immunity through the blockade of the PD-1/PD-L1 and CTLA-4 pathways. However, only 20% of patients experience durable efficacy, and the challenge of drug resistance limits the clinical application of these therapies. Drug resistance is closely linked to various factors within the tumor microenvironment, including the distribution of tumor-infiltrating lymphocytes, the function of tumor-associated macrophages, low expression levels of PD-L1, variations in tumor mutational burden, dysregulation of antigen presentation, and both genetic and epigenetic changes in tumor cells. In recent years, the importance of the neural-immune axis has gained attention. Abnormal nerve fiber growth or irregular secretion of neurotransmitters can contribute to immune evasion. Neurotransmitters such as dopamine, norepinephrine, and serotonin influence the tumor microenvironment by regulating the expression of immune checkpoints and the function of immune cells, which can promote immune escape. As a result, therapeutic strategies that target neurotransmitters and their receptors hold promise for overcoming resistance to ICIs. These strategies may significantly enhance the efficacy of ICIs and pave the way for new approaches in cancer therapy. This article reviews the relevant mechanisms and proposes potential therapeutic strategies, offering new insights for the field.

Keywords:  Drug resistance; Immune checkpoint inhibitors; Immunotherapy; Neurotransmitters; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12943-025-02413-8
J Biomed Sci. 2025 Aug 09. 32(1): 73

CD24a knockout results in an enhanced macrophage- and CD8⁺ T cell-mediated anti-tumor immune responses in tumor microenvironment in a murine triple-negative breast cancer model.

Shih-Hsuan Chan, Chin-Yu Lin, Hsuan-Jung Tseng, Lu-Hai Wang.

   BACKGROUND: CD24 plays a crucial role not only in promoting tumor progression and metastasis but also in modulating macrophage-mediated anti-tumor immunity. However, its impact on the immune landscape of the tumor microenvironment (TME) remains unexplored. Here, we investigated the role of CD24a, the murine CD24 gene, in tumor progression and TME immune dynamics in a murine triple-negative breast cancer (TNBC) model.
METHODS: Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9 knockout technology was employed to generate CD24a knockout in the murine TNBC cell line 4T1. Flow cytometry was utilized to analyze the immune cell populations, including myeloid-derived suppressor cells (MDSCs), natural killer cells, T cells, and macrophages, within tumors, spleens, and bone marrow in the orthotopic mouse 4T1 breast cancer model. Immunofluorescence (IF) staining was used to detect the immune cells in tumor sections. High-speed confocal was used to perform three-dimensional (3D) mapping of immune cells in the 4T1 orthotopic tumors.
RESULTS: Knocking out CD24a significantly reduced tumor growth kinetics and prolonged mouse survival in vivo. Flow cytometry and IF analysis of tumor samples revealed that CD24a loss significantly promoted the infiltration of M1 macrophages and cytotoxic CD8+ T cells into the TME while reducing the recruitment and expansion of granulocytic MDSCs (gMDSCs). In vitro coculture experiments showed that CD24a deficiency significantly enhanced macrophage-mediated phagocytosis and CD8⁺ T cell-mediated cytotoxicity, effects that were partially reversed by re-expression of CD24a. Moreover, in vivo depletion of macrophages and CD8+ T cells reverted the delayed tumor growth caused by CD24a knockout, underscoring their critical role in tumor growth suppression associated with CD24a knockout. 3D mapping of immune cells in the TME confirmed the anti-tumor immune landscape in the CD24a knockout 4T1 tumors. Furthermore, in vitro analysis showed that CD24a loss upregulated macrophage colony-stimulating factor expression while suppressed levels of CXCL1, CXCL5, and CXCL10, chemokines known to recruit gMDSCs, further providing a molecular basis for enhanced macrophage recruitment and diminished gMDSC accumulation.
CONCLUSIONS: Our findings suggest that CD24a may regulate immune suppression within the TNBC TME. Targeting CD24a enhances macrophage- and CD8⁺ T cell-mediated anti-tumor immune responses and is associated with a shift in the TME toward a more immunogenic state, thereby suppressing tumor growth. These results may support CD24 as a promising immunotherapeutic target for TNBC.

Keywords:  CD24a; CD8+ T cells; CRISPR/Cas9 knockout; Macrophages; Triple-negative breast cancer; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12929-025-01165-3
Pathol Res Pract. 2025 Aug 08. pii: S0344-0338(25)00356-5. [Epub ahead of print]274 156163

Targeting LAG-3: Relatlimab, Fianlimab, and ieramilimab reshape the landscape of cancer combination immunotherapy.

Kosar Ghasemi.

  In cancer immunotherapy, Relatlimab, Fianlimab, and Ieramilimab are monoclonal antibodies (mAbs) that target the lymphocyte-activation gene 3 (LAG-3), with U.S. Food and Drug Administration (FDA) approval. LAG-3 is one of the immune checkpoint receptors expressed on exhausted T cells within the tumor microenvironment (TME), thereby contributing to immune suppression. This phenomenon presents one of the main challenges in implementing immunotherapeutic methods in cancer. Targeting LAG-3 employing mAbs is designed to restore T-cell functionality and increase antitumor immunity. Clinical studies involving Relatlimab, Fianlimab, and Ieramilimab in combination with other immune checkpoint inhibitors (ICIs), such as anti-programmed cell death-1 (PD-1) mAbs, have demonstrated promising clinical outcomes in the treatment of melanoma. Notably, these combinations have been associated with improved progression-free survival (PFS) compared to monotherapy. This review discusses the biology of LAG-3, the pharmacological characteristics of Relatlimab, Fianlimab, and Ieramilimab, as well as their potential synergistic effects when combined with other ICIs. Moreover, it addresses resistance mechanisms, patient selection, and challenges with combination therapies in cancer.

Keywords:  And Ieramilimab; Cancer Immunotherapy; Fianlimab; Lymphocyte-activation gene 3; Relatlimab

DOI:  https://doi.org/10.1016/j.prp.2025.156163
Cancers (Basel). 2025 Aug 07. pii: 2593. [Epub ahead of print]17(15):

Neutrophil Dynamics in Response to Cancer Therapies.

Huazhen Xu, Xiaojun Chen, Yuqing Lu, Nihao Sun, Karis E Weisgerber, Manzhu Xu, Ren-Yuan Bai.

  Neutrophils are increasingly recognized as key players in the tumor microenvironment (TME), displaying functional plasticity that enables them to either promote or inhibit cancer progression. Depending on environmental cues, tumor-associated neutrophils (TANs) may polarize toward antitumor "N1" or protumor "N2" phenotypes, exerting diverse effects on tumor growth, metastasis, immune modulation, and treatment response. While previous studies have focused on the pathological roles of TANs in cancer, less attention has been given to how cancer therapies themselves influence the behavior of TANs. This review provides a comprehensive synthesis of current knowledge regarding the dynamics of TANs in response to major cancer treatment modalities, including chemotherapy, radiotherapy, cell-based immunotherapies, and oncolytic viral and bacterial therapies. We discuss how these therapies influence TAN recruitment, polarization, and effector functions within the TME, and highlight key molecular regulators involved. By consolidating mechanistic and translational insights, this review emphasizes the potential to therapeutically reprogram TANs to enhance treatment efficacy. A deeper understanding of context-dependent TAN roles will be essential for developing more effective, neutrophil-informed cancer therapies.

Keywords:  N1 neutrophils; N2 neutrophils; cancer immunology; cancer therapy resistance; chemotherapy; immunotherapy; inflammation and cancer; innate immunity; neutrophil polarization; neutrophils; oncolytic bacterial therapy; oncolytic virotherapy; radiotherapy; tumor microenvironment; tumor-associated neutrophils

DOI:  https://doi.org/10.3390/cancers17152593
Curr Pharm Des. 2025 Aug 13.

Exploring the Neurobiological Mechanisms of Cancer Growth.

Md Sadique Hussain, Mudasir Maqbool, Mohit Agrawal, Amita Joshi Rana, Ayesha Sultana, Nasreen Sulthana, Ajay Singh Bisht, Gyas Khan.

  Emerging evidence reveals that interactions between the nervous system and tumor biology significantly influence cancer progression, metastasis, and therapeutic outcomes. This review elucidates the neurobiological mechanisms that underpin tumor development, highlighting the dynamic role of neural components within the tumor microenvironment (TME). Neural signals and structural adaptations in the TME stimulate tumorigenesis and enable cancer cell plasticity, mimicking neurodevelopmental processes. Astrocytic glial cells release neurotrophic factors that support metastatic colonization and enhance tumor cell survival. Notably, cancer cells can establish pseudo-tripartite synapses with neurons, promoting both proliferation and invasion. We explore the cancer-neural network interplay, emphasizing how axonal remodeling, circuit reorganization, and synaptic dysfunction not only drive tumor growth but also contribute to associated symptoms like seizures and chronic pain. Molecularly, mutations such as in PIK3CA and abnormalities in neurotransmitter signaling reveal how neuro-tumors communicate and adapt. Furthermore, metabolic stress responses from tumor cells can activate nociceptive neurons, sustaining malignant progression. Understanding these neurobiological interactions opens avenues for novel therapeutic strategies. Precision neuro-oncology may benefit from targeting neurotrophic signaling, synaptic pathways, and neuronal differentiation programs. Advances in biomarker research from neuro-tumors also contribute to improved diagnostic and prognostic tools. By integrating neuroscience insights into oncological frameworks, we propose a paradigm shift toward therapies that intercept the neural circuitry sustaining malignancies. This neuro-oncological approach holds promise in addressing aggressive cancer phenotypes and improving patient outcomes.

Keywords:  Cancer metastasis; neuronal plasticity; neurotrophic factors; synaptic transmission; tumor microenvironment.

DOI:  https://doi.org/10.2174/0113816128402718250806151308
Exp Hematol Oncol. 2025 Aug 10. 14(1): 105

In-depth insight into tumor-infiltrating stromal cells linked to tertiary lymphoid structures and their prospective function in cancer immunotherapy.

Maedeh Radandish, Niloofar Mashhadi, Amir Hossein Aghayan, Motahareh Taghizadeh, Sara Salehianfard, Sheida Yahyazadeh, Omid Vakili, Somayeh Igder.

   BACKGROUND AND PURPOSE: The tumor microenvironment (TME) is widely acknowledged as a pivotal regulator of cancer progression. However, the dualistic role of tertiary lymphoid structures (TLSs), which serve as critical immune hubs within the TME, remains incompletely characterized, particularly with respect to their context-dependent capacity to either inhibit or facilitate tumor development. This review aims to synthesize current understanding of the complex interactions between stromal cells and TLSs, addressing existing gaps in mechanistic insight and exploring therapeutic avenues to exploit TLS plasticity.
KEY REVIEWED TOPICS: The current study critically reviews the mechanisms by which stromal components, including cancer-associated fibroblasts and endothelial cells, contribute to TLS neogenesis through chemokine-mediated recruitment of lymphocytes. Furthermore, it highlights the dual functional roles of TLSs as sites of both anti-tumor immune activation and immunosuppression, notably via the enrichment of regulatory T cells. The clinical implications of mature TLS presence, particularly their association with improved patient prognosis and enhanced therapeutic responsiveness, are also analyzed.
MAIN CONCLUSIONS: TLSs demonstrate a bifunctional nature, wherein their spatial organization and dynamic interactions with stromal elements dictate the balance between immune activation and tolerance within the TME. While mature TLSs are generally correlated with favorable clinical outcomes, their potential to foster immunosuppressive microenvironments necessitates the development of precision-targeted interventions. The interplay between stromal cells and TLSs represents a promising therapeutic axis for modulating the tumor immune milieu.
FUTURE PERSPECTIVES: Future research should prioritize strategies aimed at promoting TLS maturation, disrupting immunosuppressive niches, and integrating TLS-modulating agents with existing immunotherapeutic regimens to enhance clinical efficacy. Additionally, the identification of robust biomarkers reflective of TLS functional states and the rigorous validation of stromal-targeted therapies within combinatorial treatment frameworks are imperative for advancing translational applications.

Keywords:  Cancer immunotherapy; Neoplasms; Stromal cell immunomodulation; Tertiary lymphoid structures; Tumor infiltration; Tumor microenvironment

DOI:  https://doi.org/10.1186/s40164-025-00695-8
Biochim Biophys Acta Rev Cancer. 2025 Aug 08. pii: S0304-419X(25)00156-8. [Epub ahead of print]1880(5): 189414

GABAergic signaling in colorectal cancer: Mechanistic insights, tumor microenvironment crosstalk, and therapeutic opportunities.

Donghao Tang, Paola Orlandi, Qijie Li, Arianna Bandini, Guido Bocci.

  γ-Aminobutyric acid (GABA) and its receptors have emerged as critical modulators of colorectal cancer (CRC) progression and the tumor microenvironment (TME). Although GABA is traditionally recognized as an inhibitory neurotransmitter in the central nervous system, recent studies have uncovered its complex and sometimes paradoxical roles in cancer biology. In vivo, elevated GABA levels in CRC tissues have been associated with enhanced tumor growth, immune evasion, and metabolic adaptation. In contrast, in vitro studies suggest that exogenous GABA and GABA receptor agonists can inhibit CRC cell proliferation, highlighting a context-dependent role for GABAergic signaling. This duality may stem from variations in GABA receptor subtype expression, tumor-intrinsic metabolic reprogramming, and immune modulation within the TME. A better understanding of these mechanisms may offer new therapeutic opportunities. In this review, we summarize recent advances in the field, focusing on the molecular mechanisms, immune and metabolic interactions, and therapeutic potential of targeting GABAergic signaling in colorectal cancer.

Keywords:  Colorectal cancer; GABA; GABA receptor; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2025.189414
Int J Mol Sci. 2025 Aug 06. pii: 7624. [Epub ahead of print]26(15):

Transcriptional Repression of CCL2 by KCa3.1 K+ Channel Activation and LRRC8A Anion Channel Inhibition in THP-1-Differentiated M2 Macrophages.

Miki Matsui, Junko Kajikuri, Hiroaki Kito, Yohei Yamaguchi, Susumu Ohya.

  We investigated the role of the intermediate-conductance, Ca2+-activated K+ channel KCa3.1 and volume-regulatory anion channel LRRC8A in regulating C-C motif chemokine ligand 2 (CCL2) expression in THP-1-differentiated M2 macrophages (M2-MACs), which serve as a useful model for studying tumor-associated macrophages (TAMs). CCL2 is a potent chemoattractant involved in the recruitment of immunosuppressive cells and its expression is regulated through intracellular signaling pathways such as ERK, JNK, and Nrf2 in various types of cells including macrophages. The transcriptional expression of CCL2 was suppressed in M2-MACs following treatment with a KCa3.1 activator or an LRRC8A inhibitor via distinct signaling pathways: ERK-CREB2 and JNK-c-Jun pathways for KCa3.1, and the NOX2-Nrf2-CEBPB pathway for LRRC8A. Under in vitro conditions mimicking the elevated extracellular K+ concentration ([K+]e) characteristic of the tumor microenvironment (TME), CCL2 expression was markedly upregulated, and this increase was reversed by treatment with them in M2-MACs. Additionally, the WNK1-AMPK pathway was, at least in part, involved in the high [K+]e-induced upregulation of CCL2. Collectively, modulating KCa3.1 and LRRC8A activities offers a promising strategy to suppress CCL2 secretion in TAMs, potentially limiting the CCL2-induced infiltration of immunosuppressive cells (TAMs, Tregs, and MDSCs) in the TME.

Keywords:  CCL2; KCa3.1; LRRC8A; extracellular potassium ions (K+); tumor microenvironment; tumor-associated macrophage

DOI:  https://doi.org/10.3390/ijms26157624
Cancer Res. 2025 Aug 15. 85(16): 2963-2966

Tumor-Immune Cell Interactions in Cancer Progression.

Xiaoxue Zhou, Feng Xie, Long Zhang.

The tumor microenvironment is a complex ecosystem where immune cell components play a pivotal role in cancer progression. Aberrant immune responses within the tumor microenvironment are critical in tumor initiation, progression, metastasis, and prognosis, highlighting the urgent need to unravel tumor-immune interactions for improved therapies. This commentary reviews recent advancements in understanding tumor-immune interactions, focusing on both intrinsic factors, like cancer genetics and epigenetics, and extrinsic factors, such as metabolic reprogramming. We also examine key mechanisms of tumor-immune cross-talk, including exosome-mediated communication, liquid-liquid phase separation, and circulating tumor cells. Furthermore, we propose future research directions to improve strategies for combating cancer metastasis and enhancing therapeutic efficacy.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-2760
Int J Mol Sci. 2025 Jul 29. pii: 7320. [Epub ahead of print]26(15):

IL-20 Subfamily Biological Effects: Mechanistic Insights and Therapeutic Perspectives in Cancer.

Valentina Maggisano, Maria D'Amico, Saveria Aquila, Francesca Giordano, Anna Martina Battaglia, Adele Chimento, Flavia Biamonte, Diego Russo, Vincenzo Pezzi, Stefania Bulotta, Francesca De Amicis.

  The interleukin-20 (IL-20) cytokine subfamily, a subset of the IL-10 superfamily, includes IL-19, IL-20, IL-22, IL-24, and IL-26. Recently, their involvement in cancer biology has gained attention, particularly due to their impact on the tumor microenvironment (TME). Notably, IL-20 subfamily cytokines can exert both pro-tumorigenic and anti-tumorigenic effects, depending on the context. For example, IL-22 promotes tumor growth by enhancing cancer cell proliferation and protecting against apoptosis, whereas IL-24 demonstrates anti-tumor activity by inducing cancer cell death and inhibiting metastasis. Additionally, these cytokines influence macrophage polarization-an essential factor in the immune landscape of tumors-thereby modulating the inflammatory environment and immune evasion strategies. Understanding the dual role of IL-20 subfamily cytokines within the TME and their interactions with cancer cell hallmarks presents a promising avenue for therapeutic development. Interleukin-20 receptor antagonists are being researched for their role in cancer therapy, since they potentially inhibit tumor growth and progression. This review explores the relationship between IL-20 cytokines and key cancer-related processes, including growth and proliferative advantages, angiogenesis, invasion, metastasis, and TME support. Further research is necessary to unravel the specific mechanisms underlying their contributions to tumor progression and to determine their potential for targeted therapeutic strategies.

Keywords:  cancer progression; cytokines; inflammation

DOI:  https://doi.org/10.3390/ijms26157320
Cancer Cell. 2025 Jul 23. pii: S1535-6108(25)00274-0. [Epub ahead of print]

Dendritic cells function beyond antigen presentation.

Eynav Klechevsky.

In this issue of Cancer Cell, Chen et al. identify DNASE1L3-expressing dendritic cells (DCs) as enhancers of anti-tumor immunity. By degrading neutrophil extracellular traps, these DCs promote CD8⁺ T cell infiltration into tumors and enhance checkpoint blockade efficacy, extending DNASE1L3's known immune regulatory role to physical remodeling of the tumor microenvironment.

DOI: https://doi.org/10.1016/j.ccell.2025.07.003