bims-flamet 2025-06-29 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2025–06–29
28 papers selected by
Peio Azcoaga, Biodonostia HRI

Metabolism and Immune Suppressive Response in Liver Cancer.
Role of Tumor Microenvironment in Prostate Cancer Immunometabolism.
Neutrophil-driven tumor inflammation in breast cancer: Pathways and therapeutic implications: A narrative review.
Cytokine symphony: Deciphering the tumor microenvironment and metastatic axis in oral cancer.
Dynamics of inflammatory signals within the tumor microenvironment.
The role of SPP1+TAMs in cancer: Impact on patient prognosis and future therapeutic targets.
How Do Cancer Cells Create Cancer-Associated Fibroblast Subtypes? Impacts of Extracellular Vesicles on Stromal Diversity.
Lactate-Mediated Crosstalk Between Tumor Cells and Cancer-Associated Fibroblasts: Mechanisms and Therapeutic Opportunities.
Glycolytic reprogramming in macrophage polarization: New horizons in the treatment of tumor diseases.
Paracrine signaling in cancer-associated fibroblasts: central regulators of the tumor immune microenvironment.
Myeloid-derived suppressor cells modulation in the context of tumor microenvironment for gastric cancer.
The role and mechanisms of exosome microRNA in regulating metastasis within the tumor microenvironment of prostate cancer.
Intercellular communication between extracellular vesicles from conditioned macrophages and breast cancer cells drives endocrine therapy resistance.
Molecular Mechanisms of Lymph Node Metastasis in Gallbladder Cancer: Insights into the Tumor Microenvironment.
Th17 cells in cancer: plasticity-driven immunopathology and therapeutic opportunity.
Extracellular vesicles: the "Trojan Horse" within breast cancer host microenvironments.
Nanoparticle-based methionine and AICAR delivery elicits a robust antitumor immune response.
Unlocking New Frontiers in Breast Cancer: The Role of the Tumor Microenvironment, Cutting-Edge Therapies, and Immunotherapy.
The role of tumor microenvironment in lenvatinib resistance of hepatocellular carcinoma.
Anticancer Treatment Influences TREM2 in Tumor-Associated Macrophages in Lung Cancer.
Recent Advances in Cancer Immunotherapy Aided by Regulatory Non-Coding RNA: A Review.
Ferroptosis in tumor associated immune cells: a double-edged sword against tumors.
Cytokine release syndrome and CAR T Cell therapy: Modulating the intensity of the inflammatory response and resolution within the tumor microenvironment.
The Role of Immunotherapy and Immune Modulators in Hormone-Positive Breast Cancer: Implications for Localized and Metastatic Disease.
CAR Beyond αβ T Cells: Unleashing NK Cells, Macrophages, and γδ T Lymphocytes Against Solid Tumors.
CD47-mediated tumor microenvironment remodeling: a central mechanism in immune evasion.
Endoplasmic Reticulum Stress in Cancer.
Cancer cell-derived extracellular vesicles: a potential target for overcoming tumor immunotherapy resistance and immune evasion strategies.

Biomedicines. 2025 Jun 13. pii: 1461. [Epub ahead of print]13(6):

Metabolism and Immune Suppressive Response in Liver Cancer.

Patrizio Caini, Vinicio Carloni.

  Hepatocellular carcinoma (HCC) constitutes more than 90% of the primary tumor of the liver. Metabolic reprogramming is decisive in promoting HCC development. The new metabolic program drives the surrounding immune cells to an immune suppressive commitment, enabling tumor survival. The enhanced metabolic activity of cancer cells leads to competition for essential nutrients, depriving non-malignant cells of critical resources. Simultaneously, the accumulation of metabolic byproducts within the tumor microenvironment (TME) selectively favors innate immune responses while impairing adaptive immunity. Recent advances in cancer immunotherapy underscore the importance of targeting both immune cell function and metabolic pathways. In this context, reprogramming the metabolism of effector and regulatory immune cells represents a promising therapeutic avenue. This review focuses on a relatively underexplored aspect of liver cancer immunology, the immunosuppressive role of tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) driven by metabolic alterations and how these mechanisms contribute to the suppression of effective anti-tumor immune responses.

Keywords:  epigenetics; glycolysis; hypoxia; macrophages; regulatory T cells

DOI:  https://doi.org/10.3390/biomedicines13061461
Biomolecules. 2025 Jun 06. pii: 826. [Epub ahead of print]15(6):

Role of Tumor Microenvironment in Prostate Cancer Immunometabolism.

Yutao Wang, Yiming Chen, Jianfeng Wang.

  The tumor microenvironment (TME) plays a pivotal role in shaping immunometabolism in prostate cancer, influencing disease progression and therapeutic response. This review examines the dynamic interactions between tumor cells and immune cells within the prostate cancer TME, focusing on how metabolic reprogramming of both tumor and immune cells drives immunosuppression. Key immune players, including T-cells, macrophages, and myeloid-derived suppressor cells, undergo metabolic adaptations influenced by hypoxia, nutrient deprivation, and signaling from tumor cells. Additionally, we discuss the metabolic pathways involved, such as glycolysis and oxidative phosphorylation, and how these processes are exploited by cancer cells to evade immune surveillance. Furthermore, this review highlights potential therapeutic strategies targeting immunometabolism, including metabolic inhibitors and their combination with immunotherapies. A deeper understanding of the complex role of immunometabolism in prostate cancer will not only provide insights into the tumor's immune evasion mechanisms but also facilitate the development of novel treatment approaches that enhance the efficacy of current therapies.

Keywords:  immunometabolism; metabolic reprogramming; oxidative phosphorylation; prostate cancer; tumor microenvironment

DOI:  https://doi.org/10.3390/biom15060826
Medicine (Baltimore). 2025 Jun 20. 104(25): e43024

Neutrophil-driven tumor inflammation in breast cancer: Pathways and therapeutic implications: A narrative review.

Emmanuel Ifeanyi Obeagu.

  Neutrophils, a key component of the innate immune system, have emerged as significant players in the tumor microenvironment (TME) of breast cancer. Traditionally recognized for their role in defending against infections, neutrophils in cancer contribute to both tumor progression and suppression, depending on their activation state and the signals they receive. Neutrophil-driven inflammation within the TME is critical in promoting tumor growth, metastasis, and resistance to treatment. This review explores the complex role of neutrophils in breast cancer, emphasizing the mechanisms through which they influence tumor inflammation, including their interactions with other immune cells and the signaling pathways involved. Neutrophils can either support tumor progression by releasing pro-inflammatory cytokines, enzymes, and reactive oxygen species, or contribute to antitumor responses by directly killing cancer cells and stimulating adaptive immunity. The balance between these opposing functions is heavily influenced by the TME's cytokine milieu and neutrophil polarization. Key signaling pathways, such as the CXCR2-CXCL8 axis and interactions with tumor-associated macrophages, regulate neutrophil recruitment and activation in the TME, enhancing inflammation and tumorigenesis. Additionally, neutrophils' ability to form neutrophil extracellular traps further complicates their role, potentially promoting metastasis by trapping circulating tumor cells.

Keywords:  breast cancer; neutrophils; therapeutic implications; tumor inflammation; tumor microenvironment

DOI:  https://doi.org/10.1097/MD.0000000000043024
Cytokine Growth Factor Rev. 2025 Jun 16. pii: S1359-6101(25)00075-9. [Epub ahead of print]

Cytokine symphony: Deciphering the tumor microenvironment and metastatic axis in oral cancer.

Mukesh Kumar Manickasamy, Ravichandran Vishwa, Bandari BharathwajChetty, Mohammed S Alqahtani, Mohamed Abbas, Ajaikumar B Kunnumakkara.

  Oral cancer remains one of the deadliest diseases due to its aggressive nature, high metastatic potential, and limited therapeutic success. The tumor microenvironment (TME) serves as a central regulator in the metastasis of oral cancer by shaping tumor-stroma interactions, immune modulation, and metastatic dissemination. Among the key regulators of the TME, cytokines act as one of the molecular orchestrators, mediating inflammation, immune suppression, epithelial-mesenchymal transition (EMT), angiogenesis, and metastatic niche formation. This review explores the regulatory networks driven by cytokines from TME that govern tumor metastasis in oral cancer. Pro-tumorigenic cytokines such as IL-6, IL-8, TGF-β, TNF-α, etc., drive EMT, extracellular matrix (ECM) remodeling, and immune evasion, facilitating tumor invasion and metastatic colonization. Conversely, anti-tumor cytokines, including IFN-γ, IL-12, etc., play a role in immune activation but are often downregulated in the immunosuppressive TME. Additionally, the complex crosstalk between immune cells, tumor cells, tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs) further amplifies cytokine-driven tumor metastasis. Understanding the "cytokine symphony" that governs oral cancer progression and metastasis is critical for developing targeted therapies. Here, we discuss the cytokine crosstalk in TME and its implication in metastasis and conclude with an emerging cytokine-targeting strategy, including anti-IL-6/STAT3 inhibitors, IL-8 blockade, and immune checkpoint inhibitors, as potential approaches to modulate the TME and suppress oral cancer metastasis. Future clinical studies are essential to validate cytokine-based interventions and pave the way for precision medicine in oral cancer management.

Keywords:  Cancer-associated fibroblasts; Cytokines; Metastasis; Oral carcinoma; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.cytogfr.2025.06.003
World J Exp Med. 2025 Jun 20. 15(2): 102285

Dynamics of inflammatory signals within the tumor microenvironment.

Hala Issa, Lokjan Singh, Kok-Song Lai, Tina Parusheva-Borsitzky, Shamshul Ansari.

  Tumor stroma, or tumor microenvironment (TME), has been in the spotlight during recent years for its role in tumor development, growth, and metastasis. It consists of a myriad of elements, including tumor-associated macrophages, cancer-associated fibroblasts, a deregulated extracellular matrix, endothelial cells, and vascular vessels. The release of proinflammatory molecules, due to the inflamed microenvironment, such as cytokines and chemokines is found to play a pivotal role in progression of cancer and response to therapy. This review discusses the major key players and important chemical inflammatory signals released in the TME. Furthermore, the latest breakthroughs in cytokine-mediated crosstalk between immune cells and cancer cells have been highlighted. In addition, recent updates on alterations in cytokine signaling between chronic inflammation and malignant TME have also been reviewed.

Keywords:  Cytokines; Inflammatory signals; Interleukins; Transforming growth factor; Tumor microenvironment

DOI:  https://doi.org/10.5493/wjem.v15.i2.102285
Int J Cancer. 2025 Jun 26.

The role of SPP1+TAMs in cancer: Impact on patient prognosis and future therapeutic targets.

Xiang Li, Jie Lian, Haibo Lu.

  Tumor-associated macrophages (TAMs) are a critical population of immune cells that infiltrate the tumor microenvironment (TME) and significantly influence cancer progression, prognosis, and treatment. SPP1+TAMs represent a tumor-promoting subset of TAMs characterized by their ability to secrete osteopontin, along with various cytokines and chemokines, and to interact with a diverse array of ligands. Within the tumor microenvironment, SPP1+TAMs are primarily localized to hypoxic and necrotic regions, as well as along the tumor margins. Studies have shown that SPP1+TAMs promote tumor angiogenesis, invasion, metastasis, and immunosuppression. The infiltration of SPP1+TAMs has been associated with poor prognosis in cancer patients. Furthermore, their presence may influence disease progression and treatment response. Targeting SPP1+TAMs has the potential to reduce immunosuppression and augment immunotherapeutic efficacy, thereby contributing to improved treatment outcomes.

Keywords:  SPP1+TAMs; angiogenesis; cancer; immunosuppressive; prognosis

DOI:  https://doi.org/10.1002/ijc.70018
Cancer Sci. 2025 Jun 25.

How Do Cancer Cells Create Cancer-Associated Fibroblast Subtypes? Impacts of Extracellular Vesicles on Stromal Diversity.

Yutaka Naito.

  Cancer-associated fibroblasts (CAFs) are the major component of the tumor stroma. They mediate various attributes of tumor cells, such as cell growth, migration, invasion, angiogenesis, metabolic reprogramming, apoptosis, immune regulation, and extracellular matrix reconstitution, all related to cancer progression and treatment resistance. Although many researchers have recognized CAF heterogeneity, recent technological advances have emphasized the functional and phenotypic diversity of CAFs in cancer progression. Why are these CAF subtypes generated within tumor tissues? And how do cancer cells dictate such heterogeneous subtypes of CAFs? This review will highlight the CAF subtypes within the tumor microenvironment and their role in tumor progression. CAF subtype induction by extracellular vesicles (EVs) and their significance, which we reported previously, is also discussed.

Keywords:  cancer‐associated fibroblasts; extracellular vesicles; heterogeneity; subtypes; tumor microenvironment

DOI:  https://doi.org/10.1111/cas.70133
Int J Mol Sci. 2025 Jun 11. pii: 5583. [Epub ahead of print]26(12):

Lactate-Mediated Crosstalk Between Tumor Cells and Cancer-Associated Fibroblasts: Mechanisms and Therapeutic Opportunities.

Siqi Tan, Faxiao Zhou, Xiaoming Wu.

  Lactate is a key oncometabolite that plays a critical role in modulating the behavior and function of both tumor cells and tumor-associated stromal cells within the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs), as essential stromal components, engage in dynamic crosstalk with tumor cells through lactate-mediated signaling pathways. Elevated lactate levels in the TME primarily originate from metabolic reprogramming in tumor cells and CAFs. Notably, tumor-derived lactate not only promotes basement membrane remodeling and epithelial-mesenchymal transition (EMT) in CAFs but also influences their functional phenotype. Conversely, CAF-secreted lactate significantly contributes to tumor progression. Therapeutic strategies targeting lactate transport and metabolism-particularly through the inhibition of monocarboxylate transporters (MCTs) and lactate dehydrogenase (LDH)-have emerged as promising approaches in cancer treatment. This review summarizes the multifaceted roles of lactate and lactylation, elucidates the molecular mechanisms underlying lactate-mediated tumor-CAF crosstalk, and explores potential therapeutic interventions targeting lactate metabolism and CAFs.

Keywords:  CAFs; TME; lactate; lactation

DOI:  https://doi.org/10.3390/ijms26125583
Cell Signal. 2025 Jun 18. pii: S0898-6568(25)00355-9. [Epub ahead of print]134 111940

Glycolytic reprogramming in macrophage polarization: New horizons in the treatment of tumor diseases.

Dong Wang, Haoran Guan.

  Macrophages serve as sentinels on the front line of tissue defense, acting as essential components of the body's arsenal against invading pathogens. Their metabolic modes and functions are closely linked to the progression and regression of diseases. Typically, macrophages preferentially utilize the glycolytic pathway for energy production, with glycolysis being particularly dominant in hypoxic environments. Notably, tumor-associated macrophages (TAMs) also rely on glycolysis for energy production even in the presence of sufficient oxygen, a phenomenon known as the classic "Warburg effect." TAMs play a critical role in the development and progression of malignant tumors, including angiogenesis, and are considered a key component of the tumor microenvironment (TME). They promote tumor growth, invasion, metastasis, and tumor neoangiogenesis. The infiltration level and polarization status of TAMs within the tumor stroma are closely associated with patient prognosis and represent potential targets for tumor immunotherapy. Furthermore, tumor growth is heavily dependent on tumor neoangiogenesis. In this paper, we systematically reviewed the literature on macrophages and tumor therapy to elucidate and summarize the relationship between the glycometabolic mechanisms of macrophage polarization and tumors. This review aims to provide theoretical guidance for tumor treatment and the development of antitumor drugs.

Keywords:  Glucose metabolism; Immunotherapy; Macrophage polarization; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.cellsig.2025.111940
J Transl Med. 2025 Jun 23. 23(1): 697

Paracrine signaling in cancer-associated fibroblasts: central regulators of the tumor immune microenvironment.

Ye Li, Longyun Wang, Wenzhe Ma, Jibiao Wu, Qibiao Wu, Changgang Sun.

  Despite groundbreaking advances in cancer immunotherapy, clinical efficacy remains constrained by the immunosuppressive tumor microenvironment (TME). As key stromal components within this TME, cancer-associated fibroblasts (CAFs) emerge as pivotal regulators of drug resistance and immune evasion. Beyond establishing physical barriers that exclude cytotoxic T cells from tumor nests, that is creating an immune "desert", CAFs dynamically reprogram the TME through multifaceted paracrine signaling, orchestrating crosstalk among tumor cells, stromal components, and immune cells. The complex paracrine signaling network jointly promotes the recruitment of immunosuppressive cells, alters the dynamics of immune cells, remodels the extracellular matrix, and ultimately establishes the immunosuppressive TME. Emerging strategies aimed at undermining the paracrine signaling Network of CAF-TME have shown potential in clinical studies to enhance the response to immunotherapy. Natural compounds such as curcumin and Baicalein and their derivatives have further expanded therapeutic approaches by regulating the paracrine phenotype of CAF due to their inherent multi-target intervention advantages. This review describes CAF and its paracrine effect as the central regulators of TME immunosuppression, emphasizing its key role in the immunotherapy response and providing new possibilities for clinical treatment strategies to restore CAFs paracrine-mediated immunosuppression and improve the efficacy of immunotherapy.

Keywords:  Cancer-associated fibroblasts; Immune suppression; Paracrine signaling; Tumor immune microenvironment

DOI:  https://doi.org/10.1186/s12967-025-06744-4
Clin Transl Oncol. 2025 Jun 24.

Myeloid-derived suppressor cells modulation in the context of tumor microenvironment for gastric cancer.

José Dario Portillo-Miño, Jhon Jairo Calderón, Erika Ruiz-García, Cecilia Monge.

  Gastric cancer (GC) exhibits aggressive behavior and high mortality rates globally. In this respect, the effectiveness of chemotherapy and immunotherapy is hindered by various factors including tumor heterogeneity, immune phenotypes, chronic H. pylori infection, and an immunosuppressive tumor microenvironment (TME). The immunosuppressive TME is fostered by multiple immune cell subpopulations as tumor-associated neutrophils, tumor-associated macrophages, tumor-associated dendritic cells, regulatory T cells, and myeloid-derived suppressor cells (MDSCs). The MDSC abundantly infiltrates gastric TME, which interacts with H. pylori infection and is influenced by reactive oxygen species (ROS), chronic inflammation, and hypoxia. Understanding its cellular and molecular biology of GC is crucial for developing novel therapeutic options. Current preclinical evidence is emerging to support translational oncology on MDSC immunotherapy. This article review suggests MDSC modulation may be a promising avenue for enhancing chemotherapy and immunotherapy responses against GC.

Keywords:  Gastric cancer; Immunotherapy; MDSC; TME

DOI:  https://doi.org/10.1007/s12094-025-03960-8
Front Oncol. 2025 ;15 1580314

The role and mechanisms of exosome microRNA in regulating metastasis within the tumor microenvironment of prostate cancer.

Yongcheng Song, Qinzhang Wang, Bin Liang, Songnian Zou.

  Prostate cancer (PCa) metastasis remains a significant challenge in clinical treatment, resulting in limited effective treatment options and poor clinical outcomes. Recent studies have highlighted the important function of exosome microRNAs (miRNAs) in governing metastatic processes within the tumor microenvironment (TME). Our review examines the mechanisms by which exosomal miRNAs contribute to PCa metastasis, focusing on their involvement in regulating tumor invasion and migration, epithelial-mesenchymal transition, and modulating immune responses. The review also discusses the implications of these findings for therapeutic targeting of exosomal miRNAs, indicating that they may act as potential biomarkers for prognosis and therapeutic while offering novel avenues for treatment strategies aimed at inhibiting metastasis. By elucidating the intricate interplay between exosomal miRNAs and the TME, this review aims to providing new insights into PCa metastasis while offering a theoretical foundation for future clinical research.

Keywords:  PCA; epithelialmesenchymal transition; exosome microRNA; metastasis; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2025.1580314
Front Cell Dev Biol. 2025 ;13 1548724

Intercellular communication between extracellular vesicles from conditioned macrophages and breast cancer cells drives endocrine therapy resistance.

María C Rodriguez-Baili, Miguel Palma-Cobo, César G Prucca, María Yáñez-Mó, German A Gil.

   Introduction: Breast cancer is a leading cause of cancer-related mortality among women, with nearly 70% of cases being estrogen receptor-positive (ER+). While endocrine therapies, such as tamoxifen, have significantly improved patient outcomes, resistance-whether intrinsic or acquired-remains a major clinical challenge that limits treatment efficacy. Emerging evidence suggests that endocrine resistance is often driven by the presence and expansion of cancer stem cells (CSCs), which contribute to recurrence, metastasis, and therapeutic failure. The tumor microenvironment (TME), including immune cells like macrophages, soluble factors, and extracellular vesicles (EVs), plays a crucial role in promoting tumor progression and therapy resistance. EVs are small lipid bilayer-bound particles that facilitate intercellular communication by transferring bioactive cargo capable of reprogramming recipient cells.
Methods: To investigate the role of macrophage-derived EVs in endocrine resistance, we isolated EVs from TNF-α-conditioned macrophages (TNF EVs) and treated MCF-7 ER+ breast cancer cells with these vesicles. We assessed changes in proliferation, migration, epithelial-mesenchymal transition (EMT), CSC-like properties, and tamoxifen resistance. Additionally, we evaluated whether tumor-derived EVs modulate macrophage polarization by analyzing the expression of PD-1 and other immunomodulatory markers.
Results: TNF EV-treated MCF-7 cells showed significantly increased proliferation, enhanced migratory behavior, and morphological changes associated with EMT. Importantly, treated cells developed a stem-like phenotype, characterized by a larger CD44High/CD24Low subpopulation and improved spheroid-forming ability. These features correlated with sustained proliferation even in the presence of tamoxifen, supporting the development of endocrine resistance. Furthermore, EVs derived from tumor cells triggered macrophage polarization toward a tumor-associated macrophage (TAM) profile, with increased PD-1 expression, indicating a role in immune suppression and tumor immune evasion.
Discussion: These findings emphasize the dual role of TNF-α-conditioned macrophage-derived EVs in driving both endocrine resistance and immune modulation in ER+ breast cancer. By promoting stemness, EMT, and tamoxifen resistance, as well as inducing immunosuppressive macrophage polarization, these EVs emerge as key contributors to tumor progression. Our study highlights the therapeutic potential of targeting EV-mediated communication to overcome endocrine resistance and enhance clinical outcomes for ER+ breast cancer patients. This work establishes a critical framework for future studies aimed at harnessing EVs as therapeutic targets or biomarkers in breast cancer management.

Keywords:  breast cancer; cancer stem cells (CSS); endocrine resistance; epithelial-mesenchymal transition (EMT); estrogen receptor-positive (ER+); extracellular vesicles (EVs); tumor microenvironment (TME); tumor-associated macrophages (TAMs)

DOI:  https://doi.org/10.3389/fcell.2025.1548724
Biomedicines. 2025 Jun 04. pii: 1372. [Epub ahead of print]13(6):

Molecular Mechanisms of Lymph Node Metastasis in Gallbladder Cancer: Insights into the Tumor Microenvironment.

Qingyu Tang, Yichen Guan, Yubo Ma, Qi Li, Zhimin Geng.

  Gallbladder cancer (GBC) is a highly aggressive malignancy with a propensity for lymph node metastasis (LNM), which significantly worsens prognosis. This review explores the molecular mechanisms underlying LNM in GBC, focusing on the roles of vascular endothelial growth factors (VEGFs), chemokines, cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), hypoxia-inducible factors (HIFs), and non-coding RNAs (ncRNAs) in shaping the tumor microenvironment (TME). Unique features of GBC, such as its bile-rich microenvironment and hypoxia-driven lymphangiogenesis, are highlighted. We discuss how these factors promote lymphangiogenesis, immune evasion, and extracellular matrix (ECM) remodeling, collectively facilitating LNM. Potential therapeutic targets, including VEGF-C/D pathways, matrix metalloproteinase (MMP) inhibitors, and immune-modulating therapies, are also reviewed. Future research integrating single-cell omics and patient-derived organoid models is essential for advancing precision medicine in GBC.

Keywords:  gallbladder cancer; lymph node metastasis; non-coding RNAs; tumor microenvironment; vascular endothelial growth factor

DOI:  https://doi.org/10.3390/biomedicines13061372
Immunol Cell Biol. 2025 Jun 26.

Th17 cells in cancer: plasticity-driven immunopathology and therapeutic opportunity.

Henry Sutanto, Mukti Citra Ningtyas, Betty Rachma, Laras Pratiwi, Deasy Fetarayani.

  T-helper 17 (Th17) cells, a subset of CD4+ T cells, are key players in mucosal immunity and inflammation, distinguished by their production of IL-17 and related cytokines. In the context of cancer, Th17 cells exhibit extraordinary plasticity-adapting their phenotype and function in response to tumor microenvironmental cues. This review explores how Th17 cells mediate paradoxical roles in tumor biology, promoting either tumor progression or antitumor immunity depending on molecular context. Protumorigenic functions include fostering angiogenesis, chronic inflammation and immune evasion through IL-17-driven recruitment of neutrophils and myeloid-derived suppressor cells. Conversely, Th17 cells can transition into IFNγ-producing Th1-like cells, enhancing cytotoxic T-cell responses and tumor rejection. Key modulators of this plasticity include cytokines (IL-23, IL-12, TGF-β), hypoxia, metabolic shifts and epigenetic reprogramming. We further examine how Th17 plasticity contributes to metastasis, therapy resistance and immune modulation via interactions with tumor-associated macrophages and regulatory T cells. Finally, the review highlights emerging therapeutic strategies that target Th17 pathways through cytokine blockade, metabolic intervention, RORγ modulation and adoptive cell therapy. Understanding Th17 plasticity provides critical insights into tumor immunology and offers novel avenues for cancer immunotherapy.

Keywords:  Immunology; Th17; T‐helper lymphocyte; oncology; plasticity

DOI:  https://doi.org/10.1111/imcb.70043
Mol Cancer. 2025 Jun 23. 24(1): 183

Extracellular vesicles: the "Trojan Horse" within breast cancer host microenvironments.

Yue Kang, Ling'ao Meng, Shi Bai, Shenglong Li.

  Breast cancer represents a significant global health concern among women. The intricate processes and pathways underlying metastasis contribute to the challenging prognoses experienced by some patients. Extracellular vesicles (EVs) are membrane-bound structures characterized by phospholipid bilayers, capable of secretion by a multitude of cell types. The contents of these vesicles encompass a diverse assortment of lipids, proteins, nucleic acids, and cellular metabolites. The tumor microenvironment (TME) comprises a complex network involving tumor cells, non-cancerous cells, and an array of molecules they generate and release. Components include the extracellular matrix, cancer-associated fibroblasts, inflammatory immune cells, tumor-associated vasculature, and EVs discharged by these cellular entities. Within the TME, EVs serve as a mechanism akin to the "Trojan Horse," exerting significant influence in tumor initiation, progression, metastasis, and responses to therapeutic interventions. EVs originating from tumor cells and associated entities within the TME bolster processes such as stimulating angiogenesis adjacent to tumor sites, establishing pre-metastatic niches in distant anatomical regions, and inducing transformative changes in cancer cells to acquire characteristics promoting invasion, angiogenesis, immune evasion, distant metastasis, and resistance to chemotherapy. Noteworthy is the unique capacity of EVs to traverse biological barriers due to their inherent biocompatibility, rendering them promising candidates for innovative drug delivery systems. This attribute presents an avenue to surmount the constraints of traditional cancer treatments. This scholarly inquiry delves into the pathogenic mechanisms of EVs in breast cancer and delves into prospective therapeutic interventions, offering a groundwork for forthcoming precision-guided therapies tailored to breast cancer.

Keywords:  Breast cancer; Drug delivery vehicles; Drug resistance; Extracellular vesicles; Metastasis; Pre-metastatic niche; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12943-025-02358-y
J Control Release. 2025 Jun 24. pii: S0168-3659(25)00602-9. [Epub ahead of print] 113981

Nanoparticle-based methionine and AICAR delivery elicits a robust antitumor immune response.

Ye Gu, Bao Loc Nguyen, Sunil Mishra, Ram Hari Pokhrel, Manoj Sharma, Mahesh Pandit, Le Minh Pham, Basavaraj Patil, Jeonghwan Kim, Jong Oh Kim, Jae-Hoon Chang.

  Immunotherapy uses the immune system's intrinsic defense mechanisms to destroy malignancies and has garnered increasing interest in recent years. The main objectives of immunotherapy are activating immune cells and forming a strong antitumor immune response. The tumor microenvironment (TME) is a complex ecology full of chemicals that can substantially affect immune cell activity, especially the function of CD4+ T cells. In this study, we produced an artificial nanoparticle (NP) comprising methionine and AICAR with PD-1 antibodies attached to its surface, targeted at increasing effector immune responses by directly altering the TME. By targeting PD-1 receptors, this coloaded NP effectively travels to the tumor site and activates CD4+ T cells within the TME. After receiving these NPs, the mice's tumor-infiltrating CD4+ T cells expressed less PD-1, and their Th1-driven antitumor immunity increased. These effects resulted in substantial tumor inhibition. Our findings suggest that this NP-based technique, which direct regulates the TME, has the potential as a robust tool to enhance anticancer efficacy by promoting immune cell activation within the TME.

Keywords:  AICAR; Human serum albumin nanoparticle; Methionine; PD-1; Tumor

DOI:  https://doi.org/10.1016/j.jconrel.2025.113981
Anticancer Res. 2025 Jul;45(7): 2729-2747

Unlocking New Frontiers in Breast Cancer: The Role of the Tumor Microenvironment, Cutting-Edge Therapies, and Immunotherapy.

Doua Kamyan, Noha M Elemam, Noura Alkhayyal, Iman M Talaat, Riyad Bendardaf.

  Breast cancer (BC) remains the most prevalent malignancy among women worldwide, with incidence and mortality rates varying across regions due to disparities in screening, diagnosis, and treatment accessibility. Molecular classification has redefined BC management, categorizing tumors into luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)-enriched, and triple-negative breast cancer (TNBC), each with distinct prognostic and therapeutic implications. Advances in tumor microenvironment (TME) research highlight its critical role in cancer progression, immune evasion, and treatment resistance, underscoring the importance of tumor-infiltrating lymphocytes, natural killer cells, and macrophages in shaping BC outcomes. Traditional therapies, including chemotherapy, endocrine therapy, and targeted treatments such as cyclin-dependent kinase 4 and 6 (CDK4/6) and phosphatidylinositol-4,5-biphosphate 3-kinase (PI3K) inhibitors, continue to evolve to overcome resistance mechanisms. Immunotherapy, particularly immune checkpoint inhibitors targeting programmed cell death protein 1 (PD1), programmed cell death ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), has demonstrated clinical benefits, especially in TNBC. Additionally, novel strategies, including chimeric antigen receptor T-cell therapy and cancer vaccines, are emerging as promising therapeutic avenues. This review provides a comprehensive analysis of BC epidemiology, molecular subtypes, TME interactions, and cutting-edge therapeutic strategies, emphasizing the need for personalized, immune-based approaches to enhance treatment efficacy and patient outcomes.

Keywords:  Breast cancer; human epidermal growth factor receptor 2 (HER2); luminal A; luminal B; review; triple-negative breast cancer (TNBC)

DOI:  https://doi.org/10.21873/anticanres.17643
Clin Res Hepatol Gastroenterol. 2025 Jun 25. pii: S2210-7401(25)00119-6. [Epub ahead of print] 102642

The role of tumor microenvironment in lenvatinib resistance of hepatocellular carcinoma.

Yao Jiang, Yingchen Huang, Xin Hu, Guanrong Chen, Ronggao Chen, Xiao Xu.

  In 2018, lenvatinib was approved as a first-line treatment of advanced hepatocellular carcinoma (HCC). Despite the initial success, its effectiveness in long-term clinical practice is restricted by the emergence of drug resistance. The tumor microenvironment (TME), comprised of various cellular and non-cellular components,collectively drives HCC growth, invasion, and resistance to treatment. Currently, numerous investigations have elucidated that lenvatinib exerts its influence on a multitude of targets within the TME. Moreover, many components of the TME can affect the sensitivity of lenvatinib either directly through interactions or promoting tumor immune evasion. TME plays a crucial role in the development of lenvatinib resistance (LR) in HCC. This review presents an overview on the role of the TME in LR of HCC. Furthermore, it explores therapeutic strategies targeting the TME for overcoming LR. These may improve the efficacy of lenvatinib and the prognosis of advanced HCC patients.

Keywords:  Drug resistance; Hepatocellular carcinoma; Lenvatinib; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.clinre.2025.102642
Cancer Res Treat. 2025 Jun 23.

Anticancer Treatment Influences TREM2 in Tumor-Associated Macrophages in Lung Cancer.

Yoon Jin Cha, Eun Hye Lee, Chi Young Kim, Yong Jun Choi, Min Kyung Park, Sang Hoon Lee, Eun Young Kim, Yoon Soo Chang.

   Purpose: The triggering receptor expressed on myeloid cells (TREM2) creates an immunosuppressive environment, but the effects of anticancer treatment on TREM2 and the tumor microenvironment (TME) are not well established. This study investigates the impact of chemotherapy on TREM2-expressing macrophages within the lung adenocarcinoma TME.
Materials and Methods: Using single-cell RNA sequencing datasets of paired normal-appearing lung tissue (NL) and tumor (Tu), human and mouse lung cancer tissue, and THP-1 cells, we observed the effects of anticancer drugs on them.
Results: Myeloid cells (MY) were the second-most abundant non-epithelial component in the Tu, though less prevalent than in NL. Specific MY subclusters abundant in Tu showed overexpression of TREM2. In lung cancer-induced Kras-G12D mice, M2 proportion increased in Tu compared to NL; cisplatin increased TREM2+ M2 proportion in Tu. TREM2+ cells in Tu showed interactions with cell clusters showing characteristics of interstitial macrophage such as mo-lineage, mono-Mc, and CD163/LGMN cells via FN:CD44 and MIF:CD74+CXCR4, suggesting that they influence the recruitment of those cells to Tu and TME reshape. In M0-state THP-1 cells, cisplatin and osimertinib treatments induced polarization towards M1 and M2 states and increased TREM2 expression. Cisplatin promoted uptake of phosphatidylserine-coated latex beads by M0 cells, whereas osimertinib reduced uptake by polarized macrophages. These findings suggest anticancer treatments impact the lung immune microenvironment by altering the TREM2+ cells.
Conclusion: Given TREM2's central inhibitory role in the tumor immune environment, effects of chemotherapeutic agents should be considered in developing TREM2-targeting therapies.

Keywords:  Anticancer treatment; Cisplatin; Macrophages; TREM2; Tumor microenvironment

DOI:  https://doi.org/10.4143/crt.2024.1245
Asian Pac J Cancer Prev. 2025 Jun 01. pii: 91700. [Epub ahead of print]26(6): 1915-1930

Recent Advances in Cancer Immunotherapy Aided by Regulatory Non-Coding RNA: A Review.

Debabrat Baishya, Arpita Barman, Bijuli Rabha, Kaushik Kumar Bharadwaj, Joyeeta Talukdar.

  Cancer immunotherapies have remodeled the way many different forms of cancer are treated by, leveraging the immune system to recognize and attack malignant cells. These therapies have demonstrated durable responses in cancers affecting the blood, bone marrow, and lymph nodes, solidifying their role as a cornerstone of modern oncology. However, despite their success, current immunotherapy tools and techniques require further refinement.Regulatory non-coding RNAs (ncRNAs), actively transcribed by the mammalian genome, play crucial roles in regulating a wide range of cellular processes. They are key players in epigenetic mechanisms that govern differentiation, development, and the progression of invasive carcinogenesis. Emerging evidence suggests that regulatory ncRNAs are also pivotal in cancer immunity, acting as drivers of immune responses in the development of metastatic tumors. These ncRNAs influence the tumor microenvironment (TME), modulate the immune system, and affect the efficacy of immune checkpoint inhibitors and T cell therapies by regulating various signaling pathways.This review article explores the diagnostic and therapeutic potential of ncRNAs in cancer immunotherapy, highlighting their role in modulating carcinogenesis and antitumor immunity. By understanding the influence of regulatory ncRNAs, we can pave the way for the development of prognostic biomarkers and more effective tumor immunotherapies.

Keywords:  Epigenetic regulations; Immune checkpoint inhibitors; Regulatory non-coding RNAs; Tumor Microenvironment; prognostic biomarker

DOI:  https://doi.org/10.31557/APJCP.2025.26.6.1915
Crit Rev Oncol Hematol. 2025 Jun 24. pii: S1040-8428(25)00206-9. [Epub ahead of print] 104818

Ferroptosis in tumor associated immune cells: a double-edged sword against tumors.

Jiachun Hu, Lei Cui, Benxin Hou, Xinyi Ding, Haisheng Liu, Weihong Sun, Yanjun Mi, Yibing Chen, Zhengzhi Zou.

  Ferroptosis is regulated cell death due to the accumulation of iron-dependent lipid peroxidation in cells, providing a potential new strategy for anti-tumor therapy. In recent years, more and more studies have begun to explore the interaction between ferroptosis and the tumor microenvironment (TME), especially the relationship between immune cells in the TME and ferroptosis, revealing the role of ferroptosis in tumor immunotherapy. This article summarizes the main metabolic pathways and regulatory mechanisms of ferroptosis, and focuses on the new role of ferroptosis in immune cells in the TME, which may provide new diagnostic, prognostic or therapeutic opportunities for the cooperation of immunotherapy and ferroptosis treatment.

Keywords:  Cancer; Ferroptosis; Immune cell; Tumor immune microenvironment; Tumor infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.critrevonc.2025.104818
Front Pharmacol. 2025 ;16 1615526

Cytokine release syndrome and CAR T Cell therapy: Modulating the intensity of the inflammatory response and resolution within the tumor microenvironment.

David F Driscoll, Bruce R Bistrian.

  CAR T cell therapy achieves high degrees of success with respect to complete response and overall response rates in many hematological cancers, especially lymphomas. Compared to other immunotherapies, these "activated" blood products are plagued by a high incidence of a severe systemic inflammatory response syndrome, resulting from the exaggerated release of cytokines, chemokines, and other pro-inflammatory protein and lipid mediators. These can produce what is known as the "cytokine release syndrome" (CRS), associated with significant morbidity and mortality. Although successful CAR T cell therapy reduces the tumor load, the killing of large numbers of cancer cells and the persistence of apoptotic cellular debris within the tumor microenvironment (TME) may also be tumorigenic. We propose a single active pharmaceutical ingredient (API), the highly polyunsaturated omega-3 fatty acids eicosapentaenoic and docosahexaenoic acids, applying a refined and enriched fish oil, with multiple therapeutic targets that can be administered in precise doses. First, they rapidly modulate the intensity of the systemic inflammatory response, by modifying eicosanoid metabolism via intravenous administration. Second, as substrates for the production of specialized pro-resolving mediators (SPMs) of inflammation, they can help clear cellular debris within the TME, perhaps reducing the risks of new tumor formation. The employment of such a drug either in a prophylactic and/or a treatment manner might further improve the outcome of CAR T cell therapy.

Keywords:  CAR T cell therapy; cytokine release syndrome; inflammation; resolution; tumor microenvironment

DOI:  https://doi.org/10.3389/fphar.2025.1615526
J Clin Med. 2025 Jun 17. pii: 4322. [Epub ahead of print]14(12):

The Role of Immunotherapy and Immune Modulators in Hormone-Positive Breast Cancer: Implications for Localized and Metastatic Disease.

Justin O'Farrell, Caroline Lapp, Heidi Kuznia, Muhammad Z Afzal.

  Background: Hormone receptor-positive (HR+) breast cancer, which accounts for approximately 70% of all breast cancer cases, is primarily treated with endocrine therapies as monotherapy or in combination with other targeted therapies and traditional cytotoxic therapy. While these therapies have significantly improved survival outcomes, resistance often develops, especially in metastatic disease where treatment options are limited. Immunotherapy, particularly immune checkpoint inhibitors, has emerged as a promising adjunct to traditional therapies in triple negative breast cancer. However, its role in HR+ breast cancer is not well established yet and is under active investigation. In addition, a deeper understanding of the tumor microenvironment (TME) and its role in immune evasion has spurred interest in immune modulators as additional potential therapeutic strategies for HR+ breast cancers. Objective: This review aims to synthesize the current evidence on the role of immunotherapy in HR+ breast cancer, with a focus on its clinical application in both localized and metastatic disease. It also explores the impact of immune modulators within the TME, highlighting their potential to improve the efficacy of immunotherapy in this subtype of breast cancer. Methods: A thorough review of recent clinical trials, preclinical studies, and meta-analyses was conducted. Studies published from 2015 to 2024 were included to provide the most up-to-date perspectives. Key Findings: While immune checkpoint inhibitors like pembrolizumab and atezolizumab have shown promising results in combination with chemotherapy for triple negative breast cancer, their efficacy in HR+ breast cancer has generally been modest. However, recent studies indicate that such therapies may help overcome endocrine resistance in metastatic disease. Furthermore, immune modulators, including cytokines and myeloid-derived suppressor cell inhibitors, are being investigated for their ability to reshape the TME, potentially enhancing the immune response and improving treatment outcomes. Despite these advances, challenges remain in identifying predictive biomarkers and managing immune-related adverse events. Conclusions: Immunotherapy holds potential for improving outcomes in HR+ breast cancer, particularly in metastatic settings where treatment options are limited. The integration of immune modulators to enhance therapeutic efficacy in HR+ breast cancer, along with ongoing research into biomarkers, promises to refine patient selection and improve clinical outcomes.

Keywords:  endocrine resistance; hormone-positive breast cancer; immune checkpoint inhibitors; immune modulators; immunotherapy; metastatic breast cancer; tumor microenvironment

DOI:  https://doi.org/10.3390/jcm14124322
Vaccines (Basel). 2025 Jun 19. pii: 654. [Epub ahead of print]13(6):

CAR Beyond αβ T Cells: Unleashing NK Cells, Macrophages, and γδ T Lymphocytes Against Solid Tumors.

Yunjia Xian, Lu Wen.

  Chimeric antigen receptor (CAR)-engineered cell therapy represents a landmark advancement in cancer immunotherapy. While αβ CAR-T therapy has demonstrated remarkable success in hematological malignancies, its efficacy in solid tumors remains constrained mainly by factors such as antigen heterogeneity, immunosuppressive microenvironments, and on-target/off-tumor toxicity. To overcome these limitations, emerging CAR platforms that utilize alternative immune effectors, including natural killer (NK) cells, macrophages, and γδ T lymphocytes, are rapidly gaining traction. This review systematically analyzes the mechanistic advantages of CAR-NK, CAR-M, and CAR-γδ T cell therapies, while critically evaluating persistent challenges in clinical translation, including limited cell persistence, manufacturing scalability, and dynamic immune evasion mechanisms. We further discuss innovative strategies to enhance therapeutic efficacy through some viable strategies. By bridging fundamental immunology with translational engineering, this work provides a roadmap for developing CAR therapies capable of addressing the complexities of solid tumor eradication.

Keywords:  CAR-M; CAR-NK; CAR-T; CAR-γδ T; cancer immunotherapy; cell therapy; solid tumor

DOI:  https://doi.org/10.3390/vaccines13060654
Acta Biochim Biophys Sin (Shanghai). 2025 Jun 25.

CD47-mediated tumor microenvironment remodeling: a central mechanism in immune evasion.

Hemei Yuan, Lingling Zhu, Longhuan Yang, Yong Yi, Tao Lv.

  Immune evasion is a crucial strategy for tumor growth and survival, with the tumor microenvironment facilitating tumor immune evasion and cancer progression. CD47, a transmembrane protein highly expressed in various cancer cell types, interacts with its ligands SIRPα and TSP-1 to induce immune tolerance, enabling tumor cells to evade immune surveillance and phagocytosis by immune cells. Understanding the pathways driving CD47 signaling and related activation factors is essential. In this review, we discuss the interactions between CD47 and its ligands SIRPα and TSP-1; their roles in inhibiting the functions of immune cells (macrophages, dendritic cells (DCs), glial cells, T cells, NK cells, etc.); and the mechanisms involved. Furthermore, we also explore the influence of factors within the tumor microenvironment, including TNF-α, IFN-γ, ILs, HIF-1, oncogenes, isocitrate dehydrogenase 1, metabolic enzymes, and exosomes, on CD47-mediated immune evasion. Recent monoclonal antibody drugs targeting CD47 for cancer treatment have shown side effects and cause economic losses. Researchers can explore alternative approaches, such as designing targeted drugs with minimal side effects or investigating other related molecules or pathways. Combination therapy and further research into the molecular mechanisms of CD47 could offer new directions for antitumor drug development.

Keywords:  CD47; immune evasion; signal regulatory protein alpha; thrombospondin-1; tumor microenvironment

DOI:  https://doi.org/10.3724/abbs.2025071
MedComm (2020). 2025 Jul;6(7): e70263

Endoplasmic Reticulum Stress in Cancer.

Ruixin Zhou, Wenlong Wang, Baizhao Li, Zhu Li, Juan Huang, Xinying Li.

  Persistent and intense endoplasmic reticulum (ER) stress is widely acknowledged as a hallmark of tumorigenesis. To restore ER homeostasis, cells activate the unfolded protein response (UPR), which is aberrantly regulated in cancer cells. This review provides an in-depth analysis of the mechanisms through which the UPR facilitates tumor progression. The UPR is activated by ER stress sensors such as inositol-requiring enzyme 1 (IRE1α), protein kinase R-like ER-resident kinase (PERK), and activating transcription factor 6 (ATF6). These sensors regulate cancer cell proliferation, immune evasion, metastasis, and drug resistance. We summarize the crosstalk between the UPR and multiple signaling pathways, including mTOR, MAPK, and NF-κB, which collectively promote tumor growth and metastasis. Additionally, we discuss the role of the UPR in modulating the tumor microenvironment to support angiogenesis and immune evasion. We also provide an overview of pharmacological agents targeting specific UPR pathways, such as GRP78 inhibitors, IRE1α inhibitors, PERK inhibitors, and ATF6 inhibitors, with the aim of developing more effective cancer therapies. This comprehensive review highlights the potential of targeting the UPR as a novel strategy for cancer treatment and underscores the need for further research to elucidate the complex interactions between the UPR and cancer progression.

Keywords:  endoplasmic reticulum (ER); metastasis; proliferation; tumor microenvironment (TME); unfolded protein response (UPR)

DOI:  https://doi.org/10.1002/mco2.70263
Front Immunol. 2025 ;16 1601266

Cancer cell-derived extracellular vesicles: a potential target for overcoming tumor immunotherapy resistance and immune evasion strategies.

Minseo Ahn, Jeong-Geon Mun, Yohan Han, Jae Ho Seo.

  Extracellular vesicles (EVs), including exosomes and microvesicles, play crucial roles in cancer progression by mediating the communication between cancer cells and their microenvironment. Cancer cell-derived EVs promote tumor growth, metastasis, and immune evasion by carrying bioactive materials, such as proteins, RNAs, DNA fragments, and lipids but, immunotherapy aims to enhance the immune response against cancer; however, resistance remains a major challenge. Cancer cell-derived EVs contribute to this resistance by delivering immunosuppressive molecules that impair T cell activation, promote the expansion of regulatory T cells (Tregs), and reduce natural killer (NK) cell cytotoxicity, thereby allowing cancer cells to evade immune surveillance. Additionally, cancer cell-derived EVs can carry immune checkpoint proteins, such as Programmed Death-Ligand 1 (PD-L1), which bind to the Programmed Death-1 (PD-1) receptor on T cells, leading to T cell exhaustion and reduced anti-tumor activity. This mechanism reflects how cancer cells directly evade immune detection and contributes to the overall resistance to immune checkpoint blockade therapies, such as anti-PD-1 or anti-PD-L1 antibodies. By delivering these immunomodulatory molecules, EVs not only contribute to local immune suppression but also create a systemic environment that is less favorable for effective anticancer immunity. Therefore, understanding the role of EVs in the immunotherapy resistance is crucial for developing targeted strategies to counteract their effects and ultimately improve therapeutic outcomes. Here we encourage researchers to pay more attention to the role of cancer cell-derived EVs in overcoming immunotherapeutic resistance, because such efforts may be one of the most promising approaches to address immunotherapy resistance in the future.

Keywords:  cancer therapy; extracellular vesicles; immune cells; immune checkpoint inhibitors; immunotherapeutic resistance; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1601266