bims-flamet 2025-06-01 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2025–06–01
thirty-two papers selected by
Peio Azcoaga, Biodonostia HRI

Immunosuppressive tumor microenvironment in pancreatic cancer: mechanisms and therapeutic targets.
Ferroptosis in TNBC: interplay with tumor-infiltrating immune cells and therapeutic implications.
Tumor-Associated Macrophages: Polarization, Immunoregulation, and Immunotherapy.
Harnessing Dendritic Cell Function in Hepatocellular Carcinoma: Advances in Immunotherapy and Therapeutic Strategies.
Lactate-mediated metabolic reprogramming of tumor-associated macrophages: implications for tumor progression and therapeutic potential.
Molecular Mechanisms in the Carcinogenesis of Oral Squamous Cell Carcinoma: A Literature Review.
The Role of Tregs in the Tumor Microenvironment.
Cancer microbiota: a focus on tumor-resident bacteria.
CAF-Targeting Antibody-Drug Conjugates (ADCs) in Solid Cancers.
Tumor immune evasion and the Let-7 family: insights into mechanisms and therapies.
Glycopolymeric Nanoparticles Block Breast Cancer Growth by Inhibiting Efferocytosis in the Tumor Microenvironment.
Reprogramming the neuroblastoma tumor immune microenvironment to enhance GPC2 CAR T cells.
Lactylation in Tumor Microenvironment and Immunotherapy Resistance: New Mechanisms and Challenges.
Tumor-infiltrating immune cells state-implications for various breast cancer subtypes.
Tumor hypoxia shapes natural killer cell anticancer activities.
Unraveling the immunosuppressive microenvironment of glioblastoma and advancements in treatment.
Innate Immunity and Platelets: Unveiling Their Role in Chronic Pancreatitis and Pancreatic Cancer.
The Role of the Tumor Microenvironment in Pancreatic Ductal Adenocarcinoma: Recent Advancements and Emerging Therapeutic Strategies.
The Basis for Targeting the Tumor Macrophage Compartment in Glioblastoma Immunotherapy.
Immune Evasion in Cancer Metastasis: An Unappreciated Role of Monocytes.
The intricate role of adipokines in cancer-related signaling and the tumor microenvironment: Insights for future research.
The Crucial Nexus: Unveiling the Role of Collagen in Cancer Progression.
Tumor-derived vesicles in immune modulation: focus on signaling pathways.
High-order interaction modeling of tumor-microenvironment crosstalk for tumor growth.
Unconventional T Cells' Role in Cancer: Unlocking Their Hidden Potential to Guide Tumor Immunity and Therapy.
3D Bioprinted Immunomodulation─The Advancing Landscape of Next-Generation Immuno-oncology.
Modulating immune cells within pancreatic ductal adenocarcinoma via nanomedicine.
Exosomal CMTM4 Induces Immunosuppressive Macrophages to Promote Ovarian Cancer Progression and Attenuate Anti-PD-1 Immunotherapy.
Tumor-Associated Macrophages as Key Modulators of Disease Progression in Diffuse Large B-Cell Lymphoma.
Multiplex imaging reveals novel patterns of MRTFA/B activation in the breast cancer microenvironment.
Pancreatic cancer cell-intrinsic transglutaminase-2 promotes T cell suppression through microtubule-dependent secretion of immunosuppressive cytokines.
Exosomal PD-L1 derived from hypoxia nasopharyngeal carcinoma cell exacerbates CD8+ T cell suppression by promoting PD-L1 upregulation in macrophages.

Front Immunol. 2025 ;16 1582305

Immunosuppressive tumor microenvironment in pancreatic cancer: mechanisms and therapeutic targets.

Da Pan, Xinyue Li, Xiao Qiao, Qiqi Wang.

  Pancreatic cancer is projected to become the second leading cause of cancer-related death by 2030. Conventional interventions including surgery, radiotherapy, and chemotherapy provide only modest survival benefits, underscoring an urgent need for more effective therapies. Although immunotherapy has revolutionized the management of several solid tumors, its clinical benefit in pancreatic cancer has so far been disappointing. Mounting evidence indicates that a highly immunosuppressive tumor microenvironment (TME), dominated by tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), drives immune evasion, tumor progression, metastasis, and chemoresistance through complex cytokine and chemokine networks. This review summarizes current knowledge of these immunosuppressive mechanisms and provides emerging strategies aimed at re-educating or depleting these cellular constituents to enhance the efficacy of immunotherapy in pancreatic cancer.

Keywords:  PD-1; immune suppression; pancreatic cancer; regulatory T cells; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1582305
Mol Cell Biochem. 2025 May 29.

Ferroptosis in TNBC: interplay with tumor-infiltrating immune cells and therapeutic implications.

Lihong Hu, Jiejie Hu, Chengdong Qin, Siyuan Liu, Yang Yu.

  Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options and a poor prognosis. Immunotherapy has emerged as a promising approach for TNBC, with tumor-infiltrating immune cells (TICs) in the tumor microenvironment (TME) serving as a critical cellular basis for its efficacy. However, the success of immunotherapy in TNBC is often limited due to the immunosuppressive nature of the TME and the heterogeneity of TNBC. Ferroptosis, a form of iron-dependent programmed cell death regulated by metabolic networks including iron, glutathione (GSH), and lipid metabolism, has shown potential to enhance anti-tumor immunity. Recent studies have demonstrated that ferroptosis can modulate immune responses by promoting the infiltration and activation of TICs, thereby improving the outcomes of immunotherapy. However, ferroptosis in immunosuppressive cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) can trigger an "immunosuppressive wave," affecting other immune cells in the tumor immune microenvironment. This demonstrates the dual role of ferroptosis in TNBC therapy, emphasizing the need for a nuanced understanding of its effects on different immune cells and tumor cells. Herein, we further elaborate the role of ferroptosis in TNBC cells and its interactions with tumor-infiltrating immune cells (TICs) within the TME.

Keywords:  Cancer immunotherapy; Ferroptosis; Triple negative breast cancer; Tumor microenvironment; Tumor-infiltrating immune cells

DOI:  https://doi.org/10.1007/s11010-025-05305-z
Cells. 2025 05 19. pii: 741. [Epub ahead of print]14(10):

Tumor-Associated Macrophages: Polarization, Immunoregulation, and Immunotherapy.

Abdullah Farhan Saeed.

  Tumor-associated macrophages' (TAMs) origin, polarization, and dynamic interaction in the tumor microenvironment (TME) influence cancer development. They are essential for homeostasis, monitoring, and immune protection. Cells from bone marrow or embryonic progenitors dynamically polarize into pro- or anti-tumor M2 or M1 phenotypes based on cytokines and metabolic signals. Recent advances in TAM heterogeneity, polarization, characterization, immunological responses, and therapy are described here. The manuscript details TAM functions and their role in resistance to PD-1/PD-L1 blockade. Similarly, TAM-targeted approaches, such as CSF-1R inhibition or PI3Kγ-driven reprogramming, are discussed to address anti-tumor immunity suppression. Furthermore, innovative biomarkers and combination therapy may enhance TAM-centric cancer therapies. It also stresses the relevance of this distinct immune cell in human health and disease, which could impact future research and therapies.

Keywords:  TAM; cancer; immune checkpoint; immune regulation; immunotherapy; macrophage; polarization

DOI:  https://doi.org/10.3390/cells14100741
Vaccines (Basel). 2025 May 04. pii: 496. [Epub ahead of print]13(5):

Harnessing Dendritic Cell Function in Hepatocellular Carcinoma: Advances in Immunotherapy and Therapeutic Strategies.

Shiding Ying, Haiyan Liu, Yongliang Zhang, Yu Mei.

  Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. Conventional therapies are frequently limited by tumor heterogeneity and the immunosuppressive tumor microenvironment (TME). Dendritic cells (DCs), central to orchestrating antitumor immunity, have become key targets for HCC immunotherapy. This review examines the biological functions of DC subsets (cDC1, cDC2, pDC, and moDC) and their roles in initiating and modulating immune responses against HCC. We detail the mechanisms underlying DC impairment within the TME, including suppression by regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs). Additionally, we discuss novel DC-based therapeutic strategies, such as DC-based vaccines designed to enhance antigen presentation and T cell activation. Combining DC vaccines with immune checkpoint inhibitors (ICIs), including PD-1/PD-L1 and CTLA-4 blockers, demonstrates synergistic effects that can overcome immune evasion and improve clinical outcomes. Despite progress, challenges related to DC subset heterogeneity, TME complexity, and patient variability require the further optimization and personalization of DC-based therapies. Future research should focus on refining these strategies, leveraging advanced technologies like genomic profiling and artificial intelligence, to maximize therapeutic efficacy and revolutionize HCC treatment. By restoring DC function and reprogramming the TME, DC-based immunotherapy holds immense potential to transform the management of HCC and improve patient survival.

Keywords:  antigen presentation; antitumor immunity; dendritic cells; hepatocellular carcinoma; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.3390/vaccines13050496
Front Immunol. 2025 ;16 1573039

Lactate-mediated metabolic reprogramming of tumor-associated macrophages: implications for tumor progression and therapeutic potential.

Xiaohan Jin, Ni Zhang, Tinghao Yan, Jingyang Wei, Lingli Hao, Changgang Sun, Haibo Zhao, Shulong Jiang.

  The tumor microenvironment (TME) is characterized by distinct metabolic adaptations that not only drive tumor progression but also profoundly influence immune responses. Among these adaptations, lactate, a key metabolic byproduct of aerobic glycolysis, accumulates in the TME and plays a pivotal role in regulating cellular metabolism and immune cell function. Tumor-associated macrophages (TAMs), known for their remarkable functional plasticity, serve as critical regulators of the immune microenvironment and tumor progression. Lactate modulates TAM polarization by influencing the M1/M2 phenotypic balance through diverse signaling pathways, while simultaneously driving metabolic reprogramming. Furthermore, lactate-mediated histone and protein lactylation reshapes TAM gene expression, reinforcing their immunosuppressive properties. From a therapeutic perspective, targeting lactate metabolism has shown promise in reprogramming TAMs and enhancing anti-tumor immunity. Combining these metabolic interventions with immunotherapies may further augment treatment efficacy. This review underscores the crucial role of lactate in TAM regulation and tumor progression, highlighting its potential as a promising therapeutic target in cancer treatment.

Keywords:  cancer therapy; immune regulation; lactate metabolism; metabolic reprogramming; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2025.1573039
Biomolecules. 2025 Apr 25. pii: 621. [Epub ahead of print]15(5):

Molecular Mechanisms in the Carcinogenesis of Oral Squamous Cell Carcinoma: A Literature Review.

Laertty Garcia de Sousa Cabral, Isabela Mancini Martins, Ellen Paim de Abreu Paulo, Karina Torres Pomini, Jean-Luc Poyet, Durvanei Augusto Maria.

  The tumor microenvironment (TME) plays a crucial role in the development, progression, and metastasis of oral squamous cell carcinoma (OSCC). The TME comprises various cellular and acellular components, including immune cells, stromal cells, cytokines, extracellular matrix, and the oral microbiome, all of which dynamically interact with tumor cells to influence their behavior. Immunosuppression is a key feature of the OSCC TME, with regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs) contributing to an environment that allows tumor cells to evade immune surveillance and supports angiogenesis. The oral microbiome also plays a pivotal role in OSCC pathogenesis, as dysbiosis, or imbalances in the microbiota, can lead to chronic inflammation, which promotes carcinogenesis through the production of pro-inflammatory cytokines and reactive oxygen species (ROS). Pathogens like Porphyromonas gingivalis and Fusobacterium nucleatum have, hence, been implicated in OSCC-driven tumor progression, as they induce inflammation, activate oncogenic pathways, and modulate immune responses. In this review, we discuss how the interplay between immunosuppression and microbiome-driven inflammation creates a tumor-promoting environment in OSCC, leading to treatment resistance and poor patient outcomes, and explore the potential therapeutic implication of a better understanding of OSCC etiology and molecular changes.

Keywords:  oral squamous cell carcinoma; targeted therapies; tumor microenvironment

DOI:  https://doi.org/10.3390/biom15050621
Biomedicines. 2025 May 11. pii: 1173. [Epub ahead of print]13(5):

The Role of Tregs in the Tumor Microenvironment.

Yohei Sato.

  The tumor microenvironment (TME) is a unique ecosystem that surrounds tumor tissues. The TME is composed of extracellular matrix, immune cells, blood vessels, stromal cells, and fibroblasts. These environments enhance cancer development, progression, and metastasis. Recent success in immune checkpoint blockade also supports the importance of the TME and immune cells residing in the tumor niche. Although the TME can be identified in almost all cancer types, the role of the TME may not be similar among different cancer types. Regulatory T cells (Tregs) play a pivotal role in immune homeostasis and are frequently found in the TME. Owing to their suppressive function, Tregs are often considered unfavorable factors that allow the immune escape of cancer cells. However, the presence of Tregs is not always linked to an unfavorable phenotype, which can be explained by the heterogeneity and plasticity of Tregs. In this review, the current understanding of the role of Tregs in TME is addressed for each cancer cell type. Moreover, recently a therapeutic approach targeting Tregs infiltrating in the TME has been developed including drug antibody conjugate, immunotoxin, and FOXP3 inhibiting peptide. Thus, understanding the role of Tregs in the TME may lead to the development of novel therapies that directly target the TME.

Keywords:  FOXP3; cancer; immune regulation; regulatory T cells; tolerance; tumor-infiltrating lymphocyte

DOI:  https://doi.org/10.3390/biomedicines13051173
EMBO Rep. 2025 May 28.

Cancer microbiota: a focus on tumor-resident bacteria.

Gerlanda Vella, Maria Rescigno.

  Accumulating evidence highlights the presence of an intratumoral microbiota across various cancer types. Among all the microorganisms comprising the tumor-associated microbiota, tumor-resident bacteria (TRB) are increasingly recognized as critical regulators of cancer biology. Within tumor tissues, these microorganisms interact with various components of the tumor microenvironment (TME) and influence both tumor-promoting and tumor-suppressing pathways, underlying their dual role in cancer. Fully understanding the functional roles of TRB and their complex interactions with components of the TME requires the application of multimodal technologies. Developing strategies to modulate TRB-either by eradicating pathogenic populations or harnessing beneficial ones-holds great promise for advancing cancer treatment. In this review, we summarize the most recent insights into TRB. We discuss their possible origins and their implications on cancer biology, focusing on their roles in cancer development, metastasis establishment, immune modulation, and therapy response. Finally, we describe bacteria-based strategies and address the major challenges in detecting and analyzing these microbial communities in tumors.

Keywords:  Intratumoral Microbiota; Metastasis; Microbiota; Therapy Efficacy; Tumor Microenvironment

DOI:  https://doi.org/10.1038/s44319-025-00482-w
Cancers (Basel). 2025 May 14. pii: 1654. [Epub ahead of print]17(10):

CAF-Targeting Antibody-Drug Conjugates (ADCs) in Solid Cancers.

Kostas A Papavassiliou, Amalia A Sofianidi, Athanasios G Papavassiliou.

The tumor microenvironment (TME) constitutes a major part of solid malignancies and within it, cancer-associated fibroblasts (CAFs) continuously interact with cancer cells, fostering their growth and survival [...].

DOI: https://doi.org/10.3390/cancers17101654
Naunyn Schmiedebergs Arch Pharmacol. 2025 May 27.

Tumor immune evasion and the Let-7 family: insights into mechanisms and therapies.

Omer Qutaiba B Allela, Ali Fawzi Al-Hussainy, Gaurav Sanghvi, R Roopashree, Aditya Kashyap, D Alex Anand, Rajashree Panigrahi, Lilia Maratovna Garifulina, Sada Ghalib Taher, Mariem Alwan, Mahmood Jawad, Hiba Mushtaq.

  Tumor immune evasion is a complex and adaptive mechanism that allows cancer cells to escape immune detection and destruction, contributing to malignancy progression and poor therapeutic outcomes. This review article explores the integral role of the let-7 family of microRNAs (miRNAs) in mediating tumor immune evasion, particularly how these regulators influence the tumor microenvironment (TME) and immune cell functionality. The let-7 family, known for its tumor-suppressive roles, modulates key immune checkpoints, including PD-L1, and pathways linked to immune response regulation, such as the STAT3/SOCS axis, impacts macrophage polarization and modulates immune cell function. Dysregulation of let-7 miRNAs can enhance tumor immune evasion through mechanisms such as downregulating major histocompatibility complex (MHC) expressions, promoting immunosuppressive cell populations, and manipulating metabolic pathways, which together establish an immunosuppressive TME. Conversely, specific let-7 members show potential in restoring anti-tumor immunity by reversing immune suppression and improving T cell responses. By synthesizing current research, this article underscores the dual role of let-7 in both promoting and inhibiting tumor immune evasion, suggesting their potential as therapeutic targets and biomarkers in cancer immunotherapy. Future studies on the context-dependent roles and advanced delivery systems for let-7-targeting therapies are crucial for enhancing immunotherapeutic efficacy and improving patient outcomes across malignancies.

Keywords:  Immune evasion; Immunosuppressive tumor microenvironment; Let-7; Tumor microenvironment; micoRNA

DOI:  https://doi.org/10.1007/s00210-025-04283-9
ACS Appl Nano Mater. 2024 Dec 27. 7(24): 28851-28863

Glycopolymeric Nanoparticles Block Breast Cancer Growth by Inhibiting Efferocytosis in the Tumor Microenvironment.

Oluwaseyi Shofolawe-Bakare, Veeresh B Toragall, Kenneth Hulugalla, Railey Mayatt, Paige Iammarino, John P Bentley, Adam E Smith, Thomas Werfel.

  Conventional inhibitors of immune checkpoints such as anti-programmed death-1 and its ligand (anti-PD-1/PD-L1) and anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA4) have revolutionized therapeutic approaches to cancer, establishing immunotherapy as the standard of care for many cancers. A significant number of cancers, however, remain refractory to the inhibition of these immune checkpoints, leading to the search for alternative immune checkpoints that are more relevant to those diseases. Tumor-associated macrophage (TAM)-mediated efferocytosis is an increasingly appreciated immune checkpoint with a profound impact on the phenotype of the tumor microenvironment (TME). TAMs perform their efferocytic function through the receptor MerTK, and MerTK activity correlates with tumor progression. To combat efferocytosis in the TME, we developed poly[[2-(diisopropylamino)ethyl methacrylate]-b-poly(methacrylamidomannose)] nanoparticles (PMAM NPs) capable of encapsulating and preferentially delivering UNC2025 (a MerTK inhibitor) to TAMs. The NPs had suitable physicochemical properties, such as a size of 130 nm and a neutral surface charge. The PMAM NPs encapsulated hydrophobic cargo and released them in a pH-dependent manner, showing suitability for cytosolic delivery. Moreover, the PMAM NPs showed 12-fold greater macrophage internalization than traditional PEGMA NPs. Macrophage internalization was shown to be dependent on the mannose receptor CD206, as the blockade of CD206 led to a significant decrease in PMAM NP internalization. Furthermore, PMAM NPs had a lower internalization than PEGMA NPs in 4T1 cancer cells that do not express CD206, further confirming macrophage selectivity. In vivo biodistribution studies showed the PMAM NPs were capable of internalization by TAMs in the TME. Lastly, UNC2025-PMAM NPs significantly reduced tumor volume compared to free UNC2025, showing greater therapeutic efficacy in a model of triple-negative breast cancer. These glycopolymer-based, efferocytosis-blocking NPs have promise both as a class of standalone cancer immunotherapy and as an adjuvant to improve response rates to checkpoint immunotherapy.

Keywords:  Cancer Immunotherapy; Drug Delivery; Efferocytosis; Glycopolymer; Tumor-Associated Macrophages

DOI:  https://doi.org/10.1021/acsanm.4c06534
Mol Ther. 2025 May 27. pii: S1525-0016(25)00395-8. [Epub ahead of print]

Reprogramming the neuroblastoma tumor immune microenvironment to enhance GPC2 CAR T cells.

Anna Maria Giudice, Sydney L Roth, Stephanie Matlaga, Evan Cresswell-Clay, Pamela Mishra, Patrick M Schürch, Kwame Attah M Boateng-Antwi, Minu Samanta, Guillem Pascual-Pasto, Vincent Zecchino, Timothy T Spear, Brendan McIntyre, Neil Chada, Tingting Wang, Lingling Liu, Ruoning Wang, John T Wilson, Adam J Wolpaw, Kristopher R Bosse.

Poor tumor trafficking and the immunosuppressive tumor microenvironment (TME) limit chimeric antigen receptor (CAR) T cell efficacy in solid tumors, such as neuroblastoma. We previously optimized GPC2 CARs in human neuroblastoma xenografts leading to clinical translation; however, there have not been preclinical studies using immunocompetent models. Thus, here we generated murine GPC2 CAR T cells using the D3-GPC2-targeting single-chain variable fragment being utilized clinically (NCT05650749) and tested them in neuroblastoma syngeneic allografts. Immune-profiling of GPC2 CAR T cell-treated tumors revealed significant reprogramming of the TME, most notably poor intra-tumor CAR T cell persistence being associated with increased recruitment of myeloid-derived suppressor cells (MDSCs), along with MDSC-recruiting CXCL1/2 chemokines. These tumor-infiltrating MDSCs directly inhibited GPC2 CAR T cell activation, proliferation, and cytotoxicity ex vivo. To both capitalize on this chemokine gradient and mitigate MDSC-tumor trafficking, we engineered GPC2 CAR T cells to express the CXCL1/2 receptor, CXCR2. CXCR2-armored GPC2 CAR T cells migrated towards CXCL1/2 gradients, enhanced anti-neuroblastoma efficacy, and reduced the level of MDSCs in the TME. Together, these findings suggest CAR T cell studies in immunocompetent models are imperative to define mechanisms of solid tumor immune escape and rationally design armoring strategies that will lead to durable clinical efficacy.

DOI: https://doi.org/10.1016/j.ymthe.2025.05.025
Cancer Lett. 2025 May 28. pii: S0304-3835(25)00402-1. [Epub ahead of print] 217835

Lactylation in Tumor Microenvironment and Immunotherapy Resistance: New Mechanisms and Challenges.

Wenlong Zhu, Chang Fan, Yizhuo Hou, Yanjie Zhang.

  Tumor microenvironment (TME) is a highly intricate and variable system. The Warburg effect has made researchers further realize that TME is a highly hypoxic microenvironment. Currently, it is reported that lactate is not merely a metabolic waste but also serves important biological functions, which provides a large number of reaction substrates for lactylation. Post-translational modification (PTM) is crucial for signaling and physiological regulation in both normal and cancer cells. Various PTMs play pathological roles in tumor proliferation, metabolism, and the remodeling of the tumor immunosuppressive microenvironment (TIME). Lactylation, as a newly reported PTM, plays an important role in shaping TIME and aggravating tumor immunotherapy resistance. Numerous studies have demonstrated that histone lactylation can directly stimulate gene transcription within chromatin, thereby contributing to tumor promotion and diminishing the efficacy of therapeutic agents against tumors. Advancements in multi-omics technology enable researchers to investigate lactylation-related substrates more effectively. By precisely targeting these sites, it is possible to reduce histone lactylation in order to mitigate their effects on tumor immune resistance. Despite the existence of numerous studies, there remains a notable deficiency of systematic reviews in this field. Therefore, this review focuses on the novel mechanisms of lactylation that promote tumor progression and its impact on tumor immune resistance. Finally, we propose relevant therapeutic regimens for reversing lactylation to guide tumor combined therapy, thus providing benefits upon more patients with tumor immune resistance.

Keywords:  Immunotherapy resistance; Lactylation; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2025.217835
Front Immunol. 2025 ;16 1550003

Tumor-infiltrating immune cells state-implications for various breast cancer subtypes.

Tianshuang Xu, Hongjun Zhang, Burton B Yang, Javeria Qadir, Hui Yuan, Ting Ye.

  Breast cancer presents a variety of subtypes due to its cellular and molecular heterogeneity. The capacity of cancer cells to proliferate, invade, and metastasize depends not only on their intrinsic characters but also on their dynamic interaction with the host tumor microenvironment (TME), which includes immune cells. Meanwhile, the infiltration of immune cells in the TME severely affects the occurrence, development, treatment, and prognosis of breast cancer. Therefore, this review aims to explore the immune invasive tumor microenvironment in different intrinsic subtypes of breast cancer. Additionally, it highlights the mechanistic influence of the infiltrating immune cells on stage-wise dynamics of breast tumorigenesis. Moreover, the present review also attempts to discern the regulatory relationship between tumor infiltrating immune cells and immune microenvironment in different molecular subtypes of breast cancer, thus, spotlighting its clinical significance.

Keywords:  breast cancer; clinical significance; immune cell(s) infiltration; molecular subtypes; tumor microenvironment (TME)

DOI:  https://doi.org/10.3389/fimmu.2025.1550003
J Mol Med (Berl). 2025 May 30.

Tumor hypoxia shapes natural killer cell anticancer activities.

Mauricio A Retamal, Flavio Salazar-Onfray, Fermín E González, Andrés Tittarelli.

  Tumor hypoxia, a hallmark of the tumor microenvironment (TME), profoundly impacts the antitumor functionality of immune cells, particularly natural killer (NK) cells, which play a critical role in cancer immunosurveillance and immunotherapy success. This review provides a comprehensive analysis of the mechanisms by which hypoxia impairs NK cell-mediated cytotoxicity and antitumor activities, emphasizing the molecular pathways and cellular adaptations that enable cancer cell to evade NK cell attack. Key factors that participate in this phenomenon include the stabilization of hypoxia-inducible factors, metabolic reprogramming, angiogenesis, cancer stemness, autophagy, and the secretion of immunosuppressive molecules. Moreover, hypoxia induces phenotypic and functional changes in both cancer and NK cells, promoting tumor progression and resistance to immunotherapy. Emerging strategies to counteract hypoxia-induced immunosuppression are being explored, including nanotechnology-based approaches, cytokine-mediated NK cell preconditioning, and vascular normalization techniques. These interventions highlight promising avenues for enhancing NK cell functionality and synergizing with existing cancer therapies. By addressing the immunosuppressive challenges of the hypoxic TME, in this review, we underscore the potential of innovative strategies to improve therapeutic outcomes in cancer treatment.

Keywords:  Cytotoxicity; Immune suppression; Natural killer cell; Tumor hypoxia

DOI:  https://doi.org/10.1007/s00109-025-02557-6
Front Immunol. 2025 ;16 1590781

Unraveling the immunosuppressive microenvironment of glioblastoma and advancements in treatment.

Dongxin Jiang, Yunqian Li.

  Glioblastoma, the most common and aggressive primary brain tumor, remains a significant challenge in oncology due to its immunosuppressive tumor microenvironment (TME). This review summarizes the complex interplay of immune cells and cytokines within the TME, which contribute to immune evasion and tumor progression. We further emphasize the synergistic crosstalk among these components and how it shapes therapeutic vulnerability. Besides, we highlight recent advancements in immunotherapy, including immune checkpoint inhibitors, CAR-T cell therapy, NK cell therapy, oncolytic viruses, and vaccine-based strategies. Despite promising preclinical and clinical results, overcoming the immunosuppressive TME remains a critical hurdle. This review underscores the potential of targeting the TME to enhance therapeutic outcomes in glioblastoma.

Keywords:  cytokines; glioblastoma; immune checkpoint inhibitor; immune microenvironment; immunotherapy; tumor vaccine

DOI:  https://doi.org/10.3389/fimmu.2025.1590781
Cancers (Basel). 2025 May 17. pii: 1689. [Epub ahead of print]17(10):

Innate Immunity and Platelets: Unveiling Their Role in Chronic Pancreatitis and Pancreatic Cancer.

Juliane Blümke, Moritz Schameitat, Atul Verma, Celina Limbecker, Elise Arlt, Sonja M Kessler, Heike Kielstein, Sebastian Krug, Ivonne Bazwinsky-Wutschke, Monika Haemmerle.

  Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal forms of cancer, characterized by a highly desmoplastic tumor microenvironment. One main risk factor is chronic pancreatitis (CP). Progression of CP to PDAC is greatly influenced by persistent inflammation promoting genomic instability, acinar-ductal metaplasia, and pancreatic intraepithelial neoplasia (PanIN) formation. Components of the extracellular matrix, including immune cells, can modulate this progression phase. This includes cells of the innate immune system, such as natural killer (NK) cells, macrophages, dendritic cells, mast cells, neutrophils, and myeloid-derived suppressor cells (MDSCs), either promoting or inhibiting tumor growth. On one hand, innate immune cells can trigger inflammatory responses that support tumor progression by releasing cytokines and growth factors, fostering tumor cell proliferation, invasion, and metastasis. On the other hand, they can also activate immune surveillance mechanisms, which can limit tumor development. For example, NK cells are cytotoxic innate lymphoid cells that are able to kill tumor cells, and active dendritic cells are crucial for a functioning anti-tumor immune response. In contrast, mast cells and MDSCs rather support a pro-tumorigenic tumor microenvironment that is additionally sustained by platelets. Once thought to play a role in hemostasis only, platelets are now recognized as key players in inflammation and cancer progression. By releasing cytokines, growth factors, and pro-angiogenic mediators, platelets help shape an immunosuppressive microenvironment that promotes fibrotic remodeling, tumor initiation, progression, metastasis, and immune evasion. Neutrophils and macrophages exist in different functional subtypes that can both act pro- and anti-tumorigenic. Understanding the complex interactions between innate immune cells, platelets, and early precursor lesions, as well as PDAC cells, is crucial for developing new therapeutic approaches that can harness the immune and potentially also the coagulation system to target and eliminate tumors, offering hope for improved patient outcomes.

Keywords:  PDAC; immune microenvironment; innate immune cells; pancreatitis; platelets

DOI:  https://doi.org/10.3390/cancers17101689
Cancers (Basel). 2025 May 08. pii: 1599. [Epub ahead of print]17(10):

The Role of the Tumor Microenvironment in Pancreatic Ductal Adenocarcinoma: Recent Advancements and Emerging Therapeutic Strategies.

Franciszek Glapiński, Weronika Zając, Marta Fudalej, Andrzej Deptała, Aleksandra Czerw, Katarzyna Sygit, Remigiusz Kozłowski, Anna Badowska-Kozakiewicz.

  Pancreatic cancer (PC), with pancreatic ductal adenocarcinoma (PDAC) comprising about 90% of all cases, is one of the most aggressive and lethal solid tumors. PDAC remains one of the most significant challenges of oncology to this day due to its inadequate response to conventional treatment, gradual rise in incidence since 2004, and poor five-year survival rates. As cancer cells are the primary adversary in this uneven fight, they remain the primary research target. Nevertheless, increasing attention is being paid to the tumor microenvironment (TME). The most crucial TME constellation components are immune cells, especially macrophages, stellate cells and lymphocytes, fibroblasts, bacterial and fungal microflora, and neuronal cells. Depending on the particular phenotype of these cells, the composition of the microenvironment, and the cell ratio, patients can experience different disease outcomes and varying vulnerability to treatment approaches. This study aims to present the current knowledge and review the most up-to-date scientific findings regarding the microenvironment of PC. It contains detailed information on the structure and cellular composition of the stroma, including its impact on disease development, metastasis, and response to treatment, as well as the therapeutic opportunities that arise from targeting this tissue.

Keywords:  cancer-associated fibroblasts; microbiome; microenvironment; neuroinvasion; pancreatic ductal adenocarcinoma; stellate cells; stroma; tumor-associated macrophages

DOI:  https://doi.org/10.3390/cancers17101599
Cancers (Basel). 2025 May 12. pii: 1631. [Epub ahead of print]17(10):

The Basis for Targeting the Tumor Macrophage Compartment in Glioblastoma Immunotherapy.

Thomas Eckert, Chase Walton, Marcus Bell, Coulter Small, Nathan C Rowland, Charlotte Rivers, Alicia Zukas, Scott Lindhorst, Peter Fecci, Ben A Strickland.

  Background: Glioblastoma (GBM) remains the most aggressive primary brain tumor with limited treatment options. The immunosuppressive tumor microenvironment (TME), largely shaped by tumor-associated macrophages (TAMs), represents a significant barrier to effective immunotherapy. Objective: This review aims to explore the role of TAMs within the TME, highlighting the phenotypic plasticity, interactions with tumor cells, and potential therapeutic targets to enhance anti-tumor immunity. Findings: TAMs constitute a substantial portion of the TME, displaying functional plasticity between immunosuppressive and pro-inflammatory phenotypes. Strategies targeting TAMs include depletion, reprogramming, and inhibition of pro-tumor signaling pathways. Preclinical studies show that modifying TAM behavior can shift the TME towards a pro-inflammatory state, enhancing antitumor immune responses. Clinical trials investigating inhibitors of TAM recruitment, polarization, and downstream signaling pathways reveal promising yet limited results, necessitating further research to optimize approaches. Conclusions: Therapeutic strategics targeting TAM plasticity through selective depletion, phenotypic reprogramming, or modulation of downstream immunosuppressive signals represent promising avenues to overcome GBM-associated immunosuppression. Early clinical trials underscore their safety and feasibility, yet achieving meaningful clinical efficacy requires deeper mechanistic understanding and combinatorial approaches integrating macrophage-direct therapies with existing immunotherapeutic modalities.

Keywords:  glioblastoma; immunotherapy; macrophage polarization; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3390/cancers17101631
Cancers (Basel). 2025 May 12. pii: 1638. [Epub ahead of print]17(10):

Immune Evasion in Cancer Metastasis: An Unappreciated Role of Monocytes.

Marina R Patysheva, Anastasya A Fedorenko, Anna A Khozyainova, Evgeny V Denisov, Tatiana S Gerashchenko.

  Metastasis is the leading cause of cancer-related deaths. During the metastatic cascade, cancer cells tightly interact with immune cells influencing each other in the tumor microenvironment and systemically. Monocytes are important components of immune evasion and critical regulators of cancer progression. They circulate through the bloodstream and contribute to the formation of a pro-tumor microenvironment both in the tumor and pre-metastatic niche. Whereas monocyte participation in cancer development and response to therapy has been described extensively, its impact on metastasis remains a completely uncovered area. This review first summarizes data concerning the influence of monocytes on metastasis formation during their presence in the circulation, primary tumor, and pre-metastatic niche. We also highlight the latest examinations into the clinical relevance of targeting monocytes to prevent metastasis.

Keywords:  epithelial-mesenchymal plasticity; immune evasion; immunotherapy; metastasis; monocyte; monocytic myeloid-derived suppressor cell; pre-metastatic niche; progression; tumor hybrid cell

DOI:  https://doi.org/10.3390/cancers17101638
Semin Cancer Biol. 2025 May 22. pii: S1044-579X(25)00075-6. [Epub ahead of print]113 130-150

The intricate role of adipokines in cancer-related signaling and the tumor microenvironment: Insights for future research.

Dimitris Kounatidis, Natalia G Vallianou, Irene Karampela, Evgenia Grivakou, Maria Dalamaga.

  Obesity represents a global health challenge, with adipose tissue acting as a highly active endocrine organ that synthesizes and secretes a diverse array of bioactive proteins, known as adipokines. These cell signaling molecules regulate metabolic equilibrium, inflammatory cascades, and immune surveillance, exerting substantial systemic effects. A growing body of evidence has also highlighted their key role in cancer biology, through their intricate impact on oncogenic signaling networks and the tumor microenvironment (TME). The TME, a highly dynamic and heterotypic network composed of malignant cells, infiltrating immune cells, stromal constituents, and extracellular matrix elements, facilitates tumor evolution and immune evasion. Among adipokines, adiponectin and leptin have been extensively studied. Research has shown that adiponectin exhibits tumor-suppressive properties, whereas leptin enhances proliferative, angiogenic, and inflammatory pathways that promote malignancy. However, these effects are context-dependent and, at times, contradictory across different studies. Furthermore, the functional landscape of adipokines in cancer extends beyond these paradigms, with emerging research identifying a broader spectrum of novel adipokines involved in cancer reprogramming. This review delineates the molecular interplay between adipokines and oncogenic pathways, elucidating their mechanistic contributions to TME crosstalk and immune modulation. Additionally, we examine their potential as diagnostic and prognostic biomarkers and assess their viability as therapeutic targets for precision oncology. By integrating current evidence and identifying unresolved questions, this review aims to refine our understanding of adipokine-driven tumor biology and establish a platform for future research.

Keywords:  Adipokine; Adiponectin; Biomarkers; Cancer; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.semcancer.2025.05.013
Semin Oncol. 2025 May 29. pii: S0093-7754(25)00038-7. [Epub ahead of print]52(3): 152346

The Crucial Nexus: Unveiling the Role of Collagen in Cancer Progression.

Hazel Reeva, Godson Mahesh, Uma Manjunath, Nagarajan Selvamurugan, Durairaj MohanKumar.

  The complex interplay between collagen and cancer cells within the tumor microenvironment (TME) highlights the pivotal role of collagens in cancer progression, prognosis and therapy resistance. As a critical structural protein of the extracellular matrix (ECM), collagen not only maintains tissue architecture but also regulates key physiological functions through complex biosynthetic pathways. Deregulation in collagen biosynthesis, characterized by abnormal transcription, post-translational modifications, and deposition, contributes to ECM remodeling and tumor progression. This review explores the involvement of diverse collagen family members in cancer progression across multiple cancer types. Several collagen isoforms have emerged as key players in cancer progression, influencing tumor behavior and act as potential biomarkers for prognosis. Furthermore, circulating collagen fragments in blood present promising avenues for non-invasive cancer diagnosis and disease monitoring. Tumor collagen remodeling alters ECM architecture, impacting tumor-stromal interactions and fostering a microenvironment conducive to favour invasion and metastasis. Mechanistic insights reveal that collagen-induced signalling pathways are the major drivers of stemness, drug resistance, EMT, metastasis, angiogenesis and immune evasion, which collectively shape tumor cell behavior and immune infiltration dynamics. Further, targeting tumor collagen appear to be a viable and robust strategy to treat aggressive desmoplastic and metastatic cancers.

Keywords:  Collagen; Invasion; Metastasis; Stemness; Tumor microenvironment; extracellular matrix

DOI:  https://doi.org/10.1016/j.seminoncol.2025.152346
Front Immunol. 2025 ;16 1581964

Tumor-derived vesicles in immune modulation: focus on signaling pathways.

Fei Yin, Yangfang He, Yue Qiao, Yan Yan.

  Tumor-derived extracellular vesicles (TDEVs) represent a heterogeneous population of extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, which are essential for tumor growth. EVs function as natural carriers of bioactive molecules, including lipids, proteins, and nucleic acids, enabling them to influence and regulate complex cellular interactions within the tumor microenvironment (TME). The TDEVs mainly have immunosuppressive functions as a result of the inhibitory signals disrupting the immune cell anti-tumor activity. They enhance tumor progression and immune evasion by inhibiting the effector function of immune cells and by altering critical processes of immune cell recruitment, polarization, and functional suppression by different signaling pathways. In this sense, TDEVs modulate the NF-κB pathway, promoting inflammation and inducing immune evasion. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling is required for TDEV-mediated immune suppression and the manifestation of tumor-supporting features. The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling, necessary for metabolic reprogramming, is orchestrated by TDEV to abrogate immune response and drive cancer cell proliferation. Finally, exosomal cargo can modulate the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, activating pro-inflammatory responses that influence tumor development and immunomodulation. In this review, we take a deep dive into how TDEVs affect the immune cells by altering key signaling pathways. We also examine emerging therapeutic approaches aimed at disrupting EV-mediated pathways, offering promising avenues for the development of novel EV-based cancer immunotherapy.

Keywords:  TdEVs; immune modulation; immunotherapy; signaling pathways; tumor

DOI:  https://doi.org/10.3389/fimmu.2025.1581964
Phys Life Rev. 2025 May 16. pii: S1571-0645(25)00085-5. [Epub ahead of print]54 11-23

High-order interaction modeling of tumor-microenvironment crosstalk for tumor growth.

Jincan Che, Yu Wang, Li Feng, Claudia Gragnoli, Christopher Griffin, Rongling Wu.

  Signaling interactions between cancer cells and nonmalignant cells in the tumor microenvironment (TME) are believed to influence tumor progression and drug resistance. However, the genomic machineries mediating such an influence remain elusive, making it difficult to determine therapeutic targets on the tumor and its microenvironment. Here, we argue that a computational model, derived from the integration of evolutionary game theory and ecosystem theory through allometric scaling law, can chart the genomic atlas of high-order interaction networks involving tumor cells, TME, and tumor mass. We assess the application of this model to identify the causal influence of gene-induced tumor-TME crosstalk on tumor growth. The findings demonstrate that cooperation and competition between tumor cells and their infiltrating microenvironment promote or inhibit tumor growth in diverse ways. We identify specific genes that govern this promotion or inhibition, which can be used as genetic targets to alter tumor growth. This model opens up a new avenue to precisely infer the genomic underpinnings of tumor-TME interactions and their impact on tumor progression from any omics data.

Keywords:  Casual inference; Cell-cell crosstalk; Evolutionary game theory; Quasi-dynamic ordinary differential equations; Tumor; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.plrev.2025.05.007
Cells. 2025 05 15. pii: 720. [Epub ahead of print]14(10):

Unconventional T Cells' Role in Cancer: Unlocking Their Hidden Potential to Guide Tumor Immunity and Therapy.

Paola Pinco, Federica Facciotti.

  Unconventional T (UC T) cells, including invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells, γδ T cells, and double-negative (DN) T cells, are key players in immune surveillance and response due to their properties combining innate-like and adaptive-like features. These cells are widely present in mucosal tissues, where they can rapidly respond to infections and tumor-associated changes. In fact, UC T cells can have both pro- and anti-tumoral effects, with their activity influenced by factors such as microbial composition and the tumor microenvironment. In particular, intratumoral microbiota significantly impacts the development, function, and activation of UC T cells, influencing cytokine production and shaping the immune response in various cancers. The complex crosstalk between UC T cells and the surrounding factors is discussed in this review, with a focus on how these cells might be interesting candidates to explore and exploit as anticancer therapeutic agents. However, the great potential of UC T cells, not only demonstrated in the context of adoptive cell transfer, but also enhanced through techniques of engineering, is still flanked by different challenges, like the immunosuppressive tumor microenvironment and heterogeneity of target molecules associated with some specific categories of tumors, like gastrointestinal cancers.

Keywords:  anticancer therapy; cancer; intratumor microbiome; tumor immunology; unconventional T cells

DOI:  https://doi.org/10.3390/cells14100720
Biomacromolecules. 2025 May 30.

3D Bioprinted Immunomodulation─The Advancing Landscape of Next-Generation Immuno-oncology.

Souvik Debnath, Sachin Latiyan, Nipun Jain, Sudipto Datta, Dileep Pathote, Tithi Bhowmick, Avinaba Mukherjee.

Tumor microenvironment (TME) alteration can lead to tumorigenesis, where tumors evade the immune system and spread. Thus, immunomodulation inside the TME may be a useful therapeutic approach. In this regard, bioprinting has become a potential technique for developing therapeutic solutions that offer improved control over immune modulation. Through the use of novel immune cell therapies and realistic tumor models, it provides a platform for advancing cancer immunotherapy. By examining the complex mechanisms of immunomodulation in tumorigenesis, this review article clarifies how interactions between the immune system and the tumor microenvironment affect the initiation and spread of cancer. Additionally, the effectiveness of 3D bioprinting in modulating and activating immune cells, such as T cells, dendritic cells, and macrophages, has also been analyzed. A summary of current research shows the pivotal role of 3D bioprinting in establishing a solid foundation for advancing anticancer studies and revolutionizing cancer treatment through immunotherapeutic strategies.

DOI: https://doi.org/10.1021/acs.biomac.4c01816
Essays Biochem. 2025 May 26. pii: EBC20243001. [Epub ahead of print]

Modulating immune cells within pancreatic ductal adenocarcinoma via nanomedicine.

Junyi Lin, Ying Li, Jingjing Sun.

  Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by a dense extracellular matrix (ECM) and a uniquely immunosuppressive tumor microenvironment (TME), which together form a formidable barrier that hinders deep drug penetration, limiting the efficacy of conventional therapies and leading to poor patient outcomes. Nanocarrier technology emerges as a promising strategy to improve treatment efficacy in PDAC. Nanocarriers can not only improve drug penetration through their adjustable physicochemical properties but also effectively regulate immune cell function in pancreatic cancer TME and promote anti-tumor immune response. This mini-review discusses the effects of nanocarriers on the immune microenvironment of PDAC, analyzing their mechanisms in modulating immune cells, overcoming ECM barriers, and reshaping the TME.

Keywords:  immune cell; immunology; nanocarriers; pancreatic ductal adenocarcinoma; tumor microenvironment

DOI:  https://doi.org/10.1042/EBC20243001
Adv Sci (Weinh). 2025 May 28. e04436

Exosomal CMTM4 Induces Immunosuppressive Macrophages to Promote Ovarian Cancer Progression and Attenuate Anti-PD-1 Immunotherapy.

Bo Yin, Jianyi Ding, Jie Liu, Haoran Hu, Yashi Zhu, Meiqin Yang, Huijuan Zhou, Baoyou Huang, Tiefeng Huang, Mengjie Li, Yinyan He, Ang Li, Lingfei Han.

  Exosomes shape the tumor microenvironment (TME) by modulating tumor-associated macrophages (TAMs) and promoting ovarian cancer (OC) progression. This study reveals that exosomal CKLF Like MARVEL Transmembrane Domain Containing 4 (CMTM4) enhances OC malignancy and orchestrates immune evasion. Excessive macrophage infiltration in the TME, particularly in the presence of CMTM4, is strongly associated with poor prognosis. Within the TME, exosomal CMTM4 is actively internalized by macrophages, promoting M2 polarization and subsequently initiating immunosuppressive signaling. Exosomal CMTM4 activates the NF-κB pathway in TAMs, suppressing immune function through enhanced secretion of cytokines, including TGF-β1 and CXCL12, while simultaneously upregulating intercellular adhesion molecule-1 (ICAM1) expression to further promote M2 polarization and facilitate cancer metastasis. Depletion of CMTM4 increases sensitivity to anti-PD-1 therapy by reversing immunosuppression. Notably, eltrombopag is identified as a CMTM4 inhibitor that attenuates OC progression in vivo and modulates the tumor immune microenvironment, synergizing with PD-1 blockade immunotherapy to enhance therapeutic efficacy. The exosomal CMTM4-ICAM1-CD206 axis exacerbates disease risk in patients with OC. Collectively, the study highlights the critical role of tumor-derived exosomal CMTM4 in immune suppression, emphasizing its potential as both a prognostic biomarker and a therapeutic target in OC immunotherapy.

Keywords:  CMTM4; exosomal CMTM4; macrophage polarization; ovarian cancer; tumor‐associated macrophages

DOI:  https://doi.org/10.1002/advs.202504436
Biomedicines. 2025 May 01. pii: 1099. [Epub ahead of print]13(5):

Tumor-Associated Macrophages as Key Modulators of Disease Progression in Diffuse Large B-Cell Lymphoma.

Corina Joldes, Laura Jimbu, Oana Mesaros, Mihnea Zdrenghea, Bogdan Fetica.

  With the advent of new therapeutic approaches, there is hope that anticancer treatment will eventually be possible without the use of chemotherapy. Efficient immunotherapeutic options have recently emerged in many cancers, offering a less aggressive approach, with overall better tolerance, making them also suitable for frail patients. Response to immunotherapy relies on the availability, functionality, and efficacy of the host's immune effector mechanisms. One of the key factors determining the efficacy of immunotherapy is the tumor microenvironment, which encompasses various immune effectors, including macrophages, which play a crucial role in regulating immune responses through phagocytosis and antigen presentation. Macrophages are prototypically divided, according to their polarization, into either the pro-inflammatory M1 type or the anti-inflammatory M2 type. In the tumor microenvironment, M2-polarized macrophages, known as tumor-associated macrophages (TAMs), are the predominant phenotype and are associated with tumor progression. The M1/M2 paradigm contributes to the understanding of tumor progression. Due to the variable microenvironment, the mechanisms regulating TAMs can vary across different cancers. Variations in TAM polarization may account for the different treatment responses in patients with similar diseases. This paper investigates the connection between TAMs, disease progression, and treatment responses in the most frequent solid hematologic cancer, diffuse large B-cell lymphoma.

Keywords:  TAMs; macrophage polarization; non-Hodgkin lymphoma

DOI:  https://doi.org/10.3390/biomedicines13051099
J Transl Med. 2025 May 30. 23(1): 599

Multiplex imaging reveals novel patterns of MRTFA/B activation in the breast cancer microenvironment.

Stephanie M Wilk, Kihak Lee, Caitlyn C Castillo, Mohamed Haloul, Alexa M Gajda, Virgilia Macias, Elizabeth L Wiley, Zhengjia Chen, Xinyi Liu, Xiaowei Wang, Maria Sverdlov, Kent F Hoskins, Ekrem Emrah Er.

   BACKGROUND: Breast cancer progression and metastasis involve the action of multiple transcription factors in tumors and in the cells of the tumor microenvironment (TME) and understanding how these transcription factors are coordinated can guide novel therapeutic strategies. Myocardin-related transcription factors A and B (MRTFA/B also known as MKL1/2) are two related transcription factors that redundantly control cancer cell invasion and metastasis in mouse models of breast cancer, but their roles in human cancer are incompletely understood. Here, we investigated the expression and activation of these transcription factors to better assess their tumorigenic and metastatic impact on breast cancer and cells of the tumor microenvironment.
METHODS: We used a multiplexed immunofluorescence approach to label MRTFA, MRTFB, tumor cells by using pan Cytokeratin, endothelial cells by using CD31, and antigen presenting cells (APCs) by using HLA-DRA on two different breast cancer tissue microarrays (TMA): The breast cancer progression TMA provided by the Cooperative Human Tissue Network (CHTN_BrCaProg3) and the University of Illinois Breast Cancer Working Group (TMA BCWG UIC-001-TMA) that included primary tumor and lymph node metastases from patients residing in the West Side and South Side of Chicago. We also used bioinformatics analyses of the TCGA and METABRIC databases and the Broad Institute's single-cell RNA sequencing portal to investigate MRTFA/B expression patterns in the cells of the tumor microenvironment (TME).
RESULTS: We found that in human tumors, MRTFA/B are concurrently activated in cancer cells, but they show distinct patterns of expression across different histological subtypes and in the cells of the TME. Importantly, MRTFA expression was elevated in metastatic tumors of African American patients, who disproportionately die from breast cancer. Interestingly, in contrast to publicly available mRNA expression data, MRTFA was similarly expressed across estrogen receptor (ER) positive and negative breast tumors, while MRTFB expression was highest in ER+ breast tumors. Furthermore, MRTFA was specifically expressed in the perivascular antigen-presenting cells (APCs), which has been previously associated with immune suppression and breast cancer progression. We also found that MRTFA expression correlated with the expression of the immune checkpoint protein V-set immunoregulatory receptor (VSIR) in the TCGA data and found that MRTFA activity promotes VSIR expression in THP-1 monocytes and cultured HEK293 cells.
CONCLUSIONS: Our results provide unique insights into how MRTFA and MRTFB promote metastasis in human cancer, the differences of their expression patterns, and their immune suppressive function within the breast cancer TME. Our results will guide future studies on targeting MRTFA/B transcriptional activity and the resulting immune suppression in breast cancer.

Keywords:  Antigen presenting cells; Breast cancer; DCIS; Early-stage; Immune checkpoint; MAL; MKL1; MKL2; MRTFA; MRTFB; Metastasis; Myocardin related transcription factors; SRF; Tumor microenvironment; VISTA; VSIR

DOI:  https://doi.org/10.1186/s12967-025-06559-3
J Immunother Cancer. 2025 May 30. pii: e012188. [Epub ahead of print]13(5):

Pancreatic cancer cell-intrinsic transglutaminase-2 promotes T cell suppression through microtubule-dependent secretion of immunosuppressive cytokines.

Edmund K Waller, Kiranj Chaudagar.

  Pancreatic ductal adenocarcinoma (PDAC) remains resistant to immunotherapy due to a highly immunosuppressive tumor microenvironment. Lahusen et al identify transglutaminase 2 (TGM2) as a critical tumor cell-intrinsic regulator of immune suppression in PDAC. TGM2 enhances the secretion of suppressive cytokines such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage-CSF (GM-CSF) via a microtubule-dependent pathway that secondarily impairs T-cell activation and cytotoxicity. Targeting TGM2, either genetically or with microtubule-disrupting agents, restores T cell function and promotes tumor control in preclinical PDAC models. These findings are discussed in the context of our recent work on vasoactive intestinal peptide (VIP) signaling in PDAC, which independently drives immune evasion through VIP receptor (VPAC)-mediated induction of TGF-β1 secretion from tumor cells, upregulation of programmed death-ligand 1 on myeloid cells, and inhibition of effector T cells. Here, we have explored the mechanistic intersections between TGM2 and VIP signaling-including cytokine secretion, vesicle trafficking, and immune checkpoint regulation-and propose combination strategies that integrate TGM2 or VIP inhibition with checkpoint blockade. Together, these insights suggest a new framework for overcoming immune resistance in PDAC by targeting cancer cell-intrinsic secretory programs and offer a rationale for biomarker-guided, multimodal immunotherapeutic approaches.

Keywords:  Immune Checkpoint Inhibitor

DOI:  https://doi.org/10.1136/jitc-2025-012188
Cancer Immunol Immunother. 2025 May 24. 74(7): 220

Exosomal PD-L1 derived from hypoxia nasopharyngeal carcinoma cell exacerbates CD8+ T cell suppression by promoting PD-L1 upregulation in macrophages.

Xiaofei Yuan, Xiong Liu, Di Jiang, Zijun Zheng, Xuemin Ma, Shuting Wu, Xiangping Li, Juan Lu, Ming Fu.

  Immunotherapy targeting the programmed death ligand-1/programmed cell death protein-1 (PD-L1/PD-1) pathway exhibits limited effectiveness in individuals with recurrent and metastatic nasopharyngeal carcinoma (NPC). Recent studies have noted that hypoxia within the tumor microenvironment (TME) triggers intricate interplay, termed "hypoxia-induced exosome-mediated communication", between cancer cells and various immune cells. However, the role of hypoxia in modulating the immunosuppressive environment and its implications on the efficacy of immunotherapy in NPC remains poorly understood. In this study, we found hypoxia inducible factor-1 (HIF-1α) was positively associated with increased PD-L1 levels and decreased CD8+ T cell infiltration, and correlated with a poor prognosis. Mechanistically, we demonstrated that hypoxia regulated the expression of PD-L1 in NPC cells and their exosomes by activating the binding of HIF-1α to the PD-L1 promoter. Meanwhile, using in vitro approaches, we found that macrophages could upregulate their PD-L1 expression through the phagocytosis of exosomal PD-L1 derived from NPC cells. Furthermore, we confirmed that PD-L1+ macrophages could induce CD8+ T cell exhaustion and reduce their proliferation. In conclusion, our study revealed that hypoxia (via HIF-1α) upregulated the expression of PD-L1 in exosomes derived from NPC cells, while macrophages induce the suppression of CD8+ T cells by phagocytosis of exosomal PD-L1. Targeting the PD-L1+ macrophages could potentially serve as a promising approach to augment the effectiveness of immune checkpoint blockade in NPC.

Keywords:  Hypoxia; Immune escape; Macrophage; Nasopharyngeal carcinoma; PD-L1

DOI:  https://doi.org/10.1007/s00262-025-04047-7