bims-flamet 2025-04-06 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2025–04–06
25 papers selected by
Peio Azcoaga, Biodonostia HRI

Metabolic reprogramming of tumor microenviroment by engineered bacteria.
CAR T cells in lung cancer: Targeting tumor-associated antigens to revolutionize immunotherapy.
Tumor Immunotherapy Targeting B7-H3: From Mechanisms to Clinical Applications.
Role of metabolic transformation in cancer immunotherapy resistance: molecular mechanisms and therapeutic implications.
Transforming Cancer Therapy: Unlocking the Potential of Targeting Vascular and Stromal Cells in the Tumor Microenvironment.
The sweet and the bitter sides of galectin-1 in immunity: its role in immune cell functions, apoptosis, and immunotherapies for cancer with a focus on T cells.
Epithelial-mesenchymal transition orchestrates tumor microenvironment: current perceptions and challenges.
The mechanopathology of the tumor microenvironment: detection techniques, molecular mechanisms and therapeutic opportunities.
Cancer associated fibroblasts in cancer development and therapy.
Advancements and challenges in CAR T cell therapy for pediatric brain tumors: A review.
Targeting immune cells in tumor microenvironment in triple negative breast cancer therapy: future perspective to overcome doxorubicin resistance and toxicity.
The crosstalk within tumor microenvironment and exosomes in pancreatic cancer.
The clinical landscape of CAR-engineered unconventional T cells.
Glucocorticoid Receptor-Targeted Nanoliposome for STAT3 Inhibition-Led Myeloid-Derived Suppressor Cell Modulation and Efficient Colon Cancer Treatment.
A silence catalyst: CCL5-mediated intercellular communication in cancer.
Key immune cells and their crosstalk in the tumor microenvironment of bladder cancer: insights for innovative therapies.
Inflammation and cancer: molecular mechanisms and clinical consequences.
Ammonia Suppresses the Antitumor Activity of Natural Killer Cells and T Cells by Decreasing Mature Perforin.
RNA modifications in the tumor microenvironment: insights into the cancer-immunity cycle and beyond.
Carbon Dot-Linked Hydrogel for TAMs Transform: Spatiotemporal Manipulation to Reshape Tumor Microenvironment.
Combined anti-PD-L1 and anti-VEGFR2 therapy promotes the antitumor immune response in GBM by reprogramming tumor microenvironment.
CLO25-070: Effects and Mechanisms of CD16+/-NK Cells on Ovarian Malignant Tumor Cells Platinum-Based Drug Responsiveness in Tumor Microenvironment.
Gut microbial metabolite 4-hydroxybenzeneacetic acid drives colorectal cancer progression via accumulation of immunosuppressive PMN-MDSCs.
Multiparametric analysis of tumor infiltrating lymphocytes in solid tumors.
Targeting lactylation and the STAT3/CCL2 axis to overcome immunotherapy resistance in pancreatic ductal adenocarcinoma.

Semin Cancer Biol. 2025 Mar 27. pii: S1044-579X(25)00049-5. [Epub ahead of print]112 58-70

Metabolic reprogramming of tumor microenviroment by engineered bacteria.

Heng Wang, Fang Xu, Chao Wang.

  The tumor microenvironment (TME) is a complex ecosystem that plays a crucial role in tumor progression and response to therapy. The metabolic characteristics of the TME are fundamental to its function, influencing not only cancer cell proliferation and survival but also the behavior of immune cells within the tumor. Metabolic reprogramming-where cancer cells adapt their metabolic pathways to support rapid growth and immune evasion-has emerged as a key factor in cancer immunotherapy. Recently, the potential of engineered bacteria in cancer immunotherapy has gained increasing recognition, offering a novel strategy to modulate TME metabolism and enhance antitumor immunity. This review summarizes the metabolic properties and adaptations of tumor and immune cells within the TME and summarizes the strategies by which engineered bacteria regulate tumor metabolism. We discuss how engineered bacteria can overcome the immunosuppressive TME by reprogramming its metabolism to improve antitumor therapy. Furthermore, we examine the advantages, potential challenges, and future clinical translation of engineered bacteria in reshaping TME metabolism.

Keywords:  Engineered bacteria; Immunotherapy; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.semcancer.2025.03.003
Pathol Res Pract. 2025 Mar 29. pii: S0344-0338(25)00139-6. [Epub ahead of print]269 155947

CAR T cells in lung cancer: Targeting tumor-associated antigens to revolutionize immunotherapy.

Sattam Khulaif Alenezi.

  Tumor-targeted T cells engineered for targeting and killing tumor cells have revolutionized cancer treatment, specifically in hematologic malignancies, through chimeric antigen receptor (CAR) T cell therapy. However, the migration of this success to lung cancer is challenging due to the tumor microenvironment (TME), antigen heterogeneity, and limitations of T cell infiltration. This review aims to evaluate current strategies addressing these barriers, focusing on the optimization of tumor-associated antigen (TAA) targeting, such as epidermal growth factor receptor (EGFR), mucin-1 (MUC1), and mesothelin (MSLN), which are frequently overexpressed in lung cancer and offer promising targets for CAR T-cell therapy. In this review, we discuss recent progress in CAR T cell engineering, applying enhanced costimulatory molecules, cytokine-secreting CAR T cells, and engineered modifications to improve T cell resilience in immunosuppressive environments. Additionally, this review also evaluates combination therapies of immune checkpoint inhibitors and recently published clinical trials on lung cancer with CAR T cells. We offer insights into the way to optimize CAR T cell therapy for lung cancer by analyzing antigen selection, immune evasion, and the strategies to enhance T cell persistence and tumor infiltration.

Keywords:  CAR T-Cell Therapy; Immunotherapy; Lung Cancer; Solid Tumors; Tumor Microenvironment; Tumor-Associated Antigens

DOI:  https://doi.org/10.1016/j.prp.2025.155947
Immunotargets Ther. 2025 ;14 291-320

Tumor Immunotherapy Targeting B7-H3: From Mechanisms to Clinical Applications.

Yining Guo, Xudong Wang, Chen Zhang, Weiwu Chen, Yutian Fu, Yanlan Yu, Yicheng Chen, Tiejuan Shao, Jie Zhang, Guoqing Ding.

  B7-H3 (CD276) is an immune checkpoint from the B7 family of molecules and is abnormally expressed in tumor cells as a co-inhibitory molecule to promote tumor progression. Within the tumor microenvironment (TME), B7-H3 promotes tumor progression by impairing the T cell response, driving the polarization of tumor-associated macrophages (TAMs) to M2 phenotype, and inhibiting the function of other immune cells. In addition, B7-H3 promotes tumor cell proliferation, migration, invasion, metabolism disorder, angiogenesis, and resistance to treatment to promote tumor progression through its non-immunological functions. Immunotherapy targeting B7-H3, as well as combinations with other immune checkpoint therapies, have shown certain efficacy. In this review, we synthesizes the expression of B7-H3 and its mechanism to promote tumor progression through inducing immunomodulation and non-immunological functions, as well as its role of B7-H3 in tumor therapy, aiming to provide a reference for the clinical treatment of tumors.

Keywords:  B7-H3 (CD276); immune checkpoint; tumor; tumor immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.2147/ITT.S507522
Discov Oncol. 2025 Apr 02. 16(1): 453

Role of metabolic transformation in cancer immunotherapy resistance: molecular mechanisms and therapeutic implications.

Sandesh Shende, Jaishriram Rathored, Tanushree Budhbaware.

   BACKGROUND: Immunotherapy in the treatment of cancer, with immune inhibitors helps in many cancer types. Many patients still encounter resistance to these treatments, though. This resistance is mediated by metabolic changes in the tumour microenvironment and cancer cells. The development of novel treatments to overcome resistance and boost immunotherapy's effectiveness depends on these metabolic changes.
OBJECTIVE: This review concentrates on the molecular mechanisms through which metabolic transformation contributes to cancer immunotherapy resistance. Additionally, research therapeutic approaches that target metabolic pathways to enhance immunotherapy for resistance.
METHODS: We used databases available on PubMed, Scopus, and Web of Science to perform a thorough review of peer-reviewed literature. focusing on the tumor microenvironment, immunotherapy resistance mechanisms, and cancer metabolism. The study of metabolic pathways covers oxidative phosphorylation, glycolysis, lipid metabolism, and amino acid metabolism.
RESULTS: An immunosuppressive tumour microenvironment is produced by metabolic changes in cancer cells, such as dysregulated lipid metabolism, enhanced glutaminolysis, and increased glycolysis (Warburg effect). Myeloid-derived suppressor cells and regulatory T cells are promoted, immune responses are suppressed, and T cell activity is impaired when lactate and other metabolites build up. changes in the metabolism of amino acids in the pathways for arginine and tryptophan, which are nutrients crucial for immune function. By enhancing their function in the tumour microenvironment, these metabolic alterations aid in resistance to immune checkpoint inhibitors.
CONCLUSION: Metabolic change plays a key role in cancer immunotherapy resistance. Gaining knowledge of metabolic processes can help develop efficient treatments that improve immunotherapy's effectiveness. In order to determine the best targets for therapeutic intervention, future studies should concentrate on patient-specific metabolic profiling.

Keywords:  Amino acid metabolism; Cancer metabolism; Glycolysis; Immune checkpoint inhibitors; Immunotherapy resistance; Tumour microenvironment

DOI:  https://doi.org/10.1007/s12672-025-02238-3
Cancer Res. 2025 Apr 02.

Transforming Cancer Therapy: Unlocking the Potential of Targeting Vascular and Stromal Cells in the Tumor Microenvironment.

Lu Liu, Yuheng Zhang, Hanyu Liu, Jian Yang, Qi Tian, Nareekarn Chueakula, Saravana Ramasamy, Navin Kumar Verma, Christine Cheung, Anjali P Kusumbe.

The tumor microenvironment (TME) orchestrates cancer progression by fostering a complex interplay between cancer cells and the surrounding cellular and acellular elements. Through dynamic interactions with cancer cells, vascular and stromal cells not only promote tumor growth but also enhance metastatic potential and restrict therapeutic responses. Vascular and stromal cells play a critical role in regulating epithelial-mesenchymal transition (EMT) and sustaining resistance pathways, making them compelling targets for innovative therapies. This review delves into the vascular and stromal components of the TME, their contributions to EMT and resistance mechanisms, and emerging strategies to target these interactions for improved cancer therapy outcomes.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-4744
Semin Immunopathol. 2025 Apr 03. 47(1): 24

The sweet and the bitter sides of galectin-1 in immunity: its role in immune cell functions, apoptosis, and immunotherapies for cancer with a focus on T cells.

Julianna Novák, Tamás Takács, Álmos Tilajka, Loretta László, Orsolya Oravecz, Emese Farkas, Nándor Gábor Than, László Buday, Andrea Balogh, Virág Vas.

  Galectin-1 (Gal-1), a member of the β-galactoside-binding soluble lectin family, is a double-edged sword in immunity. On one hand, it plays a crucial role in regulating diverse immune cell functions, including the apoptosis of activated T cells. These processes are key in resolving inflammation and preventing autoimmune diseases. On the other hand, Gal-1 has significant implications in cancer, where tumor cells and the tumor microenvironment (TME) (e.g., tumor-associated fibroblasts, myeloid-derived suppressor cells) secrete Gal-1 to evade immune surveillance and promote cancer cell growth. Within the TME, Gal-1 enhances the differentiation of tolerogenic dendritic cells, induces the apoptosis of effector T cells, and enhances the proliferation of regulatory T cells, collectively facilitating tumor immune escape. Therefore, targeting Gal-1 holds the potential to boost anti-tumor immunity and improve the efficacy of cancer immunotherapy. This review provides insights into the intricate role of Gal-1 in immune cell regulation, with an emphasis on T cells, and elucidates how tumors exploit Gal-1 for immune evasion and growth. Furthermore, we discuss the potential of Gal-1 as a therapeutic target to augment current immunotherapies across various cancer types.

Keywords:  Apoptosis; Cancer immune evasion; Galectin-1; Immune checkpoint inhibitors; Immunotherapy; T lymphocytes

DOI:  https://doi.org/10.1007/s00281-025-01047-8
J Transl Med. 2025 Apr 02. 23(1): 386

Epithelial-mesenchymal transition orchestrates tumor microenvironment: current perceptions and challenges.

Yuqi Xie, Xuan Wang, Wenquan Wang, Ning Pu, Liang Liu.

  The epithelial-mesenchymal transition (EMT) is a critical process in cancer progression, facilitating tumor cells to develop invasive traits and augmenting their migratory capabilities. EMT is primed by tumor microenvironment (TME)-derived signals, whereupon cancer cells undergoing EMT in turn remodel the TME, thereby modulating tumor progression and therapeutic response. This review discusses the mechanisms by which EMT coordinates TME dynamics, including secretion of soluble factors, direct cell contact, release of exosomes and enzymes, as well as metabolic reprogramming. Recent evidence also indicates that cells undergoing EMT may differentiate into cancer-associated fibroblasts, thereby establishing themselves as functional constituents of the TME. Elucidating the relationship between EMT and the TME offers novel perspectives for therapeutic strategies to enhance cancer treatment efficacy. Although EMT-directed therapies present significant therapeutic potential, the current lack of effective targeting approaches-attributable to EMT complexity and its microenvironmental context dependency-underscores the necessity for mechanistic investigations and translational clinical validation.

Keywords:  Epithelial-mesenchymal transition (EMT); Plasticity; Tumor microenvironment (TME); Tumor progression

DOI:  https://doi.org/10.1186/s12967-025-06422-5
Front Cell Dev Biol. 2025 ;13 1564626

The mechanopathology of the tumor microenvironment: detection techniques, molecular mechanisms and therapeutic opportunities.

Stella Angeli, Constantina Neophytou, Maria Kalli, Triantafyllos Stylianopoulos, Fotios Mpekris.

  The mechanical properties of the tumor microenvironment (TME) undergo significant changes during tumor growth, primarily driven by alterations in extracellular (ECM) stiffness and tumor viscoelasticity. These mechanical changes not only promote tumor progression but also hinder therapeutic efficacy by impairing drug delivery and activating mechanotransduction pathways that regulate crucial cellular processes such as migration, proliferation, and resistance to therapy. In this review, we examine the mechanisms through which tumor cells sense and transmit mechanical signals to maintain homeostasis in the biomechanically altered TME. We explore current computational modelling strategies for mechanotransduction pathways, highlighting the need for developing models that incorporate additional components of the mechanosignaling machinery. Furthermore, we review available methods for measuring the mechanical properties of tumors in clinical settings and strategies aiming at restoring the TME and blocking deregulated mechanotransduction pathways. Finally, we propose that proper characterization and a deeper understanding of the mechanical landscape of the TME, both at the tissue and cellular levels, are essential for developing therapeutic strategies that account for the influence of mechanical forces on treatment efficacy.

Keywords:  cellular mechanotransduction; computational modelling; mechanical forces; mechanopathology; tissue stiffness; tumor microenvironment

DOI:  https://doi.org/10.3389/fcell.2025.1564626
J Hematol Oncol. 2025 Mar 28. 18(1): 36

Cancer associated fibroblasts in cancer development and therapy.

Hongyuan Jia, Xingmin Chen, Linling Zhang, Meihua Chen.

  Cancer-associated fibroblasts (CAFs) are key players in cancer development and therapy, and they exhibit multifaceted roles in the tumor microenvironment (TME). From their diverse cellular origins, CAFs undergo phenotypic and functional transformation upon interacting with tumor cells and their presence can adversely influence treatment outcomes and the severity of the cancer. Emerging evidence from single-cell RNA sequencing (scRNA-seq) studies have highlighted the heterogeneity and plasticity of CAFs, with subtypes identifiable through distinct gene expression profiles and functional properties. CAFs influence cancer development through multiple mechanisms, including regulation of extracellular matrix (ECM) remodeling, direct promotion of tumor growth through provision of metabolic support, promoting epithelial-mesenchymal transition (EMT) to enhance cancer invasiveness and growth, as well as stimulating cancer stem cell properties within the tumor. Moreover, CAFs can induce an immunosuppressive TME and contribute to therapeutic resistance. In this review, we summarize the fundamental knowledge and recent advances regarding CAFs, focusing on their sophisticated roles in cancer development and potential as therapeutic targets. We discuss various strategies to target CAFs, including ECM modulation, direct elimination, interruption of CAF-TME crosstalk, and CAF normalization, as approaches to developing more effective treatments. An improved understanding of the complex interplay between CAFs and TME is crucial for developing new and effective targeted therapies for cancer.

Keywords:  Cancer associated fibroblasts (CAFs); Cancer development; Cancer therapy; Extracellular matrix (ECM); Heterogeneity; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1186/s13045-025-01688-0
J Oncol Pharm Pract. 2025 Mar 29. 10781552251331609

Advancements and challenges in CAR T cell therapy for pediatric brain tumors: A review.

Yasmina Gaoual, Adam Mahyaoui, Lamyae Yachi, Mustapha Bouatia, Zineb Aliat, Younes Rahali.

  Chimeric Antigen Receptor (CAR) T cell therapy represents a groundbreaking advancement in immunotherapy, initially gaining FDA approval for treating hematological malignancies. This therapy has shown promising results in solid tumors, particularly in pediatric brain tumors, which are the leading cause of cancer-related death in children. CAR T cells are engineered to target specific antigens on tumor cells, thereby reducing off-target effects and increasing the cytotoxic impact on cancer cells. Over the years, CAR T cell technology has evolved through five generations, each enhancing the structure, functionality, and safety of these cells. Despite these advancements, the application of CAR T cells in solid tumors, especially within the central nervous system (CNS), faces significant challenges. These include the physical barrier posed by the blood-brain barrier (BBB), the immunosuppressive tumor microenvironment (TME), and the heterogeneity of tumor antigens. The review discusses several promising antigenic targets for CAR T cells in pediatric brain tumors, such as HER2, EphA2, IL-13Rα2, and Survivin, which have been explored in recent clinical trials. These trials have shown early promise in improving patient outcomes, though the risks of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) remain concerns. The future of CAR T cell therapy lies in overcoming these barriers through innovative approaches like "Armored CARs" or TRUCKs, designed to modulate the TME and improve CAR T cell efficacy in solid tumors. Additionally, combination therapies and safety switches in next-generation CAR T cells are being explored to enhance therapeutic potential while minimizing adverse effects.

Keywords:  T-cells; chimeric antigen receptor; pediatric brain tumors; solid tumor; tumor microenvironment

DOI:  https://doi.org/10.1177/10781552251331609
Med Oncol. 2025 Apr 04. 42(5): 150

Targeting immune cells in tumor microenvironment in triple negative breast cancer therapy: future perspective to overcome doxorubicin resistance and toxicity.

Dewajani Purnomosari, Bilqis Zahra Nabila, Sitarina Widyarini, Mustofa.

  Triple negative breast cancer (TNBC) has high recurrence and low survival rates among breast cancer types. So far, TNBC treatment has been limited to chemotherapy, which leads to high recurrence and drug resistance. The immune cells in the tumor microenvironment (TME) play an important role in tumor development and cancer progression. This study aimed to explore how immune cells in TME have been used to treat TNBC cases in combination with Doxorubicin (DOX). Searching was conducted for scientific publications on several databases in the past 10 years (2013-2023). Of the 7622 articles, 14 articles met the inclusion criteria and underwent the extraction process. All articles extracted in this review were preclinical studies on experimental animals. The results indicate the combination of DOX with cyclophosphamide and aminoglutethimide, increasing CD8 + infiltration resulting in tumor growth inhibition. The combination of DOX with vorinostat and molecular PepO also induces anti-tumor activity in the TME via increased infiltration of B cells and T cells and induced transition from M2 into M1. Other results, which lead to better prognosis have been obtained from the combination of DOX with losartan and anti-PD1 that leads to overhauling the immunosuppressive microenvironment. Targeting immune cells in TME such as dendritic cells, tumor-associated macrophages, CD8 + and CD4 + T cells are potentially used as therapeutic targets for TNBC treatment to optimize anti-tumor activity using combinations of DOX and certain drugs.

Keywords:  Chemotherapy; Doxorubicin; Drug resistance; Triple negative breast cancer; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12032-025-02712-6
Biochim Biophys Acta Rev Cancer. 2025 Apr 01. pii: S0304-419X(25)00050-2. [Epub ahead of print]1880(3): 189308

The crosstalk within tumor microenvironment and exosomes in pancreatic cancer.

Michael Ochieng' Otieno, Tomasz Powrózek, Jesus Garcia-Foncillas, Javier Martinez-Useros.

  Pancreatic cancer is one of the most malignant tumors with a grim prognosis. Patients develop chemoresistance that drastically decreases their survival. The chemoresistance is mainly attributed to deficient vascularization of the tumor, intratumoral heterogeneity and pathophysiological barrier due to the highly desmoplastic tumor microenvironment. The interactions of cells that constitute the tumor microenvironment change its architecture into a cancer-permissive environment and stimulate cancer development, metastasis and treatment response. The cell-cell communication in the tumor microenvironment is often mediated by exosomes that harbour a diverse repertoire of molecular cargo, such as proteins, lipids, and nucleic acid, including messenger RNAs, non-coding RNAs and DNA. Therefore, exosomes can serve as potential targets as biomarkers and improve the clinical management of pancreatic cancer to overcome chemoresistance. This review critically elucidates the role of exosomes in cell-cell communication within the tumor microenvironment and how these interactions can orchestrate chemoresistance.

Keywords:  Chemoresistance; Exosomes; Pancreatic cancer; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2025.189308
Trends Cancer. 2025 Mar 27. pii: S2405-8033(25)00069-X. [Epub ahead of print]

The clinical landscape of CAR-engineered unconventional T cells.

Yan-Ruide Li, Yichen Zhu, Yuning Chen, Lili Yang.

  Unconventional T cells, such as invariant natural killer T (iNKT), γδ T, and mucosal-associated invariant T (MAIT) cells, play a pivotal role in bridging innate and adaptive immunity. Their capacity for rapid tumor targeting and effective modulation of the tumor microenvironment (TME) makes them promising candidates for cancer immunotherapy. Advances in chimeric antigen receptor (CAR) engineering have further highlighted their therapeutic potential, particularly for treating challenging cancers. Notably, these cells exhibit favorable safety profiles, enhancing their viability as off-the-shelf therapeutic options. We provide a comprehensive analysis of the clinical applications of CAR-engineered unconventional T cells, focusing on genetic modifications, manufacturing processes, preconditioning regimens, and dosing strategies. We discuss successful examples from recent clinical trials and explore future directions for utilizing these cells in cancer therapy and beyond.

Keywords:  cancer immunotherapy; chimeric antigen receptor engineering; invariant natural killer T cell; mucosal-associated invariant T cell; unconventional T cell; γδ T cell

DOI:  https://doi.org/10.1016/j.trecan.2025.03.001
ACS Appl Bio Mater. 2025 Mar 31.

Glucocorticoid Receptor-Targeted Nanoliposome for STAT3 Inhibition-Led Myeloid-Derived Suppressor Cell Modulation and Efficient Colon Cancer Treatment.

Tithi Bhattacharyya, Pritam Das, Aasia Ansari, Adrij A Mohan, Yogesh Chandra, Kumar Pranav Narayan, Rajkumar Banerjee.

  STAT3 is an important protein responsible for cellular proliferation, motility, and immune tolerance and is hyperactive in colorectal cancer, instigating metastasis, cellular proliferation, migration, as well as inhibition. It helps in proliferation of myeloid-derived suppressor cells (MDSCs), which within the tumor microenvironment (TME) suppress T cells to encourage tumor growth, metastasis, and resistance to immunotherapy, besides playing dynamic role in regulating macrophages within the tumor. Thus, MDSC is a potential target to augment immune surveillance within the TME. Herein, we report targeting both colorectal cancer and MDSCs using a glucocorticoid receptor (GR)-targeted nanoliposomal formulation carrying GR-ligand, dexamethasone (Dex), and a STAT3 inhibitor, niclosamide (N). Our main objective was to selectively inhibit STAT3, the key immunomodulatory factor in most TME-associated cells including MDSCs, and also repurpose the use of this antihelminthic, low-cost drug N for cancer treatment. The resultant formulation D1XN exhibited better tumor regression and survivability compared to GR nontargeted formulation. Further, bone marrow cell-derived MDSCs were engineered by D1XN treatment ex vivo and were inoculated back to tumor-bearing mice. Significant tumor growth inhibition with enhanced antiproliferative immune cell signatures, such as T cell infiltration, decrease in Treg cells, and increased M1/M2 macrophage ratio within the TME were observed. This reveals the effectiveness of engineered MDSCs to modulate tumor surveillance besides reversing the aggressiveness of the tumor. Therefore, D1XN and D1XN-mediated engineered MDSCs alone or in combination can be considered as potent selective chemo-immunotherapeutic nanoliposomal agent(s) against colorectal cancer.

Keywords:  Engineered Myeloid-derived suppressor cells; GR-targeted nanoliposomes; bone marrow cells; colorectal cancer; glucocorticoid receptor (GR)

DOI:  https://doi.org/10.1021/acsabm.5c00002
Arch Toxicol. 2025 Apr 01.

A silence catalyst: CCL5-mediated intercellular communication in cancer.

Wei-Ting Hu, Ming Li, Pei-Jun Ma, Ding Yang, Xiao-Dong Liu, Yun Wang.

  Chemokine CCL5 (RANTES), as a key mediator of intercellular communication in cancers, and its role in cancer development, metastasis and immune escape has received increasing attention. CCL5 and its receptors are important components of the tumor microenvironment and play a tumor promoting role in different ways by triggering signaling pathways through binding to the primary receptor CCR5. CCL5 was viewed as indispensable "gate keepers" of immunity and inflammation, it remains unclear of CCL5-mediated intercellular communication. Therefore, in this review, we summarize the latest information on the origin, structure, and characterization of CCL5 and role of CCL5 in the tumor microenvironment. It includes CCL5-mediated intercellular communication through exosomes, microvesicles and others in breast, lung, and ovarian cancers. CCL5 has a multifaceted role in cancer and has potential applications as a biomarker for cancer diagnosis and prognosis, which provides theoretical bases and therapeutic targets for the development of new cancer therapeutic strategies.

Keywords:  CCL5; Cancer; Intercellular communication; Receptor; Tumor microenvironment

DOI:  https://doi.org/10.1007/s00204-025-04036-w
Explor Target Antitumor Ther. 2025 ;6 1002304

Key immune cells and their crosstalk in the tumor microenvironment of bladder cancer: insights for innovative therapies.

Anna Di Spirito, Sahar Balkhi, Veronica Vivona, Lorenzo Mortara.

  Bladder cancer (BC) is a heterogeneous disease associated with high mortality if not diagnosed early. BC is classified into non-muscle-invasive BC (NMIBC) and muscle-invasive BC (MIBC), with MIBC linked to poor systemic therapy response and high recurrence rates. Current treatments include transurethral resection with Bacillus Calmette-Guérin (BCG) therapy for NMIBC and radical cystectomy with chemotherapy and/or immunotherapy for MIBC. The tumor microenvironment (TME) plays a critical role in cancer progression, metastasis, and therapeutic efficacy. A comprehensive understanding of the TME's complex interactions holds substantial translational significance for developing innovative treatments. The TME can contribute to therapeutic resistance, particularly in immune checkpoint inhibitor (ICI) therapies, where resistance arises from tumor-intrinsic changes or extrinsic TME factors. Recent advancements in immunotherapy highlight the importance of translational research to address these challenges. Strategies to overcome resistance focus on remodeling the TME to transform immunologically "cold" tumors, which lack immune cell infiltration, into "hot" tumors that respond better to immunotherapy. These strategies involve disrupting cancer-microenvironment interactions, inhibiting angiogenesis, and modulating immune components to enhance anti-tumor responses. Key mechanisms include cytokine involvement [e.g., interleukin-6 (IL-6)], phenotypic alterations in macrophages and natural killer (NK) cells, and the plasticity of cancer-associated fibroblasts (CAFs). Identifying potential therapeutic targets within the TME can improve outcomes for MIBC patients. This review emphasizes the TME's complexity and its impact on guiding novel therapeutic approaches, offering hope for better survival in MIBC.

Keywords:  Bladder cancer; immune evasion; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.37349/etat.2025.1002304
Front Oncol. 2025 ;15 1564572

Inflammation and cancer: molecular mechanisms and clinical consequences.

Hikmet Akkız, Halis Şimşek, Deniz Balcı, Yakup Ülger, Engin Onan, Nevin Akçaer, Anıl Delik.

  Inflammation, a hallmark of cancer, has been associated with tumor progression, transition into malignant phenotype and efficacy of anticancer treatments in cancer. It affects all stages of cancer, from the initiation of carcinogenesis to metastasis. Chronic inflammation induces immunosup-pression, providing an environment conducive to carcinogenesis, whereas acute inflammation induces an antitumor immune response, leading to tumor suppression. Solid tumors have an inflammatory tumor microenvironment (TME) containing cancer cells, immune cells, stromal cells, and soluble molecules, which plays a key role in tumor progression and therapy response. Both cancer cells and stromal cells in the TME are highly plastic and constantly change their phenotypic and functional properties. Cancer-associated inflammation, the majority of which consists of innate immune cells, plays an important role in cancer cell plasticity, cancer progression and the development of anticancer drug resistance. Today, with the combined used of advanced technologies, such as single-cell RNA sequencing and spatial molecular imaging analysis, the pathways linking chronic inflammation to cancer have been largely elucidated. In this review article, we highlighted the molecular and cellular mechanisms involved in cancer-associated inflammation and its effects on cancer progression and treatment response. We also comprehensively review the mechanisms linking chronic inflammation to cancer in the setting of GI cancers.

Keywords:  adaptive immunity; cancer-associated fibroblasts; cancer-associated inflammation; gastro-intestinal cancer; innate immunity; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2025.1564572
Cancer Res. 2025 Mar 31.

Ammonia Suppresses the Antitumor Activity of Natural Killer Cells and T Cells by Decreasing Mature Perforin.

Joanna Domagala, Tomasz M Grzywa, Iwona Baranowska, Magdalena Justyniarska, Ryan Tannir, Agnieszka Graczyk-Jarzynka, Aleksandra Kusowska, Maria Lecka, Marcin Poreba, Klaudyna Fidyt, Katsiaryna Marhelava, Zofia Pilch, Lea K Picard, Tomasz Wegierski, Kamil Jastrzebski, Marta Krawczyk, Marta Klopotowska, Monika Granica, Doris Urlaub, Szymon Hajduk, Alexandra Neeser, Spencer Moros, Pawel Kozlowski, Malgorzata Bobrowicz, Marta Miaczynska, Leyuan Ma, Carsten Watzl, Magdalena Winiarska.

Immunotherapy revolutionized cancer treatment in the last decade. Both natural killer (NK) cells and T cells are key components of host immunity against malignant cells that are being extensively investigated in the field of cancer immunotherapy. While approaches have been developed to improve the antitumor activity of NK and T cells, the tumor microenvironment remains an obstacle to effective NK and T cell-based therapies. Here, we demonstrated that cancer-conditioned medium suppresses the antitumor activity of NK cells. Ammonia, a by-product of cancer cell metabolism, accumulated in cancer-conditioned medium and in the tumor microenvironment, and impaired the cytotoxicity of NK cells as well as the efficacy of antibody-based and chimeric antigen receptor (CAR)-NK and CAR-T cell-based therapies in vitro. Ammonia induced NK and T cell dysfunction by decreasing the amount of mature perforin in secretory lysosomes, which was dependent on its lysosomotropic features and ability to increase pH in acidic compartments. These findings demonstrate that, in addition to its previously described role in promoting tumor growth as a source of nitrogen for tumor biomass, ammonia promotes tumor immune escape by inhibiting both NK and CAR-T cell cytotoxicity.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0749
Exp Hematol Oncol. 2025 Apr 02. 14(1): 48

RNA modifications in the tumor microenvironment: insights into the cancer-immunity cycle and beyond.

You-Peng Ding, Cui-Cui Liu, Ke-Da Yu.

  The chemical modification of biological molecules is a critical regulatory mechanism for controlling molecular functions. Although research has long focused on DNA and proteins, RNA modifications have recently attracted substantial interest with the advancement in detection technologies. In oncology, many studies have identified dysregulated RNA modifications including m6A, m1A, m5C, m7G, pseudouridylation and A to I editing, leading to disrupted downstream pathways. As the concept of the tumor microenvironment has gained prominence, studies have increasingly examined the role of RNA modifications in this context, focusing on interactions among cancer cells, immune cells, stromal cells, and other components. Here we review the RNA modifications in the tumor microenvironment through the perspective of the Cancer-Immunity Cycle. The extracellular RNA modifications including exosomes and influence of microbiome in RNA modifications are potential research questions. Additionally, RNA modifying enzymes including FTO, ALKBH5, METTL3, PUS7 are under investigation as potential biomarkers and targets for combination with immunotherapies. ADCs and mimetics of modified RNA could be potential novel drugs. This review discusses the regulatory roles of RNA modifications within the tumor microenvironment.

Keywords:  Cancer-immunity cycle; Pseudouridylation; RNA modification; Tumor microenvironment; m6A

DOI:  https://doi.org/10.1186/s40164-025-00648-1
Adv Mater. 2025 Apr 03. e2420068

Carbon Dot-Linked Hydrogel for TAMs Transform: Spatiotemporal Manipulation to Reshape Tumor Microenvironment.

Lingyun Li, Jun Wu, Xue Wu, Zhenjian Li, Xianming Zhang, Zekun Yan, Yingqi Liang, Caishi Huang, Songnan Qu.

  As one of the most crucial immune cells in the tumor microenvironment (TME), regulating tumor-associated macrophages (TAMs) is vital for enhancing antitumor immunity. Here, an injectable carbon dots (CDs)-linked egg white hydrogel was developed, termed TAMs Transform Factory (TTF-L-C), to spatiotemporally manipulate TAMs. The fabricated CDs significantly promoted macrophage migration. Notably, TTF-L-C achieved macrophage spatial enrichment through CDs-induced directional recruitment with molecular Ctnnd1 upregulation. Subsequently, the recruited macrophages were locoregionally reprogrammed within TTF-L-C, as well as blocking the upregulated PD-L1. Finally, through multi-stage regulation at spatial, cellular, and molecular levels, TTF-L-C released immune-activated M1 macrophages to the tumor site as it degraded. Moreover, TTF-L-C promoted dendritic cell (DCs) maturation and further boosted T cell activation, thereby reshaping the tumor-suppressive TME. Through peritumoral injection, TTF-L-C enhanced tumor immunotherapy in both subcutaneous and recurrent 4T1 tumor models with satisfactory biosafety. Therefore, TTF-L-C is proposed to become a safe and powerful platform for various biomedical applications.

Keywords:  carbon dots; hydrogel; macrophage recruitment; macrophage reprogram; tumor immunotherapy

DOI:  https://doi.org/10.1002/adma.202420068
Cell Death Discov. 2025 Apr 03. 11(1): 136

Combined anti-PD-L1 and anti-VEGFR2 therapy promotes the antitumor immune response in GBM by reprogramming tumor microenvironment.

Lin Yao, Hao Wang, Yongsheng Liu, Ming Feng, Yanyan Li, Zuopeng Su, Wen Li, Yun Xiong, Heyang Gao, Youxin Zhou.

Inhibitors of programmed cell death ligand 1 (PD-L1) and vascular endothelial growth factor receptor 2 (VEGFR2) are commonly used in the clinic, but they are beneficial for only a minority of glioblastoma multiforme (GBM) patients. GBM has significant immunosuppressive properties, and there are many immunosuppressive cells and dysfunctional effector T cells in the tumor microenvironment (TME), which is one of the important reasons for the failure of clinical treatment of GBM. Here, we have identified P21 activated kinase 4 (PAK4) as a pivotal immune suppressor in the TME. PAK4 is a threonine protein kinase, and PAK4 knockdown attenuates vascular abnormalities and promotes T-cell infiltration. In this study, our results showed that the expression of PAK4 was significantly downregulated after VEGFR2 knockdown. Next, we constructed a coculture system of CD8+ T cells and GBM cells. Our findings showed that combined anti-PD-L1 and anti-VEGFR2 therapy can regulate the TME and inhibit GBM cells' immune escape; overexpression of PAK4 can reverse this effect. Finally, we tested the combination therapy in mouse intracranial graft tumor models and found that combination therapy can prolong mouse survival. These findings suggest that anti-VEGFR2 therapy can downregulate PAK4, reprogram the TME by increasing cytotoxic CD8+ T cells infiltration and activation, and enhance the therapeutic effect of anti-PD-L1 therapy on GBM cells.

DOI: https://doi.org/10.1038/s41420-025-02427-7
J Natl Compr Canc Netw. 2025 Mar 28. pii: CLO25-070. [Epub ahead of print]23(3.5):

CLO25-070: Effects and Mechanisms of CD16+/-NK Cells on Ovarian Malignant Tumor Cells Platinum-Based Drug Responsiveness in Tumor Microenvironment.

Feifei Song, Xiaodong Cheng.

DOI: https://doi.org/10.6004/jnccn.2024.7153
J Clin Invest. 2025 Apr 03. pii: e181243. [Epub ahead of print]

Gut microbial metabolite 4-hydroxybenzeneacetic acid drives colorectal cancer progression via accumulation of immunosuppressive PMN-MDSCs.

Qing Liao, Ximing Zhou, Ling Wu, Yuyi Yang, Xiaohui Zhu, Hangyu Liao, Yujie Zhang, Weidong Lian, Feifei Zhang, Hui Wang, Yanqing Ding, Liang Zhao.

  Colorectal cancer (CRC) is characterized by an immune-suppressive microenvironment that contributes to tumor progression and immunotherapy resistance. The gut microbiome produces diverse metabolites that feature unique mechanisms of interaction with host targets, yet the role of many metabolites in CRC remains poorly understood. In this study, the microbial metabolite 4-hydroxybenzeneacetic acid (4-HPA) promoted the infiltration of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in the tumor microenvironment, consequently inhibiting the anti-tumor response of CD8+ T cells and promoting CRC progression in vivo. Mechanistically, 4-HPA activates the JAK2/STAT3 pathway, which upregulates CXCL3 transcription, thereby recruiting PMN-MDSCs to the CRC microenvironment. Selective knockdown of CXCL3 re-sensitized tumors to anti-PD1 immunotherapy in vivo. Chlorogenic acid (CGA) reduces the production of 4-HPA by microbiota, likewise abolishing 4-HPA-mediated immunosuppression. The 4-HPA content in CRC tissues was notably increased in patients with advanced CRC. Overall, the gut microbiome uses 4-HPA as a messenger to control chemokine-dependent accumulation of PMN-MDSC cells and regulate anti-tumor immunity in CRC. Our findings provide a scientific basis for establishing clinical intervention strategies to reverse the tumor immune microenvironment and improve the efficacy of immunotherapy by reducing the interaction between intestinal microbiota, tumor cells and tumor immune cells.

Keywords:  Cancer immunotherapy; Colorectal cancer; Gastroenterology; Immunology; Oncology

DOI:  https://doi.org/10.1172/JCI181243
Methods Cell Biol. 2025 ;pii: S0091-679X(23)00080-8. [Epub ahead of print]195 39-70

Multiparametric analysis of tumor infiltrating lymphocytes in solid tumors.

Rebecca Borella, Annamaria Paolini, Beatrice Aramini, Lara Gibellini, Valentina Masciale, Domenico Lo Tartaro, Massimo Dominici, Sara De Biasi, Andrea Cossarizza.

  The use of single-cell technologies in characterizing the interactions between immune and cancer cells is in continuous expansion. Indeed, the combination of different single-cell approaches enables the definition of novel phenotypic and functional aspects of the immune cells infiltrating the tumor microenvironment (TME). This approach is promoting the discovery of relevant and reliable predictive biomarkers, along with the development of new promising treatments. In this chapter, we describe the main subsets of tumor-infiltrating lymphocytes from a phenotypical and functional point of view and discuss the use of single-cell technologies used to characterize these cell populations within TME.

Keywords:  Flow cytometry; Immune checkpoint proteins; Single-cell technologies; Tumor infiltrating lymphocytes; Tumor microenvironment

DOI:  https://doi.org/10.1016/bs.mcb.2023.03.006
J Clin Invest. 2025 Apr 01. pii: e191422. [Epub ahead of print]135(7):

Targeting lactylation and the STAT3/CCL2 axis to overcome immunotherapy resistance in pancreatic ductal adenocarcinoma.

Qun Chen, Hao Yuan, Michael S Bronze, Min Li.

Metabolic reprogramming in pancreatic ductal adenocarcinoma (PDAC) fosters an immunosuppressive tumor microenvironment (TME) characterized by elevated lactate levels, which contribute to immune evasion and therapeutic resistance. In this issue of the JCI, Sun, Zhang, and colleagues identified nonhistone ENSA-K63 lactylation as a critical regulator that inactivates PP2A, activates STAT3/CCL2 signaling, recruits tumor-associated macrophages (TAMs), and suppresses cytotoxic T cell activity. Targeting ENSA-K63 lactylation or CCL2/CCR2 signaling reprograms the TME and enhances the efficacy of immune checkpoint blockade (ICB) in PDAC preclinical models. This work provides critical insights into the metabolic-immune crosstalk in PDAC and highlights promising therapeutic strategies for overcoming immune resistance and improving patient outcomes.

DOI: https://doi.org/10.1172/JCI191422