bims-flamet 2025-02-23 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2025–02–23
28 papers selected by
Peio Azcoaga, Biodonostia HRI

Promotion Mechanisms of Stromal Cell-Mediated Lung Cancer Development Within Tumor Microenvironment.
The role of non-malignant B cells in malignant hematologic diseases.
Lymphatic transport in anti-tumor immunity and metastasis.
Cancer-associated fibroblasts in hepatocellular carcinoma: heterogeneity, mechanisms and therapeutic targets.
Linking macrophage metabolism to function in the tumor microenvironment.
Cholesterol metabolism in tumor immunity: Mechanisms and therapeutic opportunities for cancer.
Metabolic crosstalk between platelets and cancer: Mechanisms, functions, and therapeutic potential.
Tumor-associated stroma shapes the spatial tumor immune microenvironment of primary Ewing sarcomas.
Exosomes: a double-edged sword in cancer immunotherapy.
Cancer-associated fungi: An emerging powerful player in cancer immunotherapy.
Dendritic cell immunotherapy has its antitumor action improved by the LPS in the maturation process.
Editorial: LncRNAs in tumor microenvironment: its role in immunoregulation and inflammation.
It's about TIME - Gal-9 as a potential immunotherapeutic target in pancreatic ductal adenocarcinoma.
Tumor-Associated Pericytes: Tumorigenicity and Targeting for Cancer Therapy.
CDKN2ALow cancer cells outcompete macrophages for microenvironmental zinc to drive immunotherapy resistance.
CK2: The master regulator in tumor immune-microenvironment - A crucial target in oncotherapy.
Unravelling the role of ubiquitin-specific proteases in breast carcinoma: insights into tumour progression and immune microenvironment modulation.
Revolutionizing pancreatic cancer treatment with CAR-T therapy.
Breast cancer stem cells convert anti-tumor CD4+ T cells to pro-tumor T regulatory cells: Potential role of exosomal FOXP3.
Engineering cytokines for tumor-targeting and selective T cell activation.
Research progress of HIF-1a on immunotherapy outcomes in immune vascular microenvironment.
Deterministic Role of FOXF2 in Organ-Specific Macrometastasis Transition.
Tumor-Associated Macrophages Write the Script of Cancer Obesity Paradox.
Cooperation between inhibitory immune checkpoints of senescent cells with immunosuppressive network to promote immunosenescence and the aging process.
CD96: immunoregulation and its role and prospect in immunotherapy of primary hepatocellular carcinoma.
Immunoregulatory mechanisms of the arachidonic acid pathway in cancer.
Cancer stem cells and tumor-associated macrophages as mates in tumor progression: mechanisms of crosstalk and advanced bioinformatic tools to dissect their phenotypes and interaction.
Pancreatic cancer-intrinsic HuR regulates the pro-tumorigenic properties of extracellular vesicles.

Cancer Manag Res. 2025 ;17 249-266

Promotion Mechanisms of Stromal Cell-Mediated Lung Cancer Development Within Tumor Microenvironment.

Siyu Wu, Yumeng Hu, Bowen Sui.

  Lung cancer, with its high incidence and mortality rates, has garnered significant attention in the medical community. The tumor microenvironment (TME), composed of tumor cells, stromal cells, extracellular matrix, surrounding blood vessels, and other signaling molecules, plays a pivotal role in the development of lung cancer. Stromal cells within the TME hold potential as therapeutic targets for lung cancer treatment. However, the precise and comprehensive mechanisms by which stromal cells contribute to lung cancer progression have not been fully elucidated. This review aims to explore the mechanisms through which stromal cells in the tumor microenvironment promote lung cancer development, with a particular focus on how immune cells, tumor-associated fibroblasts, and endothelial cells contribute to immune suppression, inflammation, and angiogenesis. The goal is to provide new insights and potential strategies for the diagnosis and treatment of lung cancer.

Keywords:  cancer-associated fibroblasts; endothelial cells; immune cells; lung cancer; stromal cells; tumor microenvironment

DOI:  https://doi.org/10.2147/CMAR.S505549
Hematology. 2025 Dec;30(1): 2466261

The role of non-malignant B cells in malignant hematologic diseases.

Daquan Gao.

  The tumor microenvironment (TME) represents a heterogeneous, complicated ecosystem characterized by intricate interactions between tumor cells and immune cells. During the past decade, immune cells especially T cells were found to play an important role in the progression of tumor and many related immune checkpoints drugs were created. In recent years, more and more scientists revealed the critical role of B-cells within the TME, particularly various populations of non-malignant B cells. Some studies indicated that non-malignant B cells may exert a 'double-edged sword' role in solid tumors. However, there has been comparatively less focus on the role of non-malignant B cells in hematologic malignancies. In this review, we characterized the development of B cells and summarized its functions of antitumor immunity within TME, with an emphasis on elucidating the roles and potential mechanisms of non-malignant B cells in the progression of hematologic diseases including classical Hodgkin's lymphoma, non-Hodgkin's B-cell lymphoma, non-Hodgkin's T-cell lymphoma, leukemia and multiple myeloma.

Keywords:  Non-malignant B cells; TME; hematologic malignancies

DOI:  https://doi.org/10.1080/16078454.2025.2466261
J Exp Med. 2025 Mar 03. pii: e20231954. [Epub ahead of print]222(3):

Lymphatic transport in anti-tumor immunity and metastasis.

Mengzhu Sun, Julien Angelillo, Stéphanie Hugues.

Although lymphatic vessels (LVs) are present in many tumors, their importance in cancer has long been underestimated. In contrast to the well-studied tumor-associated blood vessels, LVs were previously considered to function as passive conduits for tumor metastasis. However, emerging evidence over the last two decades has shed light on their critical role in locally shaping the tumor microenvironment (TME). Here we review the involvement of LVs in tumor progression, metastasis, and modulation of anti-tumor immune response.

DOI: https://doi.org/10.1084/jem.20231954
Hepatol Int. 2025 Feb 20.

Cancer-associated fibroblasts in hepatocellular carcinoma: heterogeneity, mechanisms and therapeutic targets.

Yutong Li, Mawieh Hamad, Eyad Elkord.

  Hepatocellular carcinoma (HCC) is one of the common malignant cancers worldwide. Although immunotherapy has improved the treatment outcome in HCC, a significant percentage of patients with advanced HCC still cannot benefit from immunotherapy. Therefore, developing new targets or combination therapeutic strategies to improve the efficacy of immunotherapy is urgently needed. A deeper understanding of the mechanisms underlying immune regulation may help in this regard. The tumor microenvironment (TME) consists of a diverse set of components modulating the efficacy of immunotherapy. Cancer-associated fibroblasts (CAFs) are critical components of the TME and can regulate both tumor and immune cells through secreted cytokines and exosomes that impact various signaling pathways in target cells. CAF-derived cytokines can also participate in extracellular matrix (ECM) remodeling, thereby impacting cancer progression and tumor responsiveness to immunotherapy among other effects. A thorough understanding of the phenotypic and functional profile dynamism of CAFs may lead the way for new treatment strategies and/or better treatment outcomes in HCC patients. In this review, we outline the biomarkers and functional heterogeneity of CAFs in HCC and elaborate on molecular mechanisms of CAFs, including anti-programmed cell death protein 1 (PD-1)/PD-ligand 1 (PD-L1) immunotherapy. We also examine current clinical implications of CAFs-related targets as potential therapeutic candidates in HCC.

Keywords:  Cancer-associated fibroblasts; Hepatocellular carcinoma; Immunotherapy; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12072-025-10788-5
Nat Cancer. 2025 Feb 17.

Linking macrophage metabolism to function in the tumor microenvironment.

Robbie Jin, Luke Neufeld, Tracy L McGaha.

Macrophages are present at high frequency in most solid tumor types, and their relative abundance negatively correlates with therapy responses and survival outcomes. Tissue-resident macrophages are highly tuned to integrate tissue niche signals, and multiple factors within the idiosyncratic tumor microenvironment (TME) drive macrophages to polarization states that favor immune suppression, tumor growth and metastasis. These diverse functional states are underpinned by extensive and complex rewiring of tumor-associated macrophage (TAM) metabolism. In this Review, we link distinct and specific macrophage functional states within the TME to major, phenotype-sustaining metabolic programs and discuss the metabolic impact of macrophage-modulating therapeutic interventions.

DOI: https://doi.org/10.1038/s43018-025-00909-2
Biochem Pharmacol. 2025 Feb 13. pii: S0006-2952(25)00064-4. [Epub ahead of print]234 116802

Cholesterol metabolism in tumor immunity: Mechanisms and therapeutic opportunities for cancer.

Xiao-Jia Guo, Bo-Bo Zhu, Jing Li, Ping Guo, Yin-Bo Niu, Jun-Ling Shi, Wallace Yokoyama, Qing-Sheng Huang, Dong-Yan Shao.

  Cholesterol is an essential component of the cell membrane which plays a critical role in the survival of immune and tumor cells. Reprogramming of cholesterol metabolism in both tumor cells and immune cells can impact tumor progression and anti-tumor immune responses. Strategies aimed at modulating cholesterol metabolism have been demonstrated to be effective in hindering tumor growth and boosting anti-tumor immune functions. This review provides a thorough analysis of intracellular cholesterol homeostasis regulation in cells, focusing on key genes and signaling pathways. It particularly emphasizes the regulatory mechanisms and importance of the cholesterol presence state (esterified/free), levels of cholesterol, and its metabolites in immune and tumor cells. Additionally, the review thoroughly explores how cholesterol metabolism and sources (endogenous/exogenous) in the tumor microenvironment (TME) contribute to the interplay among tumor cells, immune suppressor cells, and immune effector cells, promoting cancer progression and immune evasion. It also delves into current insights on the influence of cholesterol metabolites and related drugs in regulating tumor development or immunotherapy. Finally, it presents an overview of recent advancements in clinical and preclinical trials investigating the efficacy of targeted cholesterol metabolism treatments and combination therapies in cancer management, while proposing potential future research directions in tumor immunity. This review is poised to offer fresh perspectives and avenues for examining the potential of cancer immunotherapy centered on cholesterol metabolism regulation.

Keywords:  Cholesterol metabolism; Immune; NK cells; T cells; Tumor; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bcp.2025.116802
Semin Cancer Biol. 2025 Feb 13. pii: S1044-579X(25)00013-6. [Epub ahead of print]110 65-82

Metabolic crosstalk between platelets and cancer: Mechanisms, functions, and therapeutic potential.

Zhixue Chen, Lin Xu, Yejv Yuan, Si Zhang, Ruyi Xue.

  Platelets, traditionally regarded as passive mediators of hemostasis, are now recognized as pivotal regulators in the tumor microenvironment, establishing metabolic feedback loops with tumor and immune cells. Tumor-derived signals trigger platelet activation, which induces rapid metabolic reprogramming, particularly glycolysis, to support activation-dependent functions such as granule secretion, morphological changes, and aggregation. Beyond self-regulation, platelets influence the metabolic processes of adjacent cells. Through direct mitochondrial transfer, platelets reprogram tumor and immune cells, promoting oxidative phosphorylation. Additionally, platelet-derived cytokines, granules, and extracellular vesicles drive metabolic alterations in immune cells, fostering suppressive phenotypes that facilitate tumor progression. This review examines three critical aspects: (1) the distinctive metabolic features of platelets, particularly under tumor-induced activation; (2) the metabolic crosstalk between activated platelets and other cellular components; and (3) the therapeutic potential of targeting platelet metabolism to disrupt tumor-promoting networks. By elucidating platelet metabolism, this review highlights its essential role in tumor biology and its therapeutic implications.

Keywords:  Cancer therapy; Energy metabolism; Mitochondrial transfer; Platelet

DOI:  https://doi.org/10.1016/j.semcancer.2025.02.001
bioRxiv. 2025 Feb 06. pii: 2025.01.31.635996. [Epub ahead of print]

Tumor-associated stroma shapes the spatial tumor immune microenvironment of primary Ewing sarcomas.

Christopher Kuo, Krinio Giannikou, Nuoya Wang, Mikako Warren, Andrew Goodspeed, Nick Shillingford, Masanori Hayashi, Micha Sam Brickman Raredon, James F Amatruda.

To date, few studies have detailed the tumor microenvironment (TME) of Ewing sarcoma (EwS). The TME has a vital role in cancer survival and progression with implications in drug resistance and immune escape. By performing spatially resolved transcriptomic analysis of primary treatment-naïve EwS samples, we discovered greater stromal enrichment in localized EwS tumors compared to metastatic EwS tumors. Through spatial ligand-receptor analysis, we show that the stromal enriched regions harbor unique extracellular matrix related cytokines, immune recruitment and proinflammatory microenvironmental signals, implying EwS stroma may play an anti-tumorigenic role by acting as an immune recruitment center. All EwS tumors expressed pro-tumorigenic MIF-CD74 immune signaling, suggesting a potential immune-evasive mechanism and immunotherapy target. Our findings provide insight into tumor cell/stromal cell interactions in EwS and serve as a valuable resource for further investigations in the tumor immune microenvironment of EwS.

DOI: https://doi.org/10.1101/2025.01.31.635996
MedComm (2020). 2025 Mar;6(3): e70095

Exosomes: a double-edged sword in cancer immunotherapy.

Jiayi Chen, Siyuan Hu, Jiayi Liu, Hao Jiang, Simiao Wang, Zhaogang Yang.

  Over the past few decades, immunotherapy has emerged as a powerful strategy to overcome the limitations of conventional cancer treatments. The use of extracellular vesicles, particularly exosomes, which carry cargoes capable of modulating the immune response, has been extensively explored as a potential therapeutic approach in cancer immunotherapy. Exosomes can deliver their cargo to target cells, thereby influencing their phenotype and immunomodulatory functions. They exhibit either immunosuppressive or immune-activating characteristics, depending on their internal contents. These exosomes originate from diverse cell sources, and their internal contents can vary, suggesting that there may be a delicate balance between immune suppression and stimulation when utilizing them for immunotherapy. Therefore, a thorough understanding of the molecular mechanisms underlying the role of exosomes in cancer progression is essential. This review focuses on the molecular mechanisms driving exosome function and their impact on the tumor microenvironment (TME), highlighting the intricate balance between immune suppression and activation that must be navigated in exosome-based therapies. Additionally, it underscores the challenges and ongoing efforts to optimize exosome-based immunotherapies, thereby making a significant contribution to the advancement of cancer immunotherapy research.

Keywords:  exosome; immune stimulatory; immune suppressive; tumor

DOI:  https://doi.org/10.1002/mco2.70095
Biochim Biophys Acta Rev Cancer. 2025 Feb 17. pii: S0304-419X(25)00029-0. [Epub ahead of print] 189287

Cancer-associated fungi: An emerging powerful player in cancer immunotherapy.

Tianhang Li, Xiangyu Wu, Xiangyang Li, Ming Chen.

  The role of the human microbiome in cancer has been extensively studied, focusing mainly on bacteria-host interactions and their impact on tumor development and treatment response. However, fungi, an immune-active component of the human microbiome, have received less attention regarding their roles in cancer. Recent studies have identified the widespread and specific colonization and distribution of fungi in multiple sites in patients across various cancer types. Importantly, host-fungal immune interactions significantly influence immune regulation within the tumor microenvironment. The rapid advancement of immune-checkpoint blockade (ICB)-based cancer immunotherapy creates an urgent need for effective biomarkers and synergistic therapeutic targets. Cancer-associated fungi and their associated antifungal immunity demonstrate significant potential and efficacy in enhancing cancer immunotherapy. This review summarizes and discusses the growing evidence of the functions and mechanisms of commensal and pathogenic cancer-associated fungi in cancer immunotherapy. Additionally, we emphasize the potential of fungi as predictive biomarkers and therapeutic targets in cancer immunotherapy.

Keywords:  Antifungal immunity; CLRs; ICB; Mycobiome; TME

DOI:  https://doi.org/10.1016/j.bbcan.2025.189287
Clin Transl Oncol. 2025 Feb 20.

Dendritic cell immunotherapy has its antitumor action improved by the LPS in the maturation process.

Angela Maria Moed Lopes, Jéssica Ferreira Vieira, Saulo Fernando Moreira da Silva, Eddie Fernando Candido Murta, Márcia Antoniazi Michelin.

  Immunotherapy with dendritic cells (DCs) in cancer patients aims to activate the immune response to eliminate neoplastic cells. The present study aimed to investigate lipopolysaccharide (LPS)-stimulated bone marrow-derived dendritic cells in investigating antitumor immune response in experimental breast cancer. For this, we submitted bone marrow pluripotent cells of Balb/c mice differentiated by GM-CSF and IL-4 to maturation with TNF-α and tumor lysate (DCs protocol) or with TNF-α, LPS, and tumor lysate (LPS/DCs protocol). Both immunotherapies were tested in 4T1 breast cancer to evaluate their impact on splenic and tumor microenvironment. We observed that DCs and LPS/DCs reduce the tumor growth rate (p < 0.0001). Besides, the LPS/DCs vaccine shows higher splenic and intratumoral T helper lymphocytes (p < 0.001). Both vaccines increased the production of IFN-γ in the tumor microenvironment (p < 0.0001). The LPS/DCs induced lower Treg lymphocytes and macrophages in the tumor microenvironment (p < 0.0001). The results allow us to conclude that bone marrow-derived dendritic cells stimulated with LPS have been shown to reduce tumor growth rate efficiently and could be better immunotherapy in breast cancer by reducing immunosuppressive cells and increasing antitumoral immune cells in the tumor microenvironment.

Keywords:  Antitumor immune response; Bone marrow-derived dendritic cells; Breast cancer; Dendritic cell immunotherapy

DOI:  https://doi.org/10.1007/s12094-025-03858-5
Front Cell Dev Biol. 2025 ;13 1560928

Editorial: LncRNAs in tumor microenvironment: its role in immunoregulation and inflammation.

Dipanjan Ghosh.



Keywords:  cancer; cancer therapy; inflammation; lncRNA; tumor microenvironment

DOI:  https://doi.org/10.3389/fcell.2025.1560928
Front Immunol. 2025 ;16 1495907

It's about TIME - Gal-9 as a potential immunotherapeutic target in pancreatic ductal adenocarcinoma.

Christin Knickmeier, Gaetan Aime Noubissi Nzeteu, Bernhard F Gibbs, Frederik J H Hoogwater, Maarten W Nijkamp, Maximilian Bockhorn, N Helge Meyer.

  Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by an extremely poor prognosis and limited therapeutic options. Central to the progression and immune evasion of PDAC is the tumor (immune) microenvironment (TIME), where immune checkpoint proteins such as galectin-9 (Gal-9) play pivotal roles. Gal-9 significantly contributes to the immunosuppressive milieu of PDAC by interacting with various immune cells, such as T cells, macrophages, and myeloid-derived suppressor cells (MDSCs). These interactions suppress anti-tumor immunity, thus facilitating tumor growth and metastasis. This review comprehensively examines the multifaceted role of Gal-9 in the TIME of PDAC, detailing its mechanisms of action, including the induction of regulatory T cells, polarization of tumor-associated macrophages, and modulation of apoptotic pathways via Tim-3 and caspase activation. The therapeutic potential of targeting Gal-9, either alone or in combination with other immune checkpoint inhibitors such as anti-PD-L1, is also discussed, highlighting preclinical findings that suggest promising avenues for enhancing anti-tumor immune responses. By elucidating the complex biological activities of Gal-9 and its interactions within the TIME, this review underscores the importance of innovative therapeutic strategies aimed at mitigating the immunosuppressive effects of Gal-9 in PDAC.

Keywords:  galectin-9; immune checkpoints; immunotherapy; macrophage (re-)polarization; myeloid-derived suppressor cells; pancreatic ductal adenocarcinoma; tumor immune microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1495907
Curr Vasc Pharmacol. 2025 Feb 19.

Tumor-Associated Pericytes: Tumorigenicity and Targeting for Cancer Therapy.

Jiale Tan, Zihang Yu, Ruozheng Pi, Yan Lin, Wei Wang, Minfeng Chen, Xue Bai.

  Pericytes, also known as mural cells, are cells embedded between endothelial cells and the basement membrane of capillaries, where they orchestrate the morphological and functional homeostasis of blood vessels. Within the tumor microenvironment, pericytes interact closely with various cellular components, including tumor cells, stromal cells, and immune cells. Through these dynamic interactions, pericytes are activated and subsequently transform into tumor-associated pericytes (TPCs). The origin of TPCs varies depending on the tissue and tumor type, contributing to their phenotypic and functional heterogeneity. TPCs play pivotal roles in facilitating tumor progression, metastasis, immune evasion, and therapeutic resistance by promoting angiogenesis, engaging in reciprocal interactions with tumor cells, remodeling the extracellular matrix, and fostering an immunosuppressive microenvironment. This review synthesizes the latest significant advancements in targeted therapies against TPCs. It underscores the challenges inherent in developing effective anti-TPC therapies, which include the heterogeneity and pluripotency of TPCs, the absence of specific markers for precise TPC targeting, and the limited understanding of how current anti-tumor therapies affect TPCs and vice versa. This review furnishes a comprehensive understanding of the origins, markers, and functions of TPCs, and their interplays within the tumor microenvironment, providing prospective strategies for more effective anti-tumor therapy.

Keywords:  Tumor-associated pericytes; angiogenesis; cancer therapy; heterogeneity; immunomodulation.; tumor microenvironment

DOI:  https://doi.org/10.2174/0115701611365339250213101338
bioRxiv. 2025 Feb 08. pii: 2025.02.08.637227. [Epub ahead of print]

CDKN2ALow cancer cells outcompete macrophages for microenvironmental zinc to drive immunotherapy resistance.

Raquel Buj, Aidan R Cole, Jeff Danielson, Jimmy Xu, Drew Hurd, Akash Kishore, Katarzyna M Kedziora, Jie Chen, Baixue Yang, David Barras, Apoorva Uboveja, Amandine Amalric, Juan J Apiz Saab, Jayamanna Wickramasinghe, Naveen Kumar Tangudu, Evan Levasseur, Hui Wang, Aspram Minasyan, Rebekah E Dadey, Allison C Sharrow, Frank P Vendetti, Dayana B Rivadeneira, Christopher J Bakkenist, Greg M Delgoffe, Nadine Hempel, Nathaniel W Snyder, Riyue Bao, Adam C Soloff, John M Kirkwood, Denarda Dangaj Laniti, Andrew V Kossenkov, Alexander Muir, Jishnu Das, Diwakar Davar, Clementina Mesaros, Katherine M Aird.

Approximately 50% of cancers exhibit decreased CDKN2A expression ( CDKN2A Low ), which is linked to immune checkpoint blockade (ICB) resistance. While CDKN2A is traditionally recognized as a tumor suppressor and cell cycle regulator, we have previously put forth a new paradigm demonstrating its role in intracellular metabolic reprogramming. Whether the metabolic derangement due to CDKN2A loss alters metabolites within the tumor microenvironment (TME) and how that affects the immune compartment and ICB response has never been investigated. Here we found that CDKN2A Low cancer cells reorganize zinc compartmentalization by upregulating the zinc importer SLC39A9 in the plasma membrane, leading to intracellular zinc accumulation in cancer cells and concurrent zinc depletion in the TME. This competition for zinc results in zinc-starved macrophages, leading to reduced phagocytic activity. Remarkably, restoring zinc levels in the TME through a dietary intervention re-educates macrophages to a pro-phagocytic phenotype, sensitizing CDKN2A Low tumors to ICB. Unexpectedly, T cells are not required for this response. Clinically, macrophages from CDKN2A Low cancer patients have decreased zinc signatures, corresponding to reduced phagocytosis signatures. Moreover, patients with low circulating zinc levels have reduced time-to-event outcomes compared to those with higher zinc levels. Our work reveals a previously unrecognized mechanism through which CDKN2A Low cancer cells outcompete macrophages for zinc, directly disrupting their function and ICB efficacy.

DOI: https://doi.org/10.1101/2025.02.08.637227
Eur J Pharmacol. 2025 Feb 12. pii: S0014-2999(25)00129-3. [Epub ahead of print]994 177376

CK2: The master regulator in tumor immune-microenvironment - A crucial target in oncotherapy.

Subhajit Karmakar, Mouli Chatterjee, Malini Basu, Mrinal K Ghosh.

  A constitutively active serine/threonine kinase, casein kinase 2 (CK2) is involved in several physiological functions, such as DNA repair, apoptosis, and cell cycle control. New research emphasizes how critical CK2 is to the immune system's dysregulation in the tumor immune-microenvironment (TIME). The inhibition of immunological responses, including the downregulation of immune effector cells and the elevation of immunosuppressive proteins that aid in the development of tumor and immune evasion, has been linked to CK2 overexpression. CK2 maintains an immunosuppressive milieu that impedes anti-tumor immunity by encouraging the expressions and activities of immune checkpoint markers, regulating cytokines release, and boosting immune-suppressive cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) to maintain immune evasion. It is a promising target for cancer treatment due to its complex role in immune regulation and oncogenic pathways. In this study, we address the therapeutic perspectives of targeting CK2 in oncotherapy and investigate the mechanisms by which it controls immunological responses in the TME. This review, comprehending the function of CK2 in immune suppression can facilitate the creation of innovative treatment approaches aimed at augmenting anti-tumor immunity and enhancing immunotherapy effectiveness.

Keywords:  CK2; Immune system; Regulation; Therapeutics; Tumor immune microenvironment (TIME)

DOI:  https://doi.org/10.1016/j.ejphar.2025.177376
World J Surg Oncol. 2025 Feb 20. 23(1): 60

Unravelling the role of ubiquitin-specific proteases in breast carcinoma: insights into tumour progression and immune microenvironment modulation.

Huiyuan Yang, Tingting Sun, Zhenni Sun, Haining Wang, Dongjie Liu, Dapeng Wu, Tao Qin, Mi Zhou.

  Breast cancer is a prevalent malignancy worldwide, and its treatment has increasingly shifted towards precision medicine, with immunotherapy emerging as a key therapeutic strategy. Deubiquitination, an essential epigenetic modification, is regulated by deubiquitinating enzymes (DUBs) and plays a critical role in immune function and tumor progression. Ubiquitin-specific proteases (USPs), a prominent subgroup of DUBs, are involved in regulating immune cell functions, antigen processing, and T cell development in the context of breast cancer. Certain USPs also modulate the differentiation of immune cells, such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), within the breast cancer immune microenvironment. Furthermore, several USPs influence the expression of PD-L1, thus affecting the efficacy of immune checkpoint inhibitors. The overexpression of USPs may promote immune evasion, contributing to the development of treatment resistance. This review elucidates the role of USPs in modulating the immune microenvironment and immune responses in breast cancer. Additionally, it discusses effective strategies for combining USP inhibitors with other therapeutic agents to enhance treatment outcomes. Therefore, targeting USPs presents the potential to enhance the efficacy of immunotherapy and overcome drug resistance, offering a more effective treatment strategy for breast cancer patients.

Keywords:  Breast carcinoma; Immune microenvironment; Immune response; PD-L1; Tumour microenvironment; Ubiquitin-specific proteases

DOI:  https://doi.org/10.1186/s12957-025-03667-8
Adv Protein Chem Struct Biol. 2025 ;pii: S1876-1623(24)00109-3. [Epub ahead of print]144 331-353

Revolutionizing pancreatic cancer treatment with CAR-T therapy.

Kirti Baghel, Sanjana Mehrotra, Vijay Kumar Prajapati.

  Pancreatic cancer remains one of the most lethal malignancies, with a five-year survival rate among the lowest of all cancers. This poor prognosis is largely due to the aggressive nature of the disease and its resistance to conventional treatments such as surgery, chemotherapy, and radiation therapy. Chimeric antigen receptor (CAR) T-cell therapy, a novel immunotherapeutic approach leverages the patient's own immune system to specifically target and eliminate cancer cells by genetically engineering T cells to express CARs that recognize tumor-specific antigens. While CAR-T therapy has demonstrated remarkable success in treating hematologic malignancies, its application to solid tumors like pancreatic cancer presents significant challenges. Recent advancements in CAR-T cell design, like the addition of co-stimulatory domains and dual-targeting CARs, have enhanced their efficacy against solid tumors. Additionally, strategies to modify the tumor microenvironment (TME), such as combining CAR-T therapy with immune checkpoint inhibitors and cytokine modulation, are being investigated to boost CAR-T cell activity against pancreatic cancer. Early-phase clinical trials targeting antigens such as carcinoembryonic antigen (CEA) and mesothelin (MSLN) in pancreatic cancer have yielded encouraging results, though obstacles like antigen escape and limited T-cell persistence remain significant challenges. This chapter outlines the current state of CAR-T therapy for pancreatic cancer, focusing on the emerging approaches to address these obstacles and underscore the potential of CAR-T therapy to transform the future of pancreatic cancer treatment.

Keywords:  CAR T cells; Immunotherapy; Pancreatic antigens; Pancreatic cancer; Tumor microenvironment

DOI:  https://doi.org/10.1016/bs.apcsb.2024.10.008
Cell Immunol. 2025 Feb 20. pii: S0008-8749(25)00016-4. [Epub ahead of print]409-410 104931

Breast cancer stem cells convert anti-tumor CD4+ T cells to pro-tumor T regulatory cells: Potential role of exosomal FOXP3.

Udit Basak, Sourio Chakraborty, Sumon Mukherjee, Subhadip Pati, Poulami Khan, Subhajit Ghosh, Arghya Adhikary, Kuladip Jana, Gaurisankar Sa, Tanya Das.

  Cancer progression and its treatment-response are regulated by the tumor microenvironment (TME). Tumor-initiating cancer stem cells (CSCs) remain in constant communication with the TME, and modulate it through several mechanisms. Here, from in-silico findings and analyzing breast cancer patient tissue-derived data, CSCs and Tregs were found to be positively correlated. Furthermore, our in-silico analyses highlighted a positive relationship between CSC genes and Treg signature marker, FOXP3, even in cancer cell lines that do not contain any T cell or Treg cells, thus raising the possibility of CSCs expressing FOXP3. Validating our hypothesis, higher expression of FOXP3, both at mRNA and protein levels, was observed in breast CSCs than non-stem cancer cells. Since a small population of CSCs initiate tumor in immune cell-dominated TME, we aimed at exploring whether breast CSCs directly transfer FOXP3 to CD4+T cells to generate immunosuppressive Treg cells. First, our search revealed CSC-derived exosomes (CDEs) generated CD4+CD25+FOXP3+ Tregs at an early time-point of 24 h, which were immunosuppressive in nature. Next, detecting presence of FOXP3 protein in CDEs showed a strong possibility of FOXP3 transfer through CDEs. This was supported by detecting elevated FOXP3 levels from 12 h in translation inhibitor-treated T cells upon CDE-exposure. Finally, exosomes derived from FOXP3 attenuated-CSCs furnished lower FOXP3 in T cells than control CDEs. This mechanism was validated in in-vivo murine model. Together these results indicate a hitherto unexplored role of CSC-derived FOXP3 in reprogramming T cells into immunosuppressive Treg cells.

Keywords:  Cancer stem cells; Exosome; FOXP3; Immunosuppressive; Treg cells; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.cellimm.2025.104931
Trends Mol Med. 2025 Feb 14. pii: S1471-4914(25)00010-3. [Epub ahead of print]

Engineering cytokines for tumor-targeting and selective T cell activation.

Kun Peng, Yang-Xin Fu, Yong Liang.

  Cytokines are promising therapeutic agents for cancer due to their immune-stimulating properties. However, their clinical application is limited by a narrow therapeutic window and dose-limiting on-target, off-tumor toxicity. Advances in protein engineering enable the selective delivery of cytokines to the tumor microenvironment (TME) and antigen-specific T cells, enhancing antitumor efficacy while reducing systemic side effects. This review focuses on selected cytokines and outlines their developmental trajectory for treating solid tumors. We highlight strategies for constructing cis-signaling immunocytokines and procytokines for precise delivery to tumor sites and discuss the biological mechanisms through which these cytokines reactivate antitumor immunity. We also discuss the challenges and future directions for creating more effective cytokine-based therapeutics.

Keywords:  cis-signaling; immunocytokines; immunotherapy; procytokines; protein engineering

DOI:  https://doi.org/10.1016/j.molmed.2025.01.010
Front Immunol. 2025 ;16 1549276

Research progress of HIF-1a on immunotherapy outcomes in immune vascular microenvironment.

Shaoyan Shi, Xuehai Ou, Chao Liu, Hao Wen, Jiang Ke.

  The hypoxia-inducible factor-1α (HIF-1α) plays a key role in facilitating the adaptation of cells to hypoxia, profoundly influencing the immune vascular microenvironment (IVM) and immunotherapy outcomes. HIF-1α-mediated tumor hypoxia drives angiogenesis, immune suppression, and extracellular matrix remodeling, creating an environment that promotes tumor progression and resistance to immunotherapies. HIF-1α regulates critical pathways, including the expression of vascular endothelial growth factor and immune checkpoint upregulation, leading to tumor-infiltrating lymphocyte dysfunction and recruitment of immunosuppressive cells like regulatory T cells and myeloid-derived suppressor cells. These alterations reduce the efficacy of checkpoint inhibitors and other immunotherapies. Recent studies highlight therapeutic strategies that target HIF-1α, such as the use of pharmacological inhibitors, gene editing techniques, and hypoxia-modulating treatments, which show promise in enhancing responses to immunotherapy. This review explores the molecular mechanisms of action of HIF-1α in IVM, its impact on immunotherapy resistance, as well as potential interventions, emphasizing the need for innovative approaches to circumvent hypoxia-driven immunosuppression in cancer therapy.

Keywords:  HIF-1 α; VEGF; immune vascular microenvironment; immune vascular microenvironment and immunotherapy; immunotherapy resistance; machine learning HIF-1a; personalized cancer therapy

DOI:  https://doi.org/10.3389/fimmu.2025.1549276
Cancer Res. 2025 Feb 17. 85(4): 639-641

Deterministic Role of FOXF2 in Organ-Specific Macrometastasis Transition.

Igor L Bado.

The mechanisms contributing to metastasis tropism in breast cancer are far from being understood. The ability of cancer cells to adapt to new microenvironments plays a crucial role in that process. In this issue of Cancer Research, Jiang and colleagues explored the tumor-intrinsic differences that affect seeding and tissue colonization by focusing on two major sites of breast cancer metastasis: the lung and bone. They used genetic approaches and metastasis modeling to assess the role of forkhead box F2 (FOXF2) in remodeling the tumor microenvironment and promoting metastasis outgrowth. Their findings suggest that FOXF2 promotes a micrometastasis-to-macrometastasis transition in bones through the direct activation of NF-κB and BMP4 signaling pathways, independently of tumor subtype. In contrast, FOXF2 was found to hinder the ability of basal models to colonize the lung microenvironment through inhibition of TGFβ signaling. Collectively, these findings underscore the subtype-specific and tissue-dependent roles of FOXF2 in organotropism. See related article by Jiang et al., p. 644.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-4078
Bioessays. 2025 Feb 19. e202400264

Tumor-Associated Macrophages Write the Script of Cancer Obesity Paradox.

Anshul Sharma, Alok K Mishra.

Obesity paradoxically advances cancer progression while enhancing certain immunotherapies, like anti-PD-1/PD-L1. Bader et al. discovered that obesity-driven factors increase PD-1 on tumor-associated macrophages (TAMs), suppressing anti-tumor responses. Remarkably, anti-PD-1 therapy reverses this metabolic dysfunction, boosting immune checkpoint blockade (ICB) effectiveness by reactivating PD-1+ TAMs.

DOI: https://doi.org/10.1002/bies.202400264
Ageing Res Rev. 2025 Feb 19. pii: S1568-1637(25)00040-6. [Epub ahead of print] 102694

Cooperation between inhibitory immune checkpoints of senescent cells with immunosuppressive network to promote immunosenescence and the aging process.

Antero Salminen.

  The accumulation of senescent cells within tissues promotes the aging process by remodelling the functions of the immune system. For many years, it has been known that senescent cells secrete pro-inflammatory cytokines and chemokines, a phenotype called the senescence-associated secretory phenotype (SASP). Chemokines and colony-stimulating factors stimulate myelopoiesis and recruit myeloid cells into aging tissues. Interestingly, recent studies have demonstrated that senescent cells are not only secretory but they also express an increased level of ligand proteins for many inhibitory immune checkpoint receptors. These ligands represent "don't eat me" markers in senescent cells and moreover, they are able to induce an exhaustion of many immune cells, such as surveying natural killer (NK) cells, cytotoxic CD8+ T cells, and macrophages. The programmed cell death protein-1 (PD-1) and its ligand PD-L1 represent the best known inhibitory immune checkpoint pathway. Importantly, the activation of inhibitory checkpoint receptors, e.g., in chronic inflammatory states, can also induce certain immune cells to differentiate toward their immunosuppressive phenotype. This can be observed in myeloid derived suppressor cells (MDSC), tissue regulatory T cells (Treg), and M2 macrophages. Conversely, these immunosuppressive cells stimulate in senescent cells the expression of many ligand proteins for inhibitory checkpoint receptors. Paradoxically, senescent cells not only promote the pro-inflammatory state but they maintain it at a low-grade level by expressing ligands for inhibitory immune checkpoint receptors. Thus, the cooperation between senescent cells and immunosuppressive cells enhances the senescence state of immune cells, i.e., immune senescence/exhaustion, and cellular senescence within tissues via bystander effects.

Keywords:  Ageing; Immune surveillance; Immune tolerance; Immunosuppression; Senotherapeutics

DOI:  https://doi.org/10.1016/j.arr.2025.102694
Eur J Gastroenterol Hepatol. 2025 Jan 06.

CD96: immunoregulation and its role and prospect in immunotherapy of primary hepatocellular carcinoma.

Jiaqi Chai, Luyang Li, Qimei Wu, Shuhan Zhang.

Recently, immune checkpoint inhibitors have been widely used in the treatment of advanced liver cancer. Immune checkpoints are a type of molecules that play an important role in the self-regulation of the immune system. In tumor immunity, their activation by immune checkpoints leads to the inhibition of effector lymphocyte activation or the mediation of cytotoxic T cell dysfunction, resulting in immune escape. These immune checkpoints include programmed death receptor 1 (PD-1) and its ligand PD-L1, as well as cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and others. Immune checkpoint inhibitors block the interaction between immune checkpoint receptors and ligands, thereby relieving the immune suppression caused by immune checkpoints, and reactivating immune cells to exert antitumor effects. With the continuous progress of immunotherapy research, drugs targeting PDL-1, PD-1, and CTLA-4 have played an important role in clinical treatment. However, some patients still cannot benefit from immunotherapy; therefore, multitarget immunotherapy is an important way to improve the response rate of immunotherapy. CD96 is one of the members of the immunoglobulin superfamily receptors, which mainly functions by regulating natural killer cells and CD8+ T cells, and is expected to become a new generation of immune checkpoints. This article reviews the molecular structure of CD96, its role in tumor immunity, and its application in hepatocellular carcinoma, hoping to provide reference for related research.

DOI: https://doi.org/10.1097/MEG.0000000000002916
FEBS Lett. 2025 Feb 20.

Immunoregulatory mechanisms of the arachidonic acid pathway in cancer.

Maria Tredicine, Matteo Mucci, Antonio Recchiuti, Domenico Mattoscio.

  The arachidonic acid (AA) pathway promotes tumor progression by modulating the complex interactions between cancer and immune cells within the microenvironment. In this Review, we summarize the knowledge acquired thus far concerning the intricate mechanisms through which eicosanoids either promote or suppress the antitumor immune response. In addition, we will discuss the impact of eicosanoids on immune cells and how they affect responsiveness to immunotherapy, as well as potential strategies for manipulating the AA pathway to improve anticancer immunotherapy. Understanding the molecular pathways and mechanisms underlying the role played by AA and its metabolites in tumor progression may contribute to the development of more effective anticancer immunotherapies.

Keywords:  arachidonic acid; cancer; cyclooxygenases; eicosanoids; immunity; immunotherapy; leukotrienes; lipoxygenases; prostaglandins; pro‐resolving mediators

DOI:  https://doi.org/10.1002/1873-3468.70013
Front Immunol. 2025 ;16 1529847

Cancer stem cells and tumor-associated macrophages as mates in tumor progression: mechanisms of crosstalk and advanced bioinformatic tools to dissect their phenotypes and interaction.

Francesco Verona, Sebastiano Di Bella, Roberto Schirano, Camilla Manfredi, Francesca Angeloro, Giulia Bozzari, Matilde Todaro, Giuseppe Giannini, Giorgio Stassi, Veronica Veschi.

  Cancer stem cells (CSCs) are a small subset within the tumor mass significantly contributing to cancer progression through dysregulation of various oncogenic pathways, driving tumor growth, chemoresistance and metastasis formation. The aggressive behavior of CSCs is guided by several intracellular signaling pathways such as WNT, NF-kappa-B, NOTCH, Hedgehog, JAK-STAT, PI3K/AKT1/MTOR, TGF/SMAD, PPAR and MAPK kinases, as well as extracellular vesicles such as exosomes, and extracellular signaling molecules such as cytokines, chemokines, pro-angiogenetic and growth factors, which finely regulate CSC phenotype. In this scenario, tumor microenvironment (TME) is a key player in the establishment of a permissive tumor niche, where CSCs engage in intricate communications with diverse immune cells. The "oncogenic" immune cells are mainly represented by B and T lymphocytes, NK cells, and dendritic cells. Among immune cells, macrophages exhibit a more plastic and adaptable phenotype due to their different subpopulations, which are characterized by both immunosuppressive and inflammatory phenotypes. Specifically, tumor-associated macrophages (TAMs) create an immunosuppressive milieu through the production of a plethora of paracrine factors (IL-6, IL-12, TNF-alpha, TGF-beta, CCL1, CCL18) promoting the acquisition by CSCs of a stem-like, invasive and metastatic phenotype. TAMs have demonstrated the ability to communicate with CSCs via direct ligand/receptor (such as CD90/CD11b, LSECtin/BTN3A3, EPHA4/Ephrin) interaction. On the other hand, CSCs exhibited their capacity to influence immune cells, creating a favorable microenvironment for cancer progression. Interestingly, the bidirectional influence of CSCs and TME leads to an epigenetic reprogramming which sustains malignant transformation. Nowadays, the integration of biological and computational data obtained by cutting-edge technologies (single-cell RNA sequencing, spatial transcriptomics, trajectory analysis) has significantly improved the comprehension of the biunivocal multicellular dialogue, providing a comprehensive view of the heterogeneity and dynamics of CSCs, and uncovering alternative mechanisms of immune evasion and therapeutic resistance. Moreover, the combination of biology and computational data will lead to the development of innovative target therapies dampening CSC-TME interaction. Here, we aim to elucidate the most recent insights on CSCs biology and their complex interactions with TME immune cells, specifically TAMs, tracing an exhaustive scenario from the primary tumor to metastasis formation.

Keywords:  TAMs; cancer stem cells; signaling pathway analysis; single-cell RNA sequencing (scRNA-seq); spatial transcriptomics; trajectory analysis

DOI:  https://doi.org/10.3389/fimmu.2025.1529847
bioRxiv. 2025 Feb 08. pii: 2025.02.08.637077. [Epub ahead of print]

Pancreatic cancer-intrinsic HuR regulates the pro-tumorigenic properties of extracellular vesicles.

Jennifer M Finan, Yifei Guo, Alexandra Q Bartlett, Matthew Reyer, Kevin Hawthorne, Margaret Haerr, Hen Halamish, Olayinka Lamikanra, Valerie Calvert, Canping Chen, Zheng Xia, Emanuel F Petricoin, Rosalie C Sears, Katelyn T Byrne, Jonathan R Brody.

Pancreatic ductal adenocarcinoma (PDAC) tumors contain chaotic vasculature that limits immune surveillance and promotes early events in the metastatic cascade. However, current antiangiogenic therapies have failed in PDAC, and thus, it remains important to uncover mechanisms by which cancer cells signal to endothelial cells to increase angiogenesis. Our lab has shown that the tumor-intrinsic RNA-binding protein HuR ( ELAVL1 ) plays an important role re-shaping the tumor microenvironment (TME) by regulating the stability and translation of cytokine encoding transcripts. Herein, we demonstrate that PDAC-intrinsic HuR influences endothelial cell function in the TME via extracellular vesicle (EV) signaling, an underexplored signaling axis in tumor progression. We found that HuR knockout (KO) tumors have impaired growth in an immunocompetent mouse model, and that administering purified wildtype (WT) EVs can increase tumor growth. Further, we observed that PDAC EVs contain HuR-dependent mRNA and protein cargoes relating to endothelial cell function and angiogenesis. Treatment of endothelial cells with HuR WT EVs strongly increased the expression of genes involved in barrier function and endothelial cell development, and directly increased their migratory and tube forming functions. In an immunocompetent orthotopic mouse model of PDAC, we showed that HuR increases endothelial cell presence and sprouting, while decreasing ICAM-1 expression. Importantly, we found utilizing a genetic EV reporter, that decreased ICAM-1 within WT tumors occurs in endothelial cells that have imported PDAC EVs, suggesting that this signaling axis is directly modulating endothelial cell behavior in vivo . Collectively, our data reveal a new role of HuR in EV signaling to endothelial cells, promoting angiogenesis while restricting endothelial cell leukocyte trafficking behavior.

DOI: https://doi.org/10.1101/2025.02.08.637077