bims-flamet 2025-04-20 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2025–04–20
38 papers selected by
Peio Azcoaga, Biodonostia HRI

Deciphering T-cell exhaustion in the tumor microenvironment: paving the way for innovative solid tumor therapies.
Cytokine-mediated regulation of immune cell metabolic pathways in the tumor microenvironment.
The role of CAFs in therapeutic resistance in triple negative breast cancer: an emerging challenge.
Immune microenvironment and immunotherapy in hepatocellular carcinoma: mechanisms and advances.
Decoding the immune landscape in Ewing sarcoma pathogenesis: The role of tumor infiltrating immune cells and immune milieu.
Benign non-immune cells in tumor microenvironment.
The role of the tumor microenvironment in HNSCC resistance and targeted therapy.
Metabolic Dialogue Shapes Immune Response in the Tumor Microenvironment.
Targeting the poliovirus receptor to activate T cells and induce myeloid-derived suppressor cells to differentiate to pro-inflammatory macrophages via the IFN-γ-p-STAT1-IRF8 axis in cancer therapy.
Impact of tumor metabolism on tumor progression and therapy Cathepsins: emerging targets in the tumor ecosystem to overcome cancers.
T-cell Senescence in the Tumor Microenvironment.
Metabolic Reprogramming of Glycolysis, Lipids, and Amino Acids in Tumors: Impact on CD8+ T Cell Function and Targeted Therapeutic Strategies.
Exploring the Interaction of Tumor-Derived Exosomes and Mesenchymal Stem Cells in Tumor Biology.
Immune Modulation and Immunotherapy in Solid Tumors: Mechanisms of Resistance and Potential Therapeutic Strategies.
Strategies for Altering Delivery Technologies to Optimize CAR Therapy.
CAR-T therapy in solid tumors.
Cancer-Associated Fibroblasts as the "Architect" of the Lung Cancer Immune Microenvironment: Multidimensional Roles and Synergistic Regulation with Radiotherapy.
Multifaceted roles of OCT4 in tumor microenvironment: biology and therapeutic implications.
Understanding Merkel Cell Carcinoma: Pathogenic Signaling, Extracellular Matrix Dynamics, and Novel Treatment Approaches.
Nutritional strategies in oncology: The role of dietary patterns in modulating tumor progression and treatment response.
From Bench to Bladder: The Rise in Immune Checkpoint Inhibition in the Treatment of Non-Muscle Invasive Bladder Cancer.
A new era in melanoma immunotherapy: focus on DCs metabolic reprogramming.
LILRB2 blockade facilitates macrophage repolarization and enhances T cell-mediated antitumor immunity.
A macrophage-neutrophil program drives mammary carcinogenesis.
Patient-derived tumor organoids for cancer immunotherapy: culture techniques and clinical application.
Unraveling the Complexities of Myeloid-Derived Suppressor Cells in Inflammatory Bowel Disease.
CAR T cell-driven induction of iNOS in tumor-associated macrophages promotes CAR T cell resistance in B cell lymphoma.
Cancer-associated fibroblasts: multidimensional players in liver cancer.
Neospora caninum as delivery vehicle for anti-PD-L1 scFv-Fc: A novel approach for cancer immunotherapy.
Double-Multiplex Immunostainings for Immune Profiling of Invasive Breast Carcinoma: Emerging Novel Immune-Based Biomarkers.
Epstein-Barr virus-mediated immune evasion in tumor promotion.
Overcoming myeloid-driven resistance to CAR T therapy by targeting SPP1.
Microsatellite Instability in the Tumor Microenvironment: The Role of Inflammation and the Microbiome.
Function of antigen-presenting cells in non-small-cell lung cancer (NSCLC).
Transmembrane Serine Protease TMPRSS11B promotes an acidified tumor microenvironment and immune suppression in lung squamous cell carcinoma.
Neutrophils and Neutrophil-Based Drug Delivery Systems in Anti-Cancer Therapy.
Immune microenvironment and molecular mechanisms in endometrial cancer: implications for resistance and innovative treatments.
Decoding the enigmatic role of T-cadherin in tumor angiogenesis.

Front Immunol. 2025 ;16 1548234

Deciphering T-cell exhaustion in the tumor microenvironment: paving the way for innovative solid tumor therapies.

Reshmi Nair, Veena Somasundaram, Anshu Kuriakose, Shiv Ram Krishn, David Raben, Rachel Salazar, Pradip Nair.

  In solid tumors, the tumor microenvironment (TME) is a complex mix of tumor, immune, stromal cells, fibroblasts, and the extracellular matrix. Cytotoxic T lymphocytes (CTLs) constitute a fraction of immune cells that may infiltrate into the TME. The primary function of these T-cells is to detect and eliminate tumor cells. However, due to the immunosuppressive factors present in the TME primarily mediated by Myeloid-Derived Suppressor Cells (MDSCs), Tumor associated macrophages (TAMs), Cancer Associated Fibroblasts (CAFs) as well as the tumor cells themselves, T-cells fail to differentiate into effector cells or become dysfunctional and are unable to eliminate the tumor. In addition, chronic antigen stimulation within the TME also leads to a phenomenon, first identified in chronic lymphocytic choriomeningitis virus (LCMV) infection in mice, where the T-cells become exhausted and lose their effector functions. Exhausted T-cells (Tex) are characterized by the presence of remarkably conserved inhibitory receptors, transcription and signaling factors and the downregulation of key effector molecules. Tex cells have been identified in various malignancies, including melanoma, colorectal and hepatocellular cancers. Recent studies have indicated novel strategies to reverse T-cell exhaustion. These include checkpoint inhibitor blockade targeting programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin-domain containing-3 (Tim-3), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), or combinations of different immune checkpoint therapies (ICTs) or combination of ICTs with cytokine co-stimulation. In this review, we discuss aspects of T-cell dysfunction within the TME with a focus on T-cell exhaustion. We believe that gaining insight into the mechanisms of T-cell exhaustion within the TME of human solid tumors will pave the way for developing therapeutic strategies to target and potentially re-invigorate exhausted T-cells in cancer.

Keywords:  T-cell activity; T-cell exhaustion; novel therapeutic approach; solid tumor; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1548234
Naunyn Schmiedebergs Arch Pharmacol. 2025 Apr 12.

Cytokine-mediated regulation of immune cell metabolic pathways in the tumor microenvironment.

Alireza Soleimani Mamalo, Mohammadreza Pashaei, Mohammad Valilo, Masoud Ojarudi.

  Cancer, an important global health problem, is defined by aberrant cell proliferation and continues to be the main cause of death globally. The tumor microenvironment (TME) plays an essential role in the development of cancer, resistance to therapy, and regulation of the immune response. Some immune cells in the TME, like T cells, B cells, macrophages, dendritic cells, and natural killer cells, can either stop or help tumor growth, depending on how metabolic and cytokine changes happen. Cytokines function as essential signaling molecules that modulate immune cell metabolism, altering their functionality. This review focuses on how cytokine-mediated metabolic reprogramming affects the activity of immune cells inside the TME, which can either make the immune response stronger or weaker. New ways of treating cancer that focus on metabolic pathways and cytokine signaling, such as using IL (Interleukin) - 15, IL- 10, and IL- 4, show promise in boosting immune cell activity and making cancer treatments more effective. Finding these pathways could lead to new ways to treat cancer with immunotherapy that focus on metabolic competition and immune resistance in the TME.

Keywords:  Cytokine; Immune cells; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1007/s00210-025-04133-8
Front Mol Biosci. 2025 ;12 1568865

The role of CAFs in therapeutic resistance in triple negative breast cancer: an emerging challenge.

Marianna Rita Brogna, Valeria Varone, Michele DelSesto, Gerardo Ferrara.

  The tumor microenvironment (TME) is a crucial element of cancerous tissue and has emerged as a promising target for therapeutic strategies. The complex variety of stromal cells within the TME plays a vital role in determining the tumor's aggressiveness and its resistance to treatment. Tumor progression is not solely driven by cancer cells harboring genetic mutations but is also significantly influenced by non-cancerous host cells within the TME, which strongly impact tumor growth, metastasis, and the response to therapies. Cancer-associated fibroblasts (CAFs) are a diverse group of stromal cells within the TME. They play dual roles, both promoting and inhibiting tumor growth, making them intriguing targets for enhancing cancer therapies. Their significant contribution to creating a tumor-supportive environment has diminished the effectiveness of various cancer treatments, including radiation, chemotherapy, immunotherapy, and hormone therapy. Research has increasingly focused on understanding how CAFs contribute to therapy resistance in triple-negative breast cancer (TNBC) to improve treatment outcomes. However, the ways in which CAF patterns affect the TME and the response to immunotherapy in TNBC are not yet well understood and the interactions between CAFs, tumor cells, and immune cells in TNBC remain largely unexplored. In this review, we thoroughly exam ine the relationship between TNBC progression and CAF patterns. We discuss the current understanding of CAF heterogeneity, their role in tumor progression, and their impact on the tumor's response to therapeutic agents in TNBC. Additionally, we explore the potential and possible strategies for therapies targeting CAFs.

Keywords:  CAF; TME; TNBC; cancer therapies; therapeutic resistance

DOI:  https://doi.org/10.3389/fmolb.2025.1568865
Front Immunol. 2025 ;16 1581098

Immune microenvironment and immunotherapy in hepatocellular carcinoma: mechanisms and advances.

Dong Xie, Yang Liu, Fangbiao Xu, Zhibo Dang, Mengge Li, Qinsheng Zhang, Zhongqin Dang.

  Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally. The tumor microenvironment (TME) plays a pivotal role in HCC progression, characterized by dynamic interactions between stromal components, immune cells, and tumor cells. Key immune players, including tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), cytotoxic T lymphocytes (CTLs), regulatory T cells (Tregs), MDSCs, dendritic cells (DCs), and natural killer (NK) cells, contribute to immune evasion and tumor progression. Recent advances in immunotherapy, such as immune checkpoint inhibitors (ICIs), cancer vaccines, adoptive cell therapy (ACT), and combination therapies, have shown promise in enhancing anti-tumor responses. Dual ICI combinations, ICIs with molecular targeted drugs, and integration with local treatments or radiotherapy have demonstrated improved outcomes in HCC patients. This review highlights the evolving understanding of the immune microenvironment and the therapeutic potential of immunotherapeutic strategies in HCC management.

Keywords:  CAR-T therapy; HCC; NK cell therapy; immune microenvironment; immunotherapy

DOI:  https://doi.org/10.3389/fimmu.2025.1581098
J Bone Oncol. 2025 Jun;52 100678

Decoding the immune landscape in Ewing sarcoma pathogenesis: The role of tumor infiltrating immune cells and immune milieu.

Rajiv Ranjan Kumar, Nikita Agarwal, Akshi Shree, Jaya Kanta Gorain, Ekta Rahul, Shuvadeep Ganguly, Sameer Bakhshi, Uttam Sharma.

  Ewing sarcoma (EwS) is the second most prevalent pediatric bone malignancy, characterized by its aggressive behavior and unfavorable prognosis. The tumor microenvironment (TME) of EwS is shaped by immunosuppressive components, including myeloid-derived suppressor cells, tumor-associated macrophages, and immune checkpoint molecules such as PD-1/PD-L1 and HLA-G. These elements impair anti-tumor immune responses by modulating the function of tumor-infiltrating immune cells, such as regulatory T cells (Tregs), CD8+ T cells, and natural killer cells. Chemokines, including CXCL9 and CXCL12, and cytokines, such as transforming growth factor-beta and interleukin-10, further contribute to immune suppression and promote metastatic dissemination. Recent advances in immunotherapy have highlighted the therapeutic potential of modulating immune cells and signaling pathways to enhance anti-tumor immunity. This review provides a comprehensive analysis of the complex immune landscape within the EwS TME, focusing on the mechanistic roles of key immune components and their potential as therapeutic targets. Understanding these interactions could pave the way for innovative treatment strategies to improve clinical outcomes in patients with EwS.

Keywords:  Ewing sarcoma; Immune infiltration; Immunotherapy; Tumor immune microenvironment; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.jbo.2025.100678
Front Immunol. 2025 ;16 1561577

Benign non-immune cells in tumor microenvironment.

Shaowen Liu, Chunhui Liu, Yuan He, Jun Li.

  The tumor microenvironment (TME) is a highly complex and continuous evolving ecosystem, consisting of a diverse array of cellular and non-cellular components. Among these, benign non-immune cells, including cancer-associated fibroblasts (CAFs), adipocytes, endothelial cells (ECs), pericytes (PCs), Schwann cells (SCs) and others, are crucial factors for tumor development. Benign non-immune cells within the TME interact with both tumor cells and immune cells. These interactions contribute to tumor progression through both direct contact and indirect communication. Numerous studies have highlighted the role that benign non-immune cells exert on tumor progression and potential tumor-promoting mechanisms via multiple signaling pathways and factors. However, these benign non-immune cells may play different roles across cancer types. Therefore, it is important to understand the potential roles of benign non-immune cells within the TME based on tumor heterogeneity. A deep understanding allows us to develop novel cancer therapies by targeting these cells. In this review, we will introduce several types of benign non-immune cells that exert on different cancer types according to tumor heterogeneity and their roles in the TME.

Keywords:  adipocytes; benign non-immune cells; cancer-associated fibroblasts; endothelial cells; pericytes; schwann cells; tumor heterogeneity; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1561577
Front Immunol. 2025 ;16 1554835

The role of the tumor microenvironment in HNSCC resistance and targeted therapy.

Zhaomeng Guo, Kang Li, Xiaotong Ren, Xijia Wang, Dunhui Yang, Shibo Ma, Xianhai Zeng, Peng Zhang.

  The prognosis for head and neck squamous cell carcinoma (HNSCC) remains unfavorable, primarily due to significant therapeutic resistance and the absence effective interventions. A major obstacle in cancer treatment is the persistent resistance of cancer cells to a variety of therapeutic modalities. The tumor microenvironment (TME) which includes encompasses all non-malignant components and their metabolites within the tumor tissue, plays a crucial role in this context. The distinct characteristics of the HNSCC TME facilitate tumor growth, invasion, metastasis, and resistance to treatment. This review provides a comprehensive overview of the HNSCC TME components, with a particular focus on tumor-associated macrophages (TAMs), regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), the extracellular matrix, reprogrammed metabolic processes, and metabolic products. It elucidates their contributions to modulating resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy in HNSCC, and explores novel therapeutic strategies targeting the TME for HNSCC management.

Keywords:  HNSCC; TAMs; resistance; target therapy; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1554835
Eur J Immunol. 2025 Apr;55(4): e202451102

Metabolic Dialogue Shapes Immune Response in the Tumor Microenvironment.

Fengxia Gao, Rushil Shah, Gang Xin, Ruoning Wang.

The fate of immune cells is fundamentally linked to their metabolic program, which is also influenced by the metabolic landscape of their environment. The tumor microenvironment represents a unique system for intercellular metabolic interactions, where tumor-derived metabolites suppress effector CD8+ T cells and promote tumor-promoting macrophages, reinforcing an immune-suppressive niche. This review will discuss recent advancements in metabolism research, exploring the interplay between various metabolites and their effects on immune cells within the tumor microenvironment.

DOI: https://doi.org/10.1002/eji.202451102
Cell Death Differ. 2025 Apr 14.

Targeting the poliovirus receptor to activate T cells and induce myeloid-derived suppressor cells to differentiate to pro-inflammatory macrophages via the IFN-γ-p-STAT1-IRF8 axis in cancer therapy.

Mingyang Feng, Qizhi Ma, Benxia Zhang, Yue Chen, Yang Yang, Xia He, Yao Zeng, Meng Jing, Xuejin Ou, Yixian Liu, Qian Li, Weiting Liao, Xiaoyu Li, Sirui Tan, Diyuan Qin, Dan Li, Qiu Li, Yongsheng Wang.

T cell immunoglobulin and ITIM domain (TIGIT) is one of the most important immune checkpoints expressed on lymphocytes, and poliovirus receptor (PVR, also CD155) serves as the most crucial ligand for TIGIT, harboring an important function in cancer cells and influencing the tumor microenvironment (TME). While it's well-established that TIGIT blockade could reverse immunosuppression, the question of whether direct inhibition of PVR yields comparable results remains to be fully elucidated. This study investigated the role of PVR within the TME on the LLC, CT26 and MC38 tumor models and found that direct blockade of PVR on tumor cells could trigger T cell activation, enhance the production of immunostimulatory cytokine IFN-γ, and drive the differentiation of intratumoral myeloid-derived suppressor cells (MDSCs) into pro-inflammatory macrophages through the IFN-γ-p-STAT1-IRF8 axis. Furthermore, this study found that the anti-PVR nanobody monotherapy reduced tumor volume in the CT26 and MC38 tumor models. Combination of anti-PVR nanobody and anti-PD-1 antibody was effective in the LLC, CT26 and MC38 tumor models and had acceptable toxicity. These findings collectively suggest that PVR exhibits considerable promise as a therapeutic target in the development of immunotherapies aimed at augmenting the anti-tumor immune response.

DOI: https://doi.org/10.1038/s41418-025-01496-6
Semin Cancer Biol. 2025 Apr 12. pii: S1044-579X(25)00056-2. [Epub ahead of print]

Impact of tumor metabolism on tumor progression and therapy Cathepsins: emerging targets in the tumor ecosystem to overcome cancers.

Yuki Fujii, Zahra Asadi, Kamiya Mehla.

  Cathepsins, a group of lysosomal peptidases, have traditionally been recognized as tumor facilitators. Recent research, however, highlights their critical role in orchestrating cancer and the tumor microenvironment (TME). Primality, cathepsins degrade extracellular matrix, enabling cancer cells to invade and metastasize, while also promoting vascular endothelial infiltration and subsequent angiogenesis. Additionally, cathepsins boost fibroblast growth, thereby supporting tumor progression. More importantly, cathepsins are pivotal in modulating immune cells within the TME by regulating their recruitment, antigen processing and presentation, differentiation, and cell death, primarily contributing to immune suppression. Given their overexpression in tumors and elevated levels in the circulation of cancer patients, it is crucial to consider the systemic effects of cathepsins. Although the comprehensive role of cathepsins in cancer patients' bodies remains underexplored, they likely influence systemic immunity and inflammation, cellular metabolism, muscle wasting, and distant metastasis through their unique proteolytic functions. Notably, cathepsins also confer resistance to chemoradiotherapy by rewriting the cellular profile within the TME. In this context, promising results are emerging from studies combining cathepsin inhibitors with conventional therapies to suppress tumor development effectively. This review aims to decipher the cathepsin-driven networks within cancer cells and the TME, detailing their contribution to chemoradioresistance by reshaping both micro- and macroenvironments. Furthermore, we explore current and future perspectives on therapies targeting cathepsins' interactions, offering insights into innovative treatment strategies.

Keywords:  cathepsins; chemoresistance; extracellular matrix; immune suppression; tumor microenvironment

DOI:  https://doi.org/10.1016/j.semcancer.2025.04.001
Cancer Immunol Res. 2025 Apr 15. OF1-OF15

T-cell Senescence in the Tumor Microenvironment.

Lihaoyun Huang, Cangang Zhang, Aimin Jiang, Anqi Lin, Lingxuan Zhu, Weiming Mou, Dongqiang Zeng, Zaoqu Liu, Bufu Tang, Jian Zhang, Quan Cheng, Kai Miao, Ting Wei, Peng Luo.

T-cell senescence occurs in the tumor microenvironment (TME) and influences cancer outcomes, as well as the effectiveness of immunotherapies. The TME triggers this T-cell senescence via multiple pathways, including persistent stimulation with tumor-associated antigens, altered metabolic pathways, and activation of chronic inflammatory responses. Senescent T cells exhibit characteristics such as genomic instability, loss of protein homeostasis, metabolic dysregulation, and epigenetic alterations. Direct cross-talk between senescent T cells and other immune cells further exacerbates the immunosuppressive TME. This immune-tumor cell interaction within the TME contributes to impaired tumor antigen recognition and surveillance by T cells. The presence of senescent T cells is often associated with poor prognosis and reduced efficacy of immunotherapies; thus, targeting the tumor-promoting mechanisms of T-cell senescence may provide novel insights into improving tumor immunotherapy and patient outcomes. This review explores the contributors to tumor-derived T-cell senescence, the link between T-cell senescence and tumor prognosis, and the potential for targeting T-cell senescence to enhance tumor immunotherapy.

DOI: https://doi.org/10.1158/2326-6066.CIR-24-0894
FASEB J. 2025 Apr 30. 39(8): e70520

Metabolic Reprogramming of Glycolysis, Lipids, and Amino Acids in Tumors: Impact on CD8+ T Cell Function and Targeted Therapeutic Strategies.

Panping Liang, Zedong Li, Zhengwen Chen, Zehua Chen, Tao Jin, Fengjun He, Xiaolong Chen, Hongfeng Gou, Kun Yang.

  Tumor cells undergo metabolic reprogramming to support their rapid proliferation and to adapt to the challenges of the tumor microenvironment (TME). This involves significant changes in glycolysis, lipid, and amino acid metabolism, which not only promote tumor survival but also impact CD8+ T cells within the TME. This review examines how these metabolic alterations affect CD8+ T cell function, particularly through competition for energy resources and microenvironmental changes. For instance, aerobic glycolysis in tumor cells depletes glucose and leads to lactate accumulation, both of which suppress CD8+ T cell activity. Additionally, changes in lipid metabolism affect the composition of cell membranes and disrupt signal transduction, impairing T cell function. Amino acid reprogramming, such as increased consumption of glutamine and arginine by tumor cells, further hinders the activity and proliferation of CD8+ T cells. We also explore therapeutic strategies that target these metabolic pathways in tumor cells, such as inhibitors of glycolysis and fatty acid synthesis, which may enhance the antitumor activity of CD8+ T cells. These approaches show promise in improving both T cell function and the effectiveness of immune checkpoint blockade therapies. By investigating the link between tumor metabolism and CD8+ T cell dysfunction, this review highlights mechanisms of tumor immune evasion. This understanding can guide the development of novel immunotherapies aimed at enhancing T cell function within the TME.

Keywords:  CD8+ T cell; fatty acids; glutamine; glycolysis; metabolic reprogramming

DOI:  https://doi.org/10.1096/fj.202403019R
Int J Mol Sci. 2025 Mar 27. pii: 3095. [Epub ahead of print]26(7):

Exploring the Interaction of Tumor-Derived Exosomes and Mesenchymal Stem Cells in Tumor Biology.

Konstantinos S Papadopoulos, Penelope Korkolopoulou, Christina Piperi.

  Exosomes are actively produced extracellular vesicles, released from different cell types, that exert important regulatory roles in vital cellular functions. Tumor-derived exosomes (TDEs) have received increasing attention because they enable intercellular communication between the neoplastic and non-neoplastic cells present in the microenvironment of tumors, affecting important functions of different types of mesenchymal stem cells (MSCs) with the ability to self-renew and differentiate. MSC-derived exosomes (MSC-exos) carry a variety of bioactive molecules that can interact with specific cellular targets and signaling pathways, influencing critical processes in tumor biology, and exhibiting properties that either promote or inhibit tumor progression. They can regulate the tumor microenvironment by modulating immune responses, enhancing or suppressing angiogenesis, and facilitating tumor cells' communication with distant sites, thus altering the behavior of non-cancerous cells present in the microenvironment. Herein, we explore the main functions of TDEs and their intricate interactions with MSC-exos, in terms of enhancing cancer progression, as well as their promising clinical applications as tumor microenvironment modulators.

Keywords:  TME; adipose-derived stem cells; angiogenesis; cancer; immune response; mesenchymal stem cells; tumor-derived exosomes

DOI:  https://doi.org/10.3390/ijms26073095
Int J Mol Sci. 2025 Mar 24. pii: 2923. [Epub ahead of print]26(7):

Immune Modulation and Immunotherapy in Solid Tumors: Mechanisms of Resistance and Potential Therapeutic Strategies.

Suman Giri, Gopal Lamichhane, Jitendra Pandey, Ramesh Khadayat, Sindhu K C, Hari Prasad Devkota, Dipendra Khadka.

  Understanding the modulation of specific immune cells within the tumor microenvironment (TME) offers new hope in cancer treatments, especially in cancer immunotherapies. In recent years, immune modulation and resistance to immunotherapy have become critical challenges in cancer treatments. However, novel strategies for immune modulation have emerged as promising approaches for oncology due to the vital roles of the immunomodulators in regulating tumor progression and metastasis and modulating immunological responses to standard of care in cancer treatments. With the progress in immuno-oncology, a growing number of novel immunomodulators and mechanisms are being uncovered, offering the potential for enhanced clinical immunotherapy in the near future. Thus, gaining a comprehensive understanding of the broader context is essential. Herein, we particularly summarize the paradoxical role of tumor-related immune cells, focusing on how targeted immune cells and their actions are modulated by immunotherapies to overcome immunotherapeutic resistance in tumor cells. We also highlight the molecular mechanisms employed by tumors to evade the long-term effects of immunotherapeutic agents, rendering them ineffective.

Keywords:  emerging strategies; immune cells; immune modulation; immunotherapy; therapeutic outcomes; therapeutic resistance; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms26072923
Int J Mol Sci. 2025 Mar 30. pii: 3206. [Epub ahead of print]26(7):

Strategies for Altering Delivery Technologies to Optimize CAR Therapy.

Lili Cao, Yingying Liu, Guimei Lin.

  Chimeric antigen receptor (CAR) T-cell therapy has been proven to be an effective strategy for the treatment of hematological malignancies. At present, how to prepare CAR-T cells efficiently, quickly, and safely is one of the urgent problems to be solved. The durability and activity of engineered T cells in solid tumors need to be further improved, and the strategy of T cells penetrating the tumor microenvironment also needs to be improved. In addition, although the problems mainly caused by T-cell biology are being solved, the manufacturing mode and process still need to be improved to ensure that CAR-T cell therapy can be widely used. This paper summarizes some strategies that can improve the efficacy of CAR-T cells.

Keywords:  CAR-T cells; delivery vector; immunotherapy; solid tumor

DOI:  https://doi.org/10.3390/ijms26073206
Cancer Cell. 2025 Apr 14. pii: S1535-6108(25)00120-5. [Epub ahead of print]43(4): 665-679

CAR-T therapy in solid tumors.

Bing Du, Juliang Qin, Boxu Lin, Jiqin Zhang, Dali Li, Mingyao Liu.

  While chimeric antigen receptor (CAR) T cell therapy has shown great success in hematologic malignancies, the effectiveness in solid tumors has been limited by several factors, including antigenic heterogeneity and the immunosuppressive nature of the tumor microenvironment (TME). In this review, we discuss the advancements made in clinical studies and challenges faced by CAR-T therapy for solid tumors. To enhance CAR-T cell efficacy in solid tumors, we explore strategies such as enhancing T cell persistence and cytotoxicity, targeting multiple antigens, and utilizing innovative allogeneic CAR-T cell manufacturing. Additionally, we highlight the potential benefits of combining CAR-T therapies with immune checkpoint inhibitors and other treatment modalities to overcome TME limitations. We remain optimistic about the future of CAR-T cell therapy in solid tumors, emphasizing the need for continued research to refine therapeutic approaches and address the clinical needs of patients with cancer.

Keywords:  CAR-T; gene editing; solid tumor; synthetic biology; tumor microenvironment

DOI:  https://doi.org/10.1016/j.ccell.2025.03.019
Int J Mol Sci. 2025 Mar 31. pii: 3234. [Epub ahead of print]26(7):

Cancer-Associated Fibroblasts as the "Architect" of the Lung Cancer Immune Microenvironment: Multidimensional Roles and Synergistic Regulation with Radiotherapy.

Zheng Shi, Cuilan Hu, Qiang Li, Chao Sun.

  Cancer-associated fibroblasts (CAFs), as the "architect" of the immune microenvironment in lung cancer, play a multidimensional role in tumor progression and immune regulation. In this review, we summarize the heterogeneity of the origin and the molecular phenotype of CAFs in lung cancer, and explore the complex interactions between CAFs and multiple components of the tumor microenvironment, including the regulatory relationships with innate immune cells (e.g., tumor-associated macrophages, tumor-associated neutrophils), adaptive immune cells (e.g., T cells), and extracellular matrix (ECM). CAFs significantly influence tumor progression and immunomodulation through the secretion of cytokines, remodeling of the ECM, and the regulation of immune cell function significantly affects the immune escape and treatment resistance of tumors. In addition, this review also deeply explored the synergistic regulatory relationship between CAF and radiotherapy, revealing the key role of CAF in radiotherapy-induced remodeling of the immune microenvironment, which provides a new perspective for optimizing the comprehensive treatment strategy of lung cancer. By comprehensively analyzing the multidimensional roles of CAF and its interaction with radiotherapy, this review aims to provide a theoretical basis for the precise regulation of the immune microenvironment and clinical treatment of lung cancer.

Keywords:  cancer-associated fibroblasts; lung cancer; radiotherapy; tumor immune microenvironment

DOI:  https://doi.org/10.3390/ijms26073234
Oncogene. 2025 Apr 14.

Multifaceted roles of OCT4 in tumor microenvironment: biology and therapeutic implications.

Wenjie Chen, Ying-Jie Wang.

OCT4 (Octamer-binding transcription factor 4, encoded by the POU5F1 gene) is a master transcription factor for maintaining the self-renewal and pluripotency of pluripotent stem cells, as well as a pioneer factor regulating epigenetics-driven cell reprogramming and cell fate conversion. It is also detected in a variety of cancer tissues and particularly in a small subpopulation of cancer cells known as cancer stem cells (CSCs). Accumulating evidence has revealed that CSCs are a dynamic population, exhibiting shift between multipotency and differentiation states, or quiescence and proliferation states. Such cellular plasticity of CSCs is profoundly influenced by dynamic interplay between CSCs and the tumor microenvironment (TME). Here, we review recent evidence showing that OCT4 expressed in CSCs plays a multifaceted role in shaping the TME by interacting with the cellular TME components, including cancer-associated fibroblasts, tumor endothelial cells, tumor-infiltrating immune cells, as well as the non-cellular TME components, such as extracellular matrix (ECM), metabolites, soluble factors (e.g., growth factors, cytokines and chemokines), and intra-tumoral microbiota. Together, OCT4 regulates crucial processes encompassing ECM remodeling, epithelial-mesenchymal transition, metabolic reprogramming, angiogenesis, and immune responses. The complex and bidirectional interactions between OCT4-expressing CSCs and the TME create a supportive niche for tumor growth, invasion, and resistance to therapy. Better understanding OCT4's roles in such interactions can provide deeper insights into potential therapeutic strategies and targets for disrupting the supportive environment of tumors. The emerging therapies targeting OCT4 in CSCs might hold promise to resensitize therapeutic-resistant cancer cells, and to eradicate all cancer cells when combined with other therapies targeting the bulk of differentiated cancer cells as well as the TME.

DOI: https://doi.org/10.1038/s41388-025-03408-x
Cancers (Basel). 2025 Apr 02. pii: 1212. [Epub ahead of print]17(7):

Understanding Merkel Cell Carcinoma: Pathogenic Signaling, Extracellular Matrix Dynamics, and Novel Treatment Approaches.

Maria Konstantaraki, Aikaterini Berdiaki, Monica Neagu, Sabina Zurac, Konstantinos Krasagakis, Dragana Nikitovic.

  Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer, driven by either Merkel cell polyomavirus (MCPyV) integration or ultraviolet (UV)-induced mutations. In MCPyV-positive tumors, viral T antigens inactivate tumor suppressors pRb and p53, while virus-negative MCCs harbor UV-induced mutations that activate similar oncogenic pathways. Key signaling cascades, including PI3K/AKT/mTOR and MAPK, support tumor proliferation, survival, and resistance to apoptosis. Histologically, MCC consists of small round blue cells with neuroendocrine features, high mitotic rate, and necrosis. The tumor microenvironment (TME) plays a central role in disease progression and immune escape. It comprises a mix of tumor-associated macrophages, regulatory and cytotoxic T cells, and elevated expression of immune checkpoint molecules such as PD-L1, contributing to an immunosuppressive niche. The extracellular matrix (ECM) within the TME is rich in proteoglycans, collagens, and matrix metalloproteinases (MMPs), facilitating tumor cell adhesion, invasion, and interaction with stromal and immune cells. ECM remodeling and integrin-mediated signaling further promote immune evasion and therapy resistance. Although immune checkpoint inhibitors targeting PD-1/PD-L1 have shown promise in treating MCC, resistance remains a major hurdle. Therapeutic strategies that concurrently target the TME-through inhibition of ECM components, MMPs, or integrin signaling-may enhance immune responses and improve clinical outcomes.

Keywords:  Merkel cell carcinoma; extracellular matrix; immunology; signaling pathways; targeted molecular treatment

DOI:  https://doi.org/10.3390/cancers17071212
Biochim Biophys Acta Rev Cancer. 2025 Apr 12. pii: S0304-419X(25)00064-2. [Epub ahead of print] 189322

Nutritional strategies in oncology: The role of dietary patterns in modulating tumor progression and treatment response.

Zeyao Wang, Xueying Wang, Zihan Liu, Fanxuan Huang, Zhaoyu Pan, Zhiren Zhang, Tong Liu.

  Dietary interventions can influence tumor growth by restricting tumor-specific nutritional requirements, altering the nutrient availability in the tumor microenvironment, or enhancing the cytotoxicity of anticancer drugs. Metabolic reprogramming of tumor cells, as a significant hallmark of tumor progression, has a profound impact on immune regulation, severely hindering tumor eradication. Dietary interventions can modify tumor metabolic processes to some extent, thereby further improving the efficacy of tumor treatment. In this review, we emphasize the impact of dietary patterns on tumor progression. By exploring the metabolic differences of nutrients in normal cells versus cancer cells, we further clarify how dietary patterns influence cancer treatment. We also discuss the effects of dietary patterns on traditional treatments such as immunotherapy, chemotherapy, radiotherapy, and the gut microbiome, thereby underscoring the importance of precision nutrition.

Keywords:  Diet; Metabolism; Microorganism; Nutrient; Therapy

DOI:  https://doi.org/10.1016/j.bbcan.2025.189322
Cancers (Basel). 2025 Mar 28. pii: 1135. [Epub ahead of print]17(7):

From Bench to Bladder: The Rise in Immune Checkpoint Inhibition in the Treatment of Non-Muscle Invasive Bladder Cancer.

Caitlin P Burns, Jacob M Parker, Dylan M Schaap, Mark R Wakefield, Yujiang Fang.

  Non-muscle invasive bladder cancer (NMIBC) represents a significant clinical challenge due to its high recurrence rate and need for frequent monitoring. The current treatment modality is bacillus Calmette-Guérin (BCG) therapy combined with chemotherapy after transurethral resection of the bladder tumor (TURBT), which is highly effective in most patients. Yet, the cancer becomes resistant to these treatments in 30-40% of patients, necessitating the need for new treatment modalities. In the cancer world, the development of immune checkpoint inhibitors that target molecules, such as programmed cell death protein-1 (PD-1), its ligand, PD-L1, and Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), have revolutionized the treatment of many cancer types. PD-1/PD-L1 and CTLA-4 are shown to be upregulated in NMIBC in certain circumstances. PD-1/PD-L1 interactions play a role in immune evasion by suppressing T cell activity within the tumor microenvironment (TME), while the binding of CTLA-4 on T cells leads to downregulation of the immune response, making these pathways potential immunotherapeutic targets in NMIBC. This review seeks to understand the role of these therapies in treating NMIBC. We explore the cellular and non-cellular immune landscape in the TME of NMIBC, including Tregs, T effector cells, macrophages, B cells, and relevant cytokines. We also discuss the biological role of PD-1/PD-L1 and CTLA-4 while covering the rationale for these immunotherapies in NMIBC. Finally, we cover key clinical trials that have studied these treatments in NMIBC clinically. Such a study will be helpful for urologists and oncologists to manage patients with NMIBC more effectively.

Keywords:  anti-CTLA-4; anti-PD-1/PD-L1; immune checkpoint inhibitors; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers17071135
Cancer Cell Int. 2025 Apr 15. 25(1): 149

A new era in melanoma immunotherapy: focus on DCs metabolic reprogramming.

Mina Afrashteh Nour, Mansour Rajabivahid, Marjan Sadat Seyed Mehdi, Safa Tahmasebi, Sepideh Nasirzadeh Dashtgol, Mahmoud Dehghani-Ghorbi, Ahmad Ghorbani Vanan, Farid Ghorbaninezhad.

  Melanoma, being one of the most dangerous forms of skin cancer, is characterized by its aggressive and metastatic nature, with the potential to develop resistance to various treatments. This resistance makes the disease challenging to treat, emphasizing the need for new treatment strategies. Within the tumor microenvironment (TME), melanoma cells exploit metabolic shifts, particularly glycolysis, to create an immunosuppressive TME that prevents dendritic cells (DCs) from functioning properly. Essential metabolic alterations such as lactate and lipid accumulation, and lack of tryptophan disrupt DC maturation, antigen presentation, and T cell activation. In recent years, melanoma immunotherapy has increasingly focused on reprogramming the metabolism of DCs. This review paper aims to provide insights into the metabolic suppression of melanoma-associated DCs, allowing the design of therapeutic strategies based on metabolic interventions to promote or restore DC function. This contribution reviews the metabolic reprogramming of DCs as a new approach for melanoma immunotherapy.

Keywords:  Dendritic cell; Immunotherapy; Melanoma; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12935-025-03781-3
J Immunother Cancer. 2025 Apr 17. pii: e010012. [Epub ahead of print]13(4):

LILRB2 blockade facilitates macrophage repolarization and enhances T cell-mediated antitumor immunity.

Des C Jones, Lorraine Irving, Rebecca Dudley, Seraina Blümli, Marcin Wolny, Elisavet I Chatzopoulou, Stacy Pryts, Shreya Ahuja, D Gareth Rees, Alan M Sandercock, Saravanan Rajan, Reena Varkey, Michael Kierny, Andrew Kayserian, Kathy Mulgrew, Georgina Bowyer, Saly Songvilay, Kamila Bienkowska, Matthew S Glover, Sonja Hess, Simon J Dovedi, Robert W Wilkinson, Fernanda Arnaldez, Mark Cobbold.

   BACKGROUND: Immune checkpoint inhibitors have revolutionized the treatment of solid tumors, enhancing clinical outcomes by releasing T cells from inhibitory effects of receptors like programmed cell death protein 1 (PD-1). Despite these advancements, achieving durable antitumor responses remains challenging, often due to additional immunosuppressive mechanisms within the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) contribute significantly to the immunosuppressive TME and play a pivotal role in shaping T cell-mediated antitumor responses. Leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2), expressed on myeloid cells, including TAMs, is an inhibitory receptor, which contributes to macrophage-mediated immunosuppression. In this study, we present AZD2796, a high-affinity anti-LILRB2 antibody designed to repolarize TAMs from an immunosuppressive to a proinflammatory phenotype.
METHODS: Anti-LILRB2 antibodies were identified using single-B-cell encapsulation Immune Replica technology. The ability of AZD2796 to enhance proinflammatory responses from macrophages treated with CD40 ligand or lipopolysaccharide was assessed using a macrophage stimulation assay. A tumor cell/macrophage/T cell co-culture assay was developed to evaluate the effect of AZD2796, as a single agent and in combination with an anti-PD-1 antibody, on the cytolytic activity of antigen-specific T cells. In vivo assessments were then carried out to determine the ability of AZD2796 to alter tumor growth rate in mice humanized with CD34 hematopoietic stem cells.
RESULTS: In preclinical assessments, AZD2796 skewed macrophage differentiation away from an immunosuppressive phenotype and enhanced the proinflammatory function of macrophages. AZD2796 significantly increased the anti-tumor response of T cells following PD-1 checkpoint blockade, while AZD2796 monotherapy reduced tumor growth in humanized mouse models.
CONCLUSIONS: These findings support the potential of AZD2796 as an anti-cancer therapy, with the ability to synergize with T-cell-based therapeutics.

Keywords:  Immune Checkpoint Inhibitor; Immunotherapy; Macrophage; Tumor infiltrating lymphocyte - TIL

DOI:  https://doi.org/10.1136/jitc-2024-010012
Trends Cancer. 2025 Apr 17. pii: S2405-8033(25)00093-7. [Epub ahead of print]

A macrophage-neutrophil program drives mammary carcinogenesis.

Lukas Bolini, Simon R V Knott, Lorenzo Galluzzi.

  The molecular and cellular pathways through which breast cancer evades immunosurveillance remain poorly understood. Recent data from Camargo et al. demonstrate that - on recruitment to the tumor microenvironment by ductal macrophages - a heterogeneous population of neutrophils can establish physical contacts with malignant cells within spatial niches that sustain mammary oncogenesis.

Keywords:  CCL3; MMTV-PyMT; angiogenesis; endothelial cells; three Cs; γδ T cells

DOI:  https://doi.org/10.1016/j.trecan.2025.04.001
Invest New Drugs. 2025 Apr 15.

Patient-derived tumor organoids for cancer immunotherapy: culture techniques and clinical application.

Ningning Yao, Na Jing, Jianzhong Lin, Wenxia Niu, Wenxing Yan, Hongqin Yuan, Zeyi Xiong, Qing Hou, Xiaxi Qiao, Quanming Liu, Jianzhong Cao, Ning Li.

  Cancer immunotherapy has revolutionized tumor treatment. However, robust and effective testing platforms remain lacking, especially for the selection of the optimized therapy at the patient-specific level. Unlike conventional treatment evaluations, testing platforms for cancer immunotherapy must incorporate not only tumor cells but also the tumor microenvironment (TME), including immune components. Recently, emergence of patient-derived tumor organoids (PDTOs), an in vitro preclinical model, has provided a novel approach for studying tumor evolution and assessing treatment responses, and shows great potential when coculturing with immune cells to study the mechanisms of immunotherapy efficacy and resistance. However, traditional organoid technology is limited in capturing the full impact of the TME on tumor behaviors due to the absence of stromal components. To circumvent these restrictions, complex organoid cocultures with immune cells, cancer-associated fibroblasts and vasculatures are developed. In this review, we summarized recent advances in PDTO culture techniques for modeling the TME and explored the application of complex tumor organoids in cancer immunotherapy.

Keywords:  Cancer immunotherapy; Coculture; Organoids; Tumor microenvironment

DOI:  https://doi.org/10.1007/s10637-025-01523-w
Int J Mol Sci. 2025 Apr 02. pii: 3291. [Epub ahead of print]26(7):

Unraveling the Complexities of Myeloid-Derived Suppressor Cells in Inflammatory Bowel Disease.

Yangzhuangzhuang Zhu, Siyan Cao.

  Myeloid-derived suppressor cells (MDSCs) regulate immune responses in many pathological conditions, one of which is inflammatory bowel disease (IBD), an incurable chronic disorder of the digestive tract and beyond. The pathophysiology of IBD remains unclear, likely involving aberrant innate and adaptive immunity. Studies have reported altered population of MDSCs in patients with IBD. However, their distribution varies among patients and different preclinical models of IBD. The expansion and activation of MDSCs are likely driven by various stimuli during intestinal inflammation, but the in-depth mechanisms remain poorly understood. The role of MDSCs in the pathogenesis of IBD appears to be paradoxical. In addition to intestinal inflammation, suppressive MDSCs may promote colitis-to-colon cancer transition. In this Review, we summarize recent progresses on the features, activation, and roles of MDSCs in the development of IBD and IBD-associated colon cancer.

Keywords:  colon cancer; experimental colitis; immunomodulation; inflammatory bowel disease; myeloid-derived suppressor cells

DOI:  https://doi.org/10.3390/ijms26073291
Res Sq. 2025 Mar 31. pii: rs.3.rs-3481746. [Epub ahead of print]

CAR T cell-driven induction of iNOS in tumor-associated macrophages promotes CAR T cell resistance in B cell lymphoma.

Marco Davila, Sae Bom Lee, Yun Pyo Kang, Justin Boucher, Jay Mandula, Emiliano Roselli, Darwin Chang, Rachel Jimenez, Hiroshi Kotani, Kayla Reid, Julio Vazquez-Martinez, Nolan Beatty, Payal Goala, Rosa Sierra-Mondragon, Min Liu, John Koomen, Jonathan Nguyen, Mohammad Hussaini, Timothy Shaw, Xuefeng Wang, Rawan Faramand, Michael Jain, Frederick Locke, Paulo Rodriguez, Cooper Sailer, Shannon McSain, Showkat Hamid, Muhammad Tariq, Jianmin Wang, Julieta Abraham-Miranda.

Chimeric antigen receptor (CAR) T cell therapies have revolutionized B cell malignancy treatment, but subsets of patients with large B cell lymphoma (LBCL) experience primary resistance or relapse after CAR T cell treatment. To uncover tumor microenvironment (TME)-induced resistance mechanisms, we examined patients' intratumoral immune infiltrates and observed that elevated levels of immunoregulatory macrophages in pre-infusion tumor biopsies are correlated with poor clinical responses. CAR T cell-produced interferon-gamma (IFN-γ) promotes the expression of inducible nitric oxide synthase (iNOS, NOS2) in immunoregulatory macrophages, impairing CAR T cell function. Mechanistically, iNOS-expressing macrophages upregulated the p53 pathway, mediating apoptosis and cell cycle arrest in CAR T cells, while downregulating the MYC pathway involved in ribosome biogenesis and protein synthesis. Furthermore, CAR T cell metabolism is compromised by depletion of glycolytic intermediates and rewiring of the TCA cycle. Pharmacological inhibition of iNOS enhances the CAR T cell treatment efficacy in B cell tumor-bearing mice. Notably, elevated levels of iNOS+CD14+ monocytes were observed in leukaphereses of patients with non-durable response to CAR T cell therapy. These findings suggest that mitigating iNOS in tumor-associated macrophages (TAMs) by blocking IFN-γ secretion from CAR T cells will improve outcomes for LBCL patients.

DOI: https://doi.org/10.21203/rs.3.rs-3481746/v1
Front Oncol. 2025 ;15 1454546

Cancer-associated fibroblasts: multidimensional players in liver cancer.

Yanyun Pan, Yuangang Qiu, Xinbin Zhou, Wei Mao, Xiaoming Xu.

  Cancer-associated fibroblasts (CAFs), the most abundant stromal cells in the tumor microenvironment (TME), control tumor growth through production and organization of the extracellular matrix (ECM) for a long time. However, the results from different studies that have focused on targeting CAFs to disturb tumor progression are extremely controversial. Recent studies using advanced single-cell RNA sequencing technology (scRNAseq) combined with multiple genetically engineered mouse models have identified diverse CAF subpopulations in the premalignant liver microenvironment (PME) of hepatocellular carcinoma (HCC) and TME of intrahepatic cholangiocarcinoma (ICC), providing a deeper understanding of the exact roles of each CAF subpopulation in cancer development. This review focuses on the specific protein markers, signaling pathways, and functions of various emerging CAF subclusters that contribute to the development of ICC and HCC. Elucidating the role and regulation of CAF subpopulations under different pathophysiological conditions will facilitate the discovery of new therapeutics that modulate CAF activity.

Keywords:  cancer-associated fibroblast; hepatocellular carcinoma; iCAF; intrahepatic cholangiocarcinoma; myCAF; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2025.1454546
Mol Ther Oncol. 2025 Jun 18. 33(2): 200968

Neospora caninum as delivery vehicle for anti-PD-L1 scFv-Fc: A novel approach for cancer immunotherapy.

Clément Riviere, Muna Aljieli, Marie-Noëlle Mévélec, Louis Lantier, Fanny Boursin, Laurie Lajoie, Céline Ducournau, Stéphanie Germon, Nathalie Moiré, Isabelle Dimier-Poisson, Nicolas Aubrey, Anne di Tommaso.

  Neospora caninum, a potential anticancer agent able to reactivate the immune response within the tumor microenvironment (TME), has recently shown enhanced immunomodulatory properties in different tumor models when armed with the cytokine, Il-15. In the current area of combination immunotherapy strategies designed to overcome treatment resistance, we engineered for the first time the protozoan Neospora caninum to vectorize and secrete a single-chain variable fragment fused to fragment crystallizable region (scFv-Fc) targeting human programmed cell death ligand 1 (PD-L1). Following validation of its secretion through the micronemes (protozoa secretory organelles), we demonstrated that the scFv-Fc could bind PD-L1 on mouse and human tumor cells, block the programmed cell death protein 1 (PD-1)/PD-L1 pathway leading to potentiate the T cell lymphocyte activity. Additionally, the scFv-Fc induced antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC). Those data demonstrate the feasibility of vectoring and secreting a functional antibody fragment by N. caninum, opening promising avenues for future research.

Keywords:  MT: Regular Issue; Neospora caninum; PD-L1; antibody fragment; cancer immunotherapy; immune checkpoint; scFv-Fc; secretion

DOI:  https://doi.org/10.1016/j.omton.2025.200968
Int J Mol Sci. 2025 Mar 21. pii: 2838. [Epub ahead of print]26(7):

Double-Multiplex Immunostainings for Immune Profiling of Invasive Breast Carcinoma: Emerging Novel Immune-Based Biomarkers.

Sofia D P Theodorou, Konstantinos Ntostoglou, Ilias P Nikas, Dimitrios Goutas, Vassilis Georgoulias, Christos Kittas, Ioannis S Pateras.

  The role of tumor microenvironment in invasive breast cancer prognosis and treatment is highly appreciated. With the advent of immunotherapy, immunophenotypic characterization in primary tumors is gaining attention as it can improve patient stratification. Here, we discuss the benefits of spatial analysis employing double and multiplex immunostaining, allowing the simultaneous detection of more than one protein on the same tissue section, which in turn helps us provide functional insight into infiltrating immune cells within tumors. We focus on studies demonstrating the prognostic and predictive impact of distinct tumor-infiltrating lymphocyte subpopulations including different CD8(+) T subsets as well as CD4(+) T cells and tumor-associated macrophages in invasive breast carcinoma. The clinical value of immune cell topography is also appreciated. We further refer to how the integration of digital pathology and artificial intelligence in routine practice could enhance the accuracy of multiplex immunostainings evaluation within the tumor microenvironment, maximizing our perception of host immune response, improving in turn decision-making towards more precise immune-associated therapies.

Keywords:  T lymphocytes; artificial intelligence; biomarker; digital pathology; double immunostaining; invasive breast carcinoma; macrophages; multiplex immunostaining; precision therapy

DOI:  https://doi.org/10.3390/ijms26072838
Trends Immunol. 2025 Apr 15. pii: S1471-4906(25)00081-X. [Epub ahead of print]

Epstein-Barr virus-mediated immune evasion in tumor promotion.

Lie Yuan, Ling Zhong, Claude Krummenacher, Qinjian Zhao, Xiao Zhang.

  Epstein-Barr virus (EBV) was the first DNA virus identified to be tightly associated with multiple human tumors. It promotes malignant progression of tumors - including related lymphomas, nasopharyngeal carcinoma, and gastric adenocarcinoma - in part by evading surveillance and attack by the host immune system. In this article we review the main molecular mechanisms by which EBV-encoded proteins and RNAs interact with key molecules of the host immune system to inhibit Toll-like receptor (TLR)-nuclear factor κB (NF-κB), retinoic acid-inducible gene I (RIG-I), and interferon (IFN) signaling pathways, affect antigen presentation, prevent the cytotoxic effects of CD8+ effector cells, regulate the tumor microenvironment (TME) and cell metastasis and invasion, and inhibit cell apoptosis. These interactions not only contribute to the persistence of the virus but also provide potential targets for developing new immunotherapy strategies.

Keywords:  EBV; immune escape; immune response; mechanisms; tumor

DOI:  https://doi.org/10.1016/j.it.2025.03.007
bioRxiv. 2025 Apr 03. pii: 2025.04.01.646202. [Epub ahead of print]

Overcoming myeloid-driven resistance to CAR T therapy by targeting SPP1.

Sharareh Gholamin, Heini M Natri, Yuqi Zhao, Shengchao Xu, Maryam Aftabizadeh, Begonya Comin-Anduix, Supraja Saravanakumar, Christian Masia, Robyn A Wong, Lance Peter, Mei-I Chung, Evan D Mee, Brenda Aguilar, Renate Starr, Davis Y Torrejon, Darya Alizadeh, Xiwei Wu, Anusha Kalbasi, Antoni Ribas, Stephen Forman, Behnam Badie, Nicholas E Banovich, Christine E Brown.

Chimeric antigen receptor (CAR) T cell therapy faces notable limitations in treatment of solid tumors. The suppressive tumor microenvironment (TME), characterized by complex interactions among immune and stromal cells, is gaining recognition in conferring resistance to CAR T cell therapy. Despite the abundance and diversity of macrophages in the TME, their intricate involvement in modulating responses to CAR T cell therapies remains poorly understood. Here, we conducted single-cell RNA sequencing (scRNA-seq) on tumors from 41 glioma patients undergoing IL13Rα2-targeted CAR T cell therapy, identifying elevated suppressive SPP1 signatures predominantly in macrophages from patients who were resistant to treatment. Further integrative scRNA-seq analysis of high-grade gliomas as well as an interferon-signaling deficient syngeneic mouse model-both resistant to CAR T therapy-demonstrated the role of congruent suppressive pathways in mediating resistance to CAR T cells and a dominant role for SPP1+ macrophages. SPP1 blockade with an anti-SPP1 antibody abrogates the suppressive TME effects and substantially prolongs survival in IFN signaling-deficient and glioma syngeneic mouse models resistant to CAR T cell therapy. These findings illuminate the role of SPP1+ macrophages in fueling a suppressive TME and driving solid tumor resistance to CAR cell therapies. Targeting SPP1 may serve as a universal strategy to reprogram immune dynamics in solid tumors mitigating resistance to CAR T therapies.

DOI: https://doi.org/10.1101/2025.04.01.646202
Cancer Med. 2025 Apr;14(8): e70603

Microsatellite Instability in the Tumor Microenvironment: The Role of Inflammation and the Microbiome.

Elizabeth Vargas-Castellanos, Andrés Rincón-Riveros.

   BACKGROUND: Microsatellite instability (MSI) is a hallmark of DNA mismatch repair (MMR) deficiency that leads to genomic instability and increased cancer risk. The tumor microenvironment (TME) significantly influences MSI-driven tumorigenesis, and emerging evidence points to a critical role of the microbiome in shaping this complex interplay.
METHODS: This review comprehensively examines the existing literature on the intricate relationship between MSI, microbiome, and cancer development, with a particular focus on the impact of microbial dysbiosis on the TME.
RESULTS: MSI-high tumors exhibited increased immune cell infiltration owing to the generation of neoantigens. However, immune evasion mechanisms such as PD-1/CTLA-4 upregulation limit the efficacy of immune checkpoint inhibitors (ICIs) in a subset of patients. Pathobionts, such as Fusobacterium nucleatum and Bacteroides fragilis, contribute to MSI through the production of genotoxins, further promoting inflammation and oxidative stress within the TME.
CONCLUSIONS: The microbiome profoundly affects MSI-driven tumorigenesis. Modulation of the gut microbiota through interventions such as fecal microbiota transplantation, probiotics, and dietary changes holds promise for improving ICI response rates. Further research into cancer pharmacomicrobiomics, investigating the interplay between microbial metabolites and anticancer therapies, is crucial for developing personalized treatment strategies.

Keywords:  carcinogenesis; inflammation; microbiome; microsatellites; mismatch repair

DOI:  https://doi.org/10.1002/cam4.70603
Med Oncol. 2025 Apr 12. 42(5): 162

Function of antigen-presenting cells in non-small-cell lung cancer (NSCLC).

R Ilaya Kumar, Kavya Jain, Karan Raj Rai, Prashasti Arora, Harshnna Gururajan, Koustav Sarkar.

  The most common type of lung cancer called NSCLC avoids immune monitoring by blocking antigen display and T cell response activation. Anti-tumor immunity requires the essential function of antigen-presenting cells (APCs) which include dendritic cells and macrophages and B cells. NSCLC causes APCs to stop their normal function because they fail to properly display tumor antigens and activate adaptive immune responses. APC dysfunction in NSCLC is mainly caused by the tumor microenvironment (TME) which actively reprograms these cells through inhibitory cytokines and metabolic constraints and immune checkpoints. As a result, NSCLC exhibits poor responses to immunotherapies, such as checkpoint inhibitors. The analysis of APC-TME interactions enables researchers to develop strategies that will enhance APC function along with antigen presentation while improving immunotherapy effectiveness. The research examines APC dysfunction in NSCLC together with its TME mechanisms and develops therapeutic strategies to combat immune suppression for better clinical results.

Keywords:  B cells; Dendritic cells; Immunosuppression; Macrophages; Non-small-cell lung cancer; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12032-025-02703-7
bioRxiv. 2025 Apr 03. pii: 2025.04.01.646727. [Epub ahead of print]

Transmembrane Serine Protease TMPRSS11B promotes an acidified tumor microenvironment and immune suppression in lung squamous cell carcinoma.

Hari Shankar Sunil, Jean Clemenceau, Isabel Barnfather, Sumanth R Nakkireddy, Anthony Grichuk, Luke Izzo, Bret M Evers, Lisa Thomas, Indhumathy Subramaniyan, Li Li, William T Putnam, Jingfei Zhu, Barrett Updegraff, John D Minna, Ralph J DeBerardinis, Jinming Gao, Tae Hyun Hwang, Trudy G Oliver, Kathryn A O'Donnell.

Lung cancer is the leading cause of cancer-related deaths worldwide. Existing therapeutic options have limited efficacy, particularly for lung squamous cell carcinoma (LUSC), underscoring the critical need for the identification of new therapeutic targets. We previously demonstrated that the Transmembrane Serine Protease TMPRSS11B promotes transformation of human bronchial epithelial cells and enhances lactate export from LUSC cells. To determine the impact of TMPRSS11B activity on the host immune system and the tumor microenvironment (TME), we evaluated the effect of Tmprss11b depletion in a syngeneic mouse model. Tmprss11b depletion significantly reduced tumor burden in immunocompetent mice and triggered an infiltration of immune cells. RNA FISH analysis and spatial transcriptomics in the autochthonous Rosa26-Sox2-Ires-Gfp LSL/LSL ; Nkx2-1 fl/fl ; Lkb 1 fl/fl (SNL) model revealed an enrichment of Tmprss11b expression in LUSC tumors, specifically in Krt13 + hillock-like cells. Ultra-pH sensitive nanoparticle imaging and metabolite analysis identified regions of acidification, elevated lactate, and enrichment of M2-like macrophages in LUSC tumors. These results demonstrate that TMPRSS11B promotes an acidified and immunosuppressive TME and nominate this enzyme as a therapeutic target in LUSC.

DOI: https://doi.org/10.1101/2025.04.01.646727
Cancers (Basel). 2025 Apr 05. pii: 1232. [Epub ahead of print]17(7):

Neutrophils and Neutrophil-Based Drug Delivery Systems in Anti-Cancer Therapy.

Hicham Wahnou, Riad El Kebbaj, Soufyane Hba, Zaynab Ouadghiri, Othman El Faqer, Aline Pinon, Bertrand Liagre, Youness Limami, Raphaël Emmanuel Duval.

  Neutrophils, the most abundant white blood cells, play a dual role in cancer progression. While they can promote tumor growth, metastasis, and immune suppression, they also exhibit anti-tumorigenic properties by attacking cancer cells and enhancing immune responses. This review explores the complex interplay between neutrophils and the tumor microenvironment (TME), highlighting their ability to switch between pro- and anti-tumor phenotypes based on external stimuli. Pro-tumorigenic neutrophils facilitate tumor growth through mechanisms such as neutrophil extracellular traps (NETs), secretion of pro-inflammatory cytokines, and immune evasion strategies. They contribute to angiogenesis, tumor invasion, and metastasis by releasing vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). Conversely, anti-tumor neutrophils enhance cytotoxicity by generating reactive oxygen species (ROS), promoting antibody-dependent cell-mediated cytotoxicity (ADCC), and activating other immune cells such as cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Recent advances in neutrophil-based drug delivery systems have harnessed their tumor-homing capabilities to improve targeted therapy. Neutrophil-mimicking nanoparticles and membrane-coated drug carriers offer enhanced drug accumulation in tumors, reduced systemic toxicity, and improved therapeutic outcomes. Additionally, strategies to modulate neutrophil activity, such as inhibiting their immunosuppressive functions or reprogramming them towards an anti-tumor phenotype, are emerging as promising approaches in cancer immunotherapy. Understanding neutrophil plasticity and their interactions with the TME provides new avenues for therapeutic interventions. Targeting neutrophil-mediated mechanisms could enhance existing cancer treatments and lead to the development of novel immunotherapies, ultimately improving patient survival and clinical outcomes.

Keywords:  anti-cancer therapy; drug delivery; immunotherapy; inflammation; metastasis; neutrophil extracellular traps; neutrophils; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers17071232
Discov Oncol. 2025 Apr 16. 16(1): 532

Immune microenvironment and molecular mechanisms in endometrial cancer: implications for resistance and innovative treatments.

Yijia Chen, Lai Jiang, Lanyue Zhang, Hao Chi, Qin Wang.

  This review provides a systematic overview of the molecular mechanisms of endometrial cancer and its drug resistance, particularly involving the aberrant activation of some key signaling pathways. These molecular mechanisms significantly affect the therapeutic outcome of endometrial cancer by promoting tumor cell proliferation, anti-apoptosis, and drug resistance. The article also analyzes the critical role of the immune microenvironment in cancer drug resistance, focusing on the impact of immune cells, immune checkpoints, and hypoxic metabolic reprogramming on anticancer therapies. In recent years, immunotherapy and individualized therapy have shown promising clinical outcomes, especially in advanced endometrial cancer. This article summarizes recent advances in related therapeutic strategies and proposes emerging therapeutic strategies by targeting key pathways and modulating the immune microenvironment to overcome drug resistance and improve patient prognosis.

Keywords:  Drug resistance; Endometrial cancer; Immune checkpoint inhibitors; Immunotherapy; Molecular mechanisms; Precision medicine; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12672-025-02169-z
Front Immunol. 2025 ;16 1564130

Decoding the enigmatic role of T-cadherin in tumor angiogenesis.

Yiyang Wen, Li Ma, Yuanyuan Liu, Huabao Xiong, Dongmei Shi.

  The cadherin family, which includes T-cadherin, plays a significant role in angiogenesis, a critical process involved in tumor growth, metastasis, and recurrence. T-cadherin is extensively expressed in both normal and tumor vascular tissues and has been shown to facilitate the proliferation and migration of vascular cells in some studies. However, T-cadherin also exerts inhibitory effects on angiogenesis in various tumor tissues. The functional role of T-cadherin may vary depending on the tumor type and the interaction between tumor cells and vascular cells, suggesting that it acts as a modulator rather than a primary driver of angiogenesis. Additionally, T-cadherin exhibits distinct characteristics depending on the tumor microenvironment. This review provides an overview of recent research on the role of T-cadherin in tumor angiogenesis and discusses its potential as a diagnostic or therapeutic marker in the field of tumor biology.

Keywords:  T-cadherin; VEGF; endothelial cells; tumor; tumor angiogenesis

DOI:  https://doi.org/10.3389/fimmu.2025.1564130