1
|
Bräutigam K, Skok K, Szymonski K, Rift CV, Karamitopoulou E. Tumor immune microenvironment in pancreatic ductal adenocarcinoma revisited - Exploring the "Space". Cancer Lett 2025; 622:217699. [PMID: 40204149 DOI: 10.1016/j.canlet.2025.217699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 03/24/2025] [Accepted: 04/04/2025] [Indexed: 04/11/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most deadly malignancies with a highly immunosuppressive tumor immune microenvironment (TIME) that hinders effective therapy. PDAC is characterized by significant heterogeneity in immune cell composition, spatial distribution and activation states, which impacts tumor progression and treatment response. Tumour-infiltrating lymphocytes (TILs), including CD4+ T-helper cells, CD8+ cytotoxic T-cells and FOXP3+ regulatory T-cells, play a key role in immune regulation, yet PDAC is largely an immunologically "cold" tumour with limited effector T-cell infiltration. The surrounding cellular microenvironment, particularly Cancer Associated Fibroblasts (CAFs) and macrophages, contributes to immune evasion by promoting a fibrotic and desmoplastic barrier that limits TIL infiltration. The prognostic significance of TILs is increasingly recognized, with higher densities correlating with improved survival, whereas regulatory T-cell infiltration and immunosuppressive stromal interactions are associated with poor outcomes. Emerging therapeutic strategies targeting the TIME (e.g., CAFs), immune checkpoint inhibitors, and TIL-based therapies offer the potential to overcome resistance. Future research must focus on optimizing immunotherapy strategies and unravelling the complex stromal-immune interactions to improve clinical translation.
Collapse
Affiliation(s)
- Konstantin Bräutigam
- Institute of Cancer Research, Centre for Evolution and Cancer, London, SM2 5NG, United Kingdom; Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland.
| | - Kristijan Skok
- Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria; Institute of Biomedical Sciences, Medical Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Krzysztof Szymonski
- Department of Pathomorphology, Jagiellonian University Medical College, Krakow, Poland
| | | | - Eva Karamitopoulou
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| |
Collapse
|
2
|
Toghraie FS, Bayat M, Hosseini MS, Ramezani A. Tumor-infiltrating myeloid cells; mechanisms, functional significance, and targeting in cancer therapy. Cell Oncol (Dordr) 2025; 48:559-590. [PMID: 39998754 PMCID: PMC12119771 DOI: 10.1007/s13402-025-01051-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/20/2025] [Indexed: 02/27/2025] Open
Abstract
Tumor-infiltrating myeloid cells (TIMs), which encompass tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), and tumor-associated dendritic cells (TADCs), are of great importance in tumor microenvironment (TME) and are integral to both pro- and anti-tumor immunity. Nevertheless, the phenotypic heterogeneity and functional plasticity of TIMs have posed challenges in fully understanding their complexity roles within the TME. Emerging evidence suggested that the presence of TIMs is frequently linked to prevention of cancer treatment and improvement of patient outcomes and survival. Given their pivotal function in the TME, TIMs have recently been recognized as critical targets for therapeutic approaches aimed at augmenting immunostimulatory myeloid cell populations while depleting or modifying those that are immunosuppressive. This review will explore the important properties of TIMs related to immunity, angiogenesis, and metastasis. We will also document the latest therapeutic strategies targeting TIMs in preclinical and clinical settings. Our objective is to illustrate the potential of TIMs as immunological targets that may improve the outcomes of existing cancer treatments.
Collapse
Affiliation(s)
- Fatemeh Sadat Toghraie
- Institute of Biotechnology, Faculty of the Environment and Natural Sciences, Brandenburg University of Technology, Cottbus, Germany
| | - Maryam Bayat
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahsa Sadat Hosseini
- Regenerative Medicine Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Amin Ramezani
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.
| |
Collapse
|
3
|
Ghebremedhin A, Varner JA. PI3Kγ in Tumour Inflammation: Bridging Immune Response and Cancer Progression-A Mini-Review. Immunology 2025. [PMID: 40434054 DOI: 10.1111/imm.13959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 05/04/2025] [Accepted: 05/16/2025] [Indexed: 05/29/2025] Open
Abstract
Phosphatidylinositol 3-kinase gamma (PI3Kγ), a class I PI3K family member, plays a critical role in modulating inflammation and immune responses within the tumour microenvironment. Emerging evidence suggests that PI3Kγ promotes myeloid cell trafficking and transcription, leading to tumour progression and metastasis. This review explores the multifaceted roles of PI3Kγ in tumour-associated inflammation, highlighting its involvement in immune cell polarisation, cytokine production, and the dynamic interaction between tumour cells and the surrounding stromal environment. We also discuss the potential therapeutic implications of targeting PI3Kγ to modulate inflammation and inhibit tumour growth. Given its pivotal role in immune response and tumour progression, PI3Kγ represents a promising target for future cancer therapies to reduce inflammation-driven tumorigenesis.
Collapse
Affiliation(s)
- Anghesom Ghebremedhin
- Moores Cancer Center, University of California, San Diego, California, USA
- Department of Pathology, University of California, San Diego, California, USA
| | - Judith A Varner
- Moores Cancer Center, University of California, San Diego, California, USA
- Department of Pathology, University of California, San Diego, California, USA
| |
Collapse
|
4
|
Lee E, Hong JJ, Samcam Vargas G, Sauerwald N, Wei Y, Hang X, Theesfeld CL, Volmar JAA, Miller JM, Wang W, Wang S, Laevsky G, DeCoste CJ, Kang Y. CXCR4 + mammary gland macrophageal niche promotes tumor initiating cell activity and immune suppression during tumorigenesis. Nat Commun 2025; 16:4854. [PMID: 40413176 PMCID: PMC12103607 DOI: 10.1038/s41467-025-59972-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2025] [Accepted: 05/09/2025] [Indexed: 05/27/2025] Open
Abstract
Tumor-initiating cells (TICs) share features and regulatory pathways with normal stem cells, yet how the stem cell niche contributes to tumorigenesis remains unclear. Here, we identify CXCR4+ macrophages as a niche population enriched in normal mammary ducts, where they promote the regenerative activity of basal cells in response to luminal cell-derived CXCL12. CXCL12 triggers AKT-mediated stabilization of β-catenin, which induces Wnt ligands and pro-migratory genes, enabling intraductal macrophage infiltration and supporting regenerative activity of basal cells. Notably, these same CXCR4+ niche macrophages regulate the tumor-initiating activity of various breast cancer subtypes by enhancing TIC survival and tumor-forming capacity, while promoting early immune evasion through regulatory T cell induction. Furthermore, a CXCR4+ niche macrophage gene signature correlates with poor prognosis in human breast cancer. These findings highlight the pivotal role of the CXCL12-CXCR4 axis in orchestrating interactions between niche macrophages, mammary epithelial cells, and immune cells, thereby establishing a supportive niche for both normal tissue regeneration and mammary tumor initiation.
Collapse
Affiliation(s)
- Eunmi Lee
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA
- Ludwig Institute for Cancer Research Princeton Branch, Princeton, NJ, 08544, USA
| | - Jason J Hong
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA
| | | | - Natalie Sauerwald
- Center for Computational Biology, Flatiron Institute, New York, NY, 10010, USA
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, 08544, USA
| | - Yong Wei
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA
- Ludwig Institute for Cancer Research Princeton Branch, Princeton, NJ, 08544, USA
| | - Xiang Hang
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA
- Ludwig Institute for Cancer Research Princeton Branch, Princeton, NJ, 08544, USA
| | - Chandra L Theesfeld
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, 08544, USA
| | - Jean Arly A Volmar
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, 08544, USA
| | - Jennifer M Miller
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, 08544, USA
| | - Wei Wang
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, 08544, USA
| | - Sha Wang
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA
| | - Gary Laevsky
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA
| | - Christina J DeCoste
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA
| | - Yibin Kang
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA.
- Ludwig Institute for Cancer Research Princeton Branch, Princeton, NJ, 08544, USA.
- Cancer Metabolism and Growth Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08903, USA.
| |
Collapse
|
5
|
Blümke J, Schameitat M, Verma A, Limbecker C, Arlt E, Kessler SM, Kielstein H, Krug S, Bazwinsky-Wutschke I, Haemmerle M. Innate Immunity and Platelets: Unveiling Their Role in Chronic Pancreatitis and Pancreatic Cancer. Cancers (Basel) 2025; 17:1689. [PMID: 40427186 PMCID: PMC12110028 DOI: 10.3390/cancers17101689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2025] [Revised: 05/10/2025] [Accepted: 05/14/2025] [Indexed: 05/29/2025] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal forms of cancer, characterized by a highly desmoplastic tumor microenvironment. One main risk factor is chronic pancreatitis (CP). Progression of CP to PDAC is greatly influenced by persistent inflammation promoting genomic instability, acinar-ductal metaplasia, and pancreatic intraepithelial neoplasia (PanIN) formation. Components of the extracellular matrix, including immune cells, can modulate this progression phase. This includes cells of the innate immune system, such as natural killer (NK) cells, macrophages, dendritic cells, mast cells, neutrophils, and myeloid-derived suppressor cells (MDSCs), either promoting or inhibiting tumor growth. On one hand, innate immune cells can trigger inflammatory responses that support tumor progression by releasing cytokines and growth factors, fostering tumor cell proliferation, invasion, and metastasis. On the other hand, they can also activate immune surveillance mechanisms, which can limit tumor development. For example, NK cells are cytotoxic innate lymphoid cells that are able to kill tumor cells, and active dendritic cells are crucial for a functioning anti-tumor immune response. In contrast, mast cells and MDSCs rather support a pro-tumorigenic tumor microenvironment that is additionally sustained by platelets. Once thought to play a role in hemostasis only, platelets are now recognized as key players in inflammation and cancer progression. By releasing cytokines, growth factors, and pro-angiogenic mediators, platelets help shape an immunosuppressive microenvironment that promotes fibrotic remodeling, tumor initiation, progression, metastasis, and immune evasion. Neutrophils and macrophages exist in different functional subtypes that can both act pro- and anti-tumorigenic. Understanding the complex interactions between innate immune cells, platelets, and early precursor lesions, as well as PDAC cells, is crucial for developing new therapeutic approaches that can harness the immune and potentially also the coagulation system to target and eliminate tumors, offering hope for improved patient outcomes.
Collapse
Affiliation(s)
- Juliane Blümke
- Institute of Pathology, Section of Experimental Pathology, Medical Faculty, Martin Luther University Halle-Wittenberg, 06112 Halle (Saale), Germany;
| | - Moritz Schameitat
- Institute of Anatomy and Cell Biology, Medical Faculty, Martin Luther University Halle-Wittenberg, 06108 Halle (Saale), Germany; (M.S.); (C.L.); (H.K.); (I.B.-W.)
| | - Atul Verma
- Department of Internal Medicine I, Medical Faculty, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany; (A.V.); (S.K.)
| | - Celina Limbecker
- Institute of Anatomy and Cell Biology, Medical Faculty, Martin Luther University Halle-Wittenberg, 06108 Halle (Saale), Germany; (M.S.); (C.L.); (H.K.); (I.B.-W.)
| | - Elise Arlt
- Institute of Anatomy and Cell Biology, Medical Faculty, Martin Luther University Halle-Wittenberg, 06108 Halle (Saale), Germany; (M.S.); (C.L.); (H.K.); (I.B.-W.)
| | - Sonja M. Kessler
- Institute of Pharmacy, Experimental Pharmacology for Natural Sciences, Faculty of Natural Sciences, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany;
| | - Heike Kielstein
- Institute of Anatomy and Cell Biology, Medical Faculty, Martin Luther University Halle-Wittenberg, 06108 Halle (Saale), Germany; (M.S.); (C.L.); (H.K.); (I.B.-W.)
| | - Sebastian Krug
- Department of Internal Medicine I, Medical Faculty, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany; (A.V.); (S.K.)
- Department of Internal Medicine IV, University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Ivonne Bazwinsky-Wutschke
- Institute of Anatomy and Cell Biology, Medical Faculty, Martin Luther University Halle-Wittenberg, 06108 Halle (Saale), Germany; (M.S.); (C.L.); (H.K.); (I.B.-W.)
| | - Monika Haemmerle
- Institute of Pathology, Section of Experimental Pathology, Medical Faculty, Martin Luther University Halle-Wittenberg, 06112 Halle (Saale), Germany;
| |
Collapse
|
6
|
Meng F, He Y, Zhao J, Yuan Z, Wang J, Parra KG, Fishel ML, Ratliff TL, Yeo Y. Timely administration of drug combination improves chemoimmunotherapy of an immune-cold tumor. J Control Release 2025; 381:113579. [PMID: 40023227 PMCID: PMC12002645 DOI: 10.1016/j.jconrel.2025.02.075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 02/22/2025] [Accepted: 02/25/2025] [Indexed: 03/04/2025]
Abstract
An immunoactive complex consisting of a polyethyleneimine derivative (2E'), paclitaxel (PTX), and cyclic dinucleotide (CDN) was developed for chemoimmunotherapy of solid tumors. Each component uniquely contributes to stimulating innate immune response to tumors: 2E' carries PTX and CDN while stimulating antigen-presenting cells, PTX induces immunogenic cell death, and CDN activates the STING pathway. A single intratumoral injection of 2E'/PTX/CDN inhibited the growth of MOC1 oral squamous cell carcinoma and KPCY (2838c3) pancreatic tumors, achieving complete tumor regression in 80-100 % of mice. However, 2E'/PTX/CDN showed limited therapeutic efficacy with immune-cold B16F10 melanoma, accompanied by the increase of innate immune cells in the tumor draining lymph nodes peaking on day 5 post-administration and subsiding thereafter. The addition of a complex of 2E' and siRNA targeting PD-L1 (siPD-L1) at an optimal 5-d interval improved the response in B16F10 melanoma, resulting in tumor-free survival in 50 % of mice and rejection of live tumor rechallenge in 67 % of surviving animals. Consistent with the function of each component, the timed combination of 2E'/PTX/CDN and 2E'/siPD-L1 increased the fractions of mature dendritic cells and M1 macrophages, prevented the increase of regulatory T cells in tumor-draining lymph nodes, and increased melanoma antigen-specific CD8+ T cells in the spleen. These results demonstrate the effectiveness of the 2E'/PTX/CDN complex in the chemoimmunotherapy of solid tumors and highlight the significance of timely intervention to sustain the immunoactive phenotype in its application to immune-cold tumors.
Collapse
Affiliation(s)
- Fanfei Meng
- Department of Industrial and Molecular Pharmaceutics, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA; Department of Biomedical and Nutritional Sciences, University of Massachusetts Lowell, 3 Solomont Way, Lowell, MA 01854, USA
| | - Yanying He
- Department of Industrial and Molecular Pharmaceutics, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA
| | - Jiaqi Zhao
- Department of Industrial and Molecular Pharmaceutics, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA
| | - Zhongyue Yuan
- Department of Industrial and Molecular Pharmaceutics, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA
| | - Jianping Wang
- Department of Industrial and Molecular Pharmaceutics, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA
| | - Karen Gutierrez Parra
- Department of Industrial and Molecular Pharmaceutics, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA
| | - Melissa L Fishel
- Departments of Pediatrics and of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Timothy L Ratliff
- Purdue University Institute for Cancer Research, 201 South University Street, West Lafayette, IN 47907, USA; Department of Comparative Pathobiology, Purdue University, 625 Harrison Street, West Lafayette, Indiana 47907, USA
| | - Yoon Yeo
- Department of Industrial and Molecular Pharmaceutics, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA; Purdue University Institute for Cancer Research, 201 South University Street, West Lafayette, IN 47907, USA; Weldon School of Biomedical Engineering, Purdue University, 206 S Martin Jischke Drive, West Lafayette, IN 47907, USA.
| |
Collapse
|
7
|
Glapiński F, Zając W, Fudalej M, Deptała A, Czerw A, Sygit K, Kozłowski R, Badowska-Kozakiewicz A. The Role of the Tumor Microenvironment in Pancreatic Ductal Adenocarcinoma: Recent Advancements and Emerging Therapeutic Strategies. Cancers (Basel) 2025; 17:1599. [PMID: 40427098 PMCID: PMC12110676 DOI: 10.3390/cancers17101599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2025] [Revised: 04/30/2025] [Accepted: 05/06/2025] [Indexed: 05/29/2025] Open
Abstract
Pancreatic cancer (PC), with pancreatic ductal adenocarcinoma (PDAC) comprising about 90% of all cases, is one of the most aggressive and lethal solid tumors. PDAC remains one of the most significant challenges of oncology to this day due to its inadequate response to conventional treatment, gradual rise in incidence since 2004, and poor five-year survival rates. As cancer cells are the primary adversary in this uneven fight, they remain the primary research target. Nevertheless, increasing attention is being paid to the tumor microenvironment (TME). The most crucial TME constellation components are immune cells, especially macrophages, stellate cells and lymphocytes, fibroblasts, bacterial and fungal microflora, and neuronal cells. Depending on the particular phenotype of these cells, the composition of the microenvironment, and the cell ratio, patients can experience different disease outcomes and varying vulnerability to treatment approaches. This study aims to present the current knowledge and review the most up-to-date scientific findings regarding the microenvironment of PC. It contains detailed information on the structure and cellular composition of the stroma, including its impact on disease development, metastasis, and response to treatment, as well as the therapeutic opportunities that arise from targeting this tissue.
Collapse
Affiliation(s)
- Franciszek Glapiński
- Students’ Scientific Organization of Cancer Cell Biology, Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
| | - Weronika Zając
- Students’ Scientific Organization of Cancer Cell Biology, Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
| | - Marta Fudalej
- Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland; (M.F.); (A.D.)
- Department of Oncology, National Medical Institute of the Ministry of the Interior and Administration, 02-507 Warsaw, Poland
| | - Andrzej Deptała
- Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland; (M.F.); (A.D.)
| | - Aleksandra Czerw
- Department of Health Economics and Medical Law, Medical University of Warsaw, 02-091 Warsaw, Poland;
- Department of Economic and System Analyses, National Institute of Public Health NIH—National Research Institute, 00-791 Warsaw, Poland
| | - Katarzyna Sygit
- Faculty of Health Sciences, Calisia University, 62-800 Kalisz, Poland
| | - Remigiusz Kozłowski
- Department of Management and Logistics in Healthcare, Medical University of Lodz, 90-131 Lodz, Poland
| | - Anna Badowska-Kozakiewicz
- Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland; (M.F.); (A.D.)
| |
Collapse
|
8
|
Papakonstantinou D, Wang H, Bani MA, Mulder K, Dunsmore G, Boilève A, Jules-Clément G, Panunzi L, de Sousa LR, de la Calle Fabregat C, Deloger M, Signolle N, Gessain G, Nikolaev SI, Ducreux M, Hollebecque A, Ginhoux F, Blériot C. Molecular analysis highlights TREM2 as a discriminating biomarker for patients suffering from pancreatic ductal adenocarcinoma. Cancer Treat Res Commun 2025; 43:100939. [PMID: 40354768 DOI: 10.1016/j.ctarc.2025.100939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 05/02/2025] [Accepted: 05/02/2025] [Indexed: 05/14/2025]
Abstract
Pancreatic cancer is projected to become the second leading cause of cancer-related deaths by 2030, with its mortality continuing to rise, unlike other common cancers such as breast or colorectal. Late-stage diagnosis, often accompanied by metastatic dissemination, drastically impairs patient survival and underscores the urgent need for improved biomarkers to guide therapeutic strategies. While molecular signatures have been proposed to stratify pancreatic cancer patients, their ability to predict outcomes remains limited. In this study, we applied established molecular signatures to our in-house transcriptomic data from a cohort of pancreatic cancer patients. We took advantage of published datasets to construct comprehensive atlases of cells present in primary and metastatic pancreatic cancers. The atlas of metastasis samples, representative of routinely harvested patient biopsies, revealed that monocyte/macrophage signatures provided superior discriminatory power compared to existing molecular classifications. Notably, the abundance of TREM2-expressing macrophages emerged as a significant parameter for stratifying patients. Our findings position TREM2+ macrophages as a promising biomarker for pancreatic cancer, with potential to enhance patient stratification and inform the development of targeted therapies. This work highlights the critical role of tumor-associated macrophages in pancreatic cancer progression and lays the groundwork for further functional and translational studies.
Collapse
Affiliation(s)
| | - Haiding Wang
- Gustave Roussy Cancer Campus, CNRS UMR9018, Villejuif, France
| | - Mohamed-Amine Bani
- Gustave Roussy Cancer Campus, Medical oncology department, Villejuif, France
| | - Kevin Mulder
- Gustave Roussy Cancer Campus, INSERM U1015, Villejuif, France
| | - Garett Dunsmore
- Gustave Roussy Cancer Campus, INSERM U1015, Villejuif, France
| | - Alice Boilève
- Gustave Roussy Cancer Campus, INSERM U1279, Université Paris Saclay, Villejuif, France; Gustave Roussy Cancer Campus, Biopathology department, Villejuif, France
| | - Gérôme Jules-Clément
- Gustave Roussy Cancer Campus, Bioinformatics Core Facility, CNRS, INSERM, Université Paris-Saclay, Villejuif, France
| | - Leonardo Panunzi
- Gustave Roussy Cancer Campus, INSERM U981, Université Paris Saclay, Villejuif, France
| | | | | | - Marc Deloger
- Gustave Roussy Cancer Campus, Bioinformatics Core Facility, CNRS, INSERM, Université Paris-Saclay, Villejuif, France
| | - Nicolas Signolle
- Gustave Roussy Cancer Campus, Biopathology department, Villejuif, France
| | - Grégoire Gessain
- Gustave Roussy Cancer Campus, Biopathology department, Villejuif, France
| | - Sergey I Nikolaev
- Gustave Roussy Cancer Campus, INSERM U981, Université Paris Saclay, Villejuif, France
| | - Michel Ducreux
- Gustave Roussy Cancer Campus, Medical oncology department, Villejuif, France
| | - Antoine Hollebecque
- Gustave Roussy Cancer Campus, Medical oncology department, Villejuif, France
| | - Florent Ginhoux
- Gustave Roussy Cancer Campus, INSERM U1015, Villejuif, France
| | - Camille Blériot
- Gustave Roussy Cancer Campus, INSERM U1015, Villejuif, France; Gustave Roussy Cancer Campus, CNRS UMR9018, Villejuif, France; Institut Necker Enfants Malades, CNRS, INSERM, Université Paris Cité, Paris, France.
| |
Collapse
|
9
|
Karimova AF, Khalitova AR, Suezov R, Markov N, Mukhamedshina Y, Rizvanov AA, Huber M, Simon HU, Brichkina A. Immunometabolism of tumor-associated macrophages: A therapeutic perspective. Eur J Cancer 2025; 220:115332. [PMID: 40048925 DOI: 10.1016/j.ejca.2025.115332] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 02/22/2025] [Accepted: 02/25/2025] [Indexed: 04/26/2025]
Abstract
Tumor-associated macrophages (TAMs) play a pivotal role in the tumor microenvironment (TME), actively contributing to the formation of an immunosuppressive niche that fosters tumor progression. Consequently, there has been a growing interest in targeting TAMs as a promising avenue for cancer therapy. Recent advances in the field of immunometabolism have shed light on the influence of metabolic adaptations on macrophage physiology in the context of cancer. Here, we discuss the key metabolic pathways that shape the phenotypic diversity of macrophages. We place special emphasis on how metabolic reprogramming impacts the activation status of TAMs and their functions within the TME. Additionally, we explore alterations in TAM metabolism and their effects on phagocytosis, production of cytokines/chemokines and interaction with cytotoxic T and NK immune cells. Moreover, we examine the application of nanomedical approaches to target TAMs and assess the clinical significance of modulating the metabolism of TAMs as a strategy to develop new anti-cancer therapies. Taken together, in this comprehensive review article focusing on TAMs, we provide invaluable insights for the development of effective immunotherapeutic strategies and the enhancement of clinical outcomes for cancer patients.
Collapse
Affiliation(s)
- Adelya F Karimova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Adelya R Khalitova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Roman Suezov
- Institute of Systems Immunology, Center for Tumor and Immune Biology, Philipps University of Marburg, Marburg, Germany
| | - Nikita Markov
- Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - Yana Mukhamedshina
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Albert A Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia; Division of Medical and Biological Sciences, Tatarstan Academy of Sciences, Kazan, Russia
| | - Magdalena Huber
- Institute of Systems Immunology, Center for Tumor and Immune Biology, Philipps University of Marburg, Marburg, Germany
| | - Hans-Uwe Simon
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia; Institute of Pharmacology, University of Bern, Bern, Switzerland; Institute of Biochemistry, Brandenburg Medical School, Neuruppin, Germany
| | - Anna Brichkina
- Institute of Systems Immunology, Center for Tumor and Immune Biology, Philipps University of Marburg, Marburg, Germany.
| |
Collapse
|
10
|
Shakiba M, Tuveson DA. Macrophages and fibroblasts as regulators of the immune response in pancreatic cancer. Nat Immunol 2025; 26:678-691. [PMID: 40263612 DOI: 10.1038/s41590-025-02134-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 03/13/2025] [Indexed: 04/24/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the few cancers that has yet to benefit from immunotherapies. This is primarily a result of its characteristic 'cold' tumor microenvironment composed of cancer-associated fibroblasts (CAFs), a dense network of extracellular matrix and several immune cell types, the most abundant of which are the tumor-associated macrophages (TAMs). Advances in single-cell and spatial technologies have elucidated the vast functional heterogeneity of CAFs and TAMs, their symbiotic relationship and their cooperative role in the tumor microenvironment. In this Review, we provide an overview of the heterogeneity of CAFs and TAMs, how they establish an immunosuppressive microenvironment and their collaboration in the remodeling of the extracellular matrix. Finally, we examine why the impact of immunotherapy in PDAC has been limited and how a detailed molecular and spatial understanding of the combined role of CAFs and TAMs is paramount to the design of effective therapies.
Collapse
Affiliation(s)
- Mojdeh Shakiba
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
- Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY, USA
| | - David A Tuveson
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
- Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY, USA.
| |
Collapse
|
11
|
Shi X, Askari Rizvi SF, Yang Y, Liu G. Emerging nanomedicines for macrophage-mediated cancer therapy. Biomaterials 2025; 316:123028. [PMID: 39693782 DOI: 10.1016/j.biomaterials.2024.123028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 11/22/2024] [Accepted: 12/13/2024] [Indexed: 12/20/2024]
Abstract
Tumor-associated macrophages (TAMs) contribute to tumor progression by promoting angiogenesis, remodeling the tumor extracellular matrix, inducing tumor invasion and metastasis, as well as immune evasion. Due to the high plasticity of TAMs, they can polarize into different phenotypes with distinct functions, which are primarily categorized as the pro-inflammatory, anti-tumor M1 type, and the anti-inflammatory, pro-tumor M2 type. Notably, anti-tumor macrophages not only directly phagocytize tumor cells, but also present tumor-specific antigens and activate adaptive immunity. Therefore, targeted regulation of TAMs to unleash their potential anti-tumor capabilities is crucial for improving the efficacy of cancer immunotherapy. Nanomedicine serves as a promising vehicle and can inherently interact with TAMs, hence, emerging as a new paradigm in cancer immunotherapy. Due to their controllable structures and properties, nanomedicines offer a plethora of advantages over conventional drugs, thus enhancing the balance between efficacy and toxicity. In this review, we provide an overview of the hallmarks of TAMs and discuss nanomedicines for targeting TAMs with a focus on inhibiting recruitment, depleting and reprogramming TAMs, enhancing phagocytosis, engineering macrophages, as well as targeting TAMs for tumor imaging. We also discuss the challenges and clinical potentials of nanomedicines for targeting TAMs, aiming to advance the exploitation of nanomedicine for cancer immunotherapy.
Collapse
Affiliation(s)
- Xueying Shi
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics Center for Molecular, Imaging and Translational Medicine, School of Public Health, Xiamen University, No. 4221 South Xiang'an Road, Xiang'an District, Xiamen, 361102, China
| | - Syed Faheem Askari Rizvi
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics Center for Molecular, Imaging and Translational Medicine, School of Public Health, Xiamen University, No. 4221 South Xiang'an Road, Xiang'an District, Xiamen, 361102, China; Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, 54000, Punjab, Pakistan
| | - Yinxian Yang
- School of Pharmaceutical Sciences, Xiamen University, No. 4221 South Xiang'an Road, Xiang'an District, Xiamen, 361102, China.
| | - Gang Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics Center for Molecular, Imaging and Translational Medicine, School of Public Health, Xiamen University, No. 4221 South Xiang'an Road, Xiang'an District, Xiamen, 361102, China.
| |
Collapse
|
12
|
Ma C, Zhu W, Hu X, Wu D, Zhao X, Du Y, Kong X. Acinar cells modulate the tumor microenvironment through the promotion of M1 macrophage polarization via macrophage endocytosis in pancreatic cancer. Discov Oncol 2025; 16:489. [PMID: 40198509 PMCID: PMC11979042 DOI: 10.1007/s12672-025-02244-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 03/26/2025] [Indexed: 04/10/2025] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive and fatal cancer. M1 macrophages are generally considered to have anti-tumor properties, capable of suppressing tumor growth and metastasis by secreting pro-inflammatory cytokines and enhancing the immune response. AIMS The objective of this research was to pinpoint crucial genes associated with M1 macrophages and search for a new way to activate the M1 phenotype of macrophages in PDA. METHODS The level of immune cell infiltration was assessed using CIBERSORT in TCGA-PAAD cohort and ICGC-PACA cohort. We performed weighted gene co-expression network analysis (WGCNA) to identify the module most correlated with M1 macrophages and we identified hub genes through protein-protein interaction (PPI) analyse. Through survival analysis, correlation analysis and single cell analysis, we obtained the relationship between hub genes and prognosis, and the relationship between key genes and immune cells, as well as its expression in various cells. RESULTS PRSS1 (Cationic trypsinogen) and CTRB1 (Chymosinogen B) were hub genes of the M1 macrophage-associated WGCNA module (211genes) and are closely related to the extension of survival time, which are also verified as cell growth-related genes by DepMap database. Through single-cell sequencing analysis, we determined that the expression levels of PRSS1 and CTRB1 in the acinar cells of tumor tissues were diminished. PRSS1 and CTRB1 are considered to be the signature genes of acinar cells. The proportion of acinar cells was also correlated with the infiltration of CD8T cells and M1 cells. Immunostaining revealed elevated expression levels of PRSS1 and CTRB1 in adjacent normal tissues. Cell line experiments confirmed that macrophages polarize towards M1 by engulfing pancreatic enzyme granules, thereby inhibiting the malignant phenotype of tumor cells. CONCLUSION Our findings highlight the critical role of acinar cells in modulating the immune microenvironment of pancreatic tumors by influencing macrophage polarization. This insight may provide novel opportunities for therapeutic interventions in cancer treatment.
Collapse
Affiliation(s)
- Congjia Ma
- Department of Gastroenterology, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, China
| | - Wenbo Zhu
- Department of Gastroenterology, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, China
| | - Xiulin Hu
- Department of Gastroenterology, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, China
| | - Deli Wu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Soochow University, Soochow, China
| | - Xintong Zhao
- Department of Gastroenterology, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, China
| | - Yiqi Du
- Department of Gastroenterology, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, China.
| | - Xiangyu Kong
- Department of Gastroenterology, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, China.
| |
Collapse
|
13
|
Tong Y, Chen R, Lu X, Chen C, Sun G, Yu X, Lyu S, Feng M, Long Y, Gong L, Chen L. A nanobody-enzyme fusion protein targeting PD-L1 and sialic acid exerts anti-tumor effects by C-type lectin pathway-mediated tumor associated macrophages repolarizing. Int J Biol Macromol 2025; 298:139953. [PMID: 39824395 DOI: 10.1016/j.ijbiomac.2025.139953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 01/06/2025] [Accepted: 01/14/2025] [Indexed: 01/20/2025]
Abstract
Aberrant sialylated glycosylation in the tumor microenvironment is a novel immune suppression pathway, which has garnered significant attention as a targetable glycoimmune checkpoint for cancer immunotherapy to address the dilemma of existing therapies. However, rational drug design and in-depth mechanistic studies are urgently required for tumor sialic acid to become valuable glycoimmune targets. In this study, we explored the positive correlation of PD-L1 and sialyltransferase expression in clinical colorectal cancer tissues and identified their mutual regulation effects in macrophages. Subsequently, we characterized a new sialidase with excellent properties from human oral symbiotic bacteria and then developed a novel nanobody-enzyme fusion protein, designated as Nb16-Sia, to concurrently target the PD-L1 and sialic acid. Results from syngeneic colon tumor models reveal superior efficacy of Nb16-Sia over monotherapy and combinations, which could remodel the tumor immune microenvironment. Mechanistically, Nb16-Sia, which could repolarize macrophages from the tumor-promoting M2 to anti-tumor M1 phenotype via the C-type lectin pathway, exerted its antitumor efficacy mainly by regulating tumor-associated macrophages. Our strategy of nanobody-enzyme fusion protein effectively enables the delivery of sialidase, allows the collaboration between anti-PD-L1 nanobody and sialidase in combating tumors, and holds considerable promise for further development.
Collapse
Affiliation(s)
- Yongliang Tong
- Department of Medical Microbiology, Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Runqiu Chen
- Shanghai Institute of Infectious Diseases and Biosecurity, Fudan University, Shanghai, China; Department of Microbiological and Biochemical Pharmacy, School of Pharmacy, Fudan University, Shanghai, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Xinrong Lu
- Department of Medical Microbiology, Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Cuiying Chen
- Department of Research and Development, Sysdiagno (Nanjing) Biotech Co., Ltd, Nanjing, Jiangsu Province, China
| | - Guiqin Sun
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China
| | - Xiaolu Yu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Shaoxian Lyu
- Department of Medical Microbiology, Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Meiqing Feng
- Shanghai Institute of Infectious Diseases and Biosecurity, Fudan University, Shanghai, China; Department of Microbiological and Biochemical Pharmacy, School of Pharmacy, Fudan University, Shanghai, China.
| | - Yiru Long
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
| | - Likun Gong
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
| | - Li Chen
- Department of Medical Microbiology, Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai, China; Translational Glycomics Research Center, Fudan Zhangjiang Institute, Shanghai, China.
| |
Collapse
|
14
|
Song P, Tian W, Zheng Y, Xu S, Hu Z, Jin X, Zhu X, Tan L, Chen D, Chen Y. Genomic and Immune Profiling of Esophageal Squamous Cell Carcinoma Undergoing Neoadjuvant Therapy Versus Upfront Surgery Identifies Novel Immunogenic Cell Death-Based Signatures for Predicting Clinical Outcomes. MedComm (Beijing) 2025; 6:e70171. [PMID: 40182138 PMCID: PMC11965704 DOI: 10.1002/mco2.70171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 02/02/2025] [Accepted: 02/26/2025] [Indexed: 04/05/2025] Open
Abstract
It remains undetermined regarding the impact of neoadjuvant therapy on immunogenic cell death (ICD) and subsequent tumor microenvironment (TME) remodeling in esophageal squamous cell carcinoma (ESCC). And it is of paramount significance to identify beneficiaries from neoadjuvant therapy in treatment-naïve ESCC. In this study, 88 ESCC samples undergoing neoadjuvant therapy plus surgery (NA+S) or surgery alone (SA) were subjected to bulk-RNA sequencing. A five-gene RINscore incorporating ICD-related signature genes with TME-based hub genes was established to predict clinical outcomes and pharmacological responses, in which SLAMF7 and IL1R1 were selected out as co-expressed genes. The regulatory mechanism of the repressive co-transcription factor BATF of SLAMF7 and IL1R1 was further demonstrated. Our data demonstrated that NA+S led to high abundance in kinds of T helper cells, nature killer T cells and M1-like macrophages with increased CD8+T cells infiltration compared with SA. ICD phenotypes were further characterized in treatment-naïve ESCC to determine their differences in TME and potential benefits from NA. Our findings not only offered novel insights into the distinct TME and ICD profiles of ESCC undergoing different therapeutic modes, but also provided the RINscore, which may aid oncologists in determining individualized (neo)adjuvant immunotherapy regimen.
Collapse
Affiliation(s)
- Peidong Song
- Department of Thoracic Surgerythe Second Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Wenze Tian
- Department of Thoracic Surgerythe Affiliated Huai'an First People's Hospital of Nanjing Medical UniversityHuai'anChina
| | - Yujia Zheng
- Department of Thoracic Surgerythe Second Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Sukai Xu
- Department of Thoracic Surgerythe Second Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Zihao Hu
- Department of Thoracic Surgerythe Second Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Xing Jin
- Department of Thoracic Surgerythe Second Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Xuejuan Zhu
- Department of Thoracic Surgerythe Second Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Lijie Tan
- Department of Thoracic SurgeryZhongshan HospitalFudan UniversityShanghaiChina
| | - Donglai Chen
- Department of Thoracic SurgeryZhongshan HospitalFudan UniversityShanghaiChina
| | - Yongbing Chen
- Department of Thoracic Surgerythe Second Affiliated Hospital of Soochow UniversitySuzhouChina
| |
Collapse
|
15
|
Hochstadt J, Martínez Pacheco S, Casanova-Acebes M. Embracing diversity: macrophage complexity in cancer. Trends Cancer 2025; 11:351-364. [PMID: 39753470 DOI: 10.1016/j.trecan.2024.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/27/2024] [Accepted: 12/04/2024] [Indexed: 04/11/2025]
Abstract
Macrophages are myeloid cells that receive, integrate, and respond to tumoral cues. Tumors evolve and are shaped by macrophages, with tumor-associated macrophage (TAM)-tumor sculpting capacities going beyond an increase in their cellular mass. Longitudinal and local heterogeneity of TAM states is now possible with the use of single-cell and spatial transcriptomics. However, understanding TAM biology and its fundamental functional programs is still challenging, probably because of the lack of models that fully integrate TAM complexity. Here, we aim to review TAM diversity not only at the level of single-cell phenotypes but also by integrating complex physiological signals that determine their complexity and plasticity in tumors.
Collapse
Affiliation(s)
- Jan Hochstadt
- Cancer Immunity Laboratory, Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Sarai Martínez Pacheco
- Cancer Immunity Laboratory, Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - María Casanova-Acebes
- Cancer Immunity Laboratory, Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
| |
Collapse
|
16
|
Hua Q, Li Z, Weng Y, Wu Y, Zheng L. Myeloid cells: key players in tumor microenvironments. Front Med 2025; 19:265-296. [PMID: 40048137 DOI: 10.1007/s11684-025-1124-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 12/16/2024] [Indexed: 05/04/2025]
Abstract
Cancer is the result of evolving crosstalk between neoplastic cell and its immune microenvironment. In recent years, immune therapeutics targeting T lymphocytes, such as immune checkpoint blockade (ICB) and CAR-T, have made significant progress in cancer treatment and validated targeting immune cells as a promising approach to fight human cancers. However, responsiveness to the current immune therapeutic agents is limited to only a small proportion of solid cancer patients. As major components of most solid tumors, myeloid cells played critical roles in regulating the initiation and sustentation of adaptive immunity, thus determining tumor progression as well as therapeutic responses. In this review, we discuss emerging data on the diverse functions of myeloid cells in tumor progression through their direct effects or interactions with other immune cells. We explain how different metabolic reprogramming impacts the characteristics and functions of tumor myeloid cells, and discuss recent progress in revealing different mechanisms-chemotaxis, proliferation, survival, and alternative sources-involved in the infiltration and accumulation of myeloid cells within tumors. Further understanding of the function and regulation of myeloid cells is important for the development of novel strategies for therapeutic exploitation in cancer.
Collapse
Affiliation(s)
- Qiaomin Hua
- Guangdong Provincial Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Zhixiong Li
- Guangdong Provincial Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Yulan Weng
- Guangdong Provincial Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China
| | - Yan Wu
- Guangdong Provincial Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.
| | - Limin Zheng
- Guangdong Provincial Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
| |
Collapse
|
17
|
Paradzik Simunovic M, Degoricija M, Korac-Prlic J, Lesin M, Stanic R, Puljak L, Olujic I, Marin Lovric J, Vucinovic A, Ljubic Z, Thissen J, Reen Kok C, Jaing C, Bucan K, Terzic J. Potential Role of Malassezia restricta in Pterygium Development. Int J Mol Sci 2025; 26:2976. [PMID: 40243577 PMCID: PMC11989039 DOI: 10.3390/ijms26072976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 03/11/2025] [Accepted: 03/12/2025] [Indexed: 04/18/2025] Open
Abstract
Pterygium is a condition affecting the ocular surface, marked by a triangular-shaped growth of fibrotic tissue extending from the nasal conjunctiva toward the corneal center, potentially causing visual impairment. While ultraviolet (UV )light exposure is the primary risk factor for pterygium, its underlying cause remains unclear. In order to better understand the true genesis of pterygium development, we investigated pterygium tissue and compared it with healthy conjunctiva controls. Given the eye's direct environmental exposure, we analyzed the microbiota composition using metagenomic sequencing of pterygium tissue to identify microbes potentially associated with this condition. Metagenomic sequencing revealed a higher prevalence of the fungus Malassezia restricta in five pterygium samples, confirmed by in situ hybridization. The CHIT1 gene, which plays a role in antifungal defenses, displayed the highest expression in five pterygium tissue samples compared to healthy conjunctiva controls, suggesting the potential involvement of Malassezia restricta in pterygium development. Gene expression profiling of pterygium highlighted an IL-33 and IL-4 gene expression signature, along with an increased presence of M2 macrophages, emphasizing their role in promoting fibrosis-a hallmark feature of pterygium. The detection of Malassezia restricta in the pterygium samples and associated molecular changes provides novel insights into the ocular microbiome and raises the possibility of Malassezia's involvement in pterygium pathology.
Collapse
Affiliation(s)
| | - Marina Degoricija
- Laboratory for Cancer Research, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia
- Department of Medical Chemistry and Biochemistry, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia
| | - Jelena Korac-Prlic
- Laboratory for Cancer Research, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia
| | - Mladen Lesin
- Department of Ophthalmology, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia; (M.P.S.)
| | - Robert Stanic
- Department of Ophthalmology, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia; (M.P.S.)
| | - Livia Puljak
- Center for Evidence-Based Medicine and Healthcare, Catholic University of Croatia, 10000 Zagreb, Croatia
| | - Ivana Olujic
- Department of Ophthalmology, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia; (M.P.S.)
| | - Josipa Marin Lovric
- Department of Ophthalmology, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia; (M.P.S.)
| | - Ana Vucinovic
- Department of Ophthalmology, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia; (M.P.S.)
| | - Zana Ljubic
- Department of Ophthalmology, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia; (M.P.S.)
| | - James Thissen
- Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA
| | - Car Reen Kok
- Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA
| | - Crystal Jaing
- Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA
| | - Kajo Bucan
- Department of Ophthalmology, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia; (M.P.S.)
| | - Janos Terzic
- Laboratory for Cancer Research, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia
| |
Collapse
|
18
|
Zhao T, Luo Y, Sun Y, Wei Z. Characterizing macrophage diversity in colorectal malignancies through single-cell genomics. Front Immunol 2025; 16:1526668. [PMID: 40191203 PMCID: PMC11968368 DOI: 10.3389/fimmu.2025.1526668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 03/10/2025] [Indexed: 04/09/2025] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive tract, with increasing incidence and mortality rates, posing a significant burden on human health. Its progression relies on various mechanisms, among which the tumor microenvironment and tumor-associated macrophages (TAMs) have garnered increasing attention. Macrophage infiltration in various solid tumors is associated with poor prognosis and is linked to chemotherapy resistance in many cancers. These significant biological behaviors depend on the heterogeneity of macrophages. Tumor-promoting TAMs comprise subpopulations characterized by distinct markers and unique transcriptional profiles, rendering them potential targets for anticancer therapies through either depletion or reprogramming from a pro-tumoral to an anti-tumoral state. Single-cell RNA sequencing technology has significantly enhanced our research resolution, breaking the traditional simplistic definitions of macrophage subtypes and deepening our understanding of the diversity within TAMs. However, a unified elucidation of the nomenclature and molecular characteristics associated with this diversity remains lacking. In this review, we assess the application of conventional macrophage polarization subtypes in colorectal malignancies and explore several unique subtypes defined from a single-cell omics perspective in recent years, categorizing them based on their potential functions.
Collapse
Affiliation(s)
- Tingshuo Zhao
- First Clinical Medical College, Shanxi Medical University, Tai Yuan, China
| | - Yinyi Luo
- First Clinical Medical College, Shanxi Medical University, Tai Yuan, China
| | - Yuanjie Sun
- First Clinical Medical College, Shanxi Medical University, Tai Yuan, China
| | - Zhigang Wei
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Shanxi Medical University, Tai Yuan, China
| |
Collapse
|
19
|
Han HV, Efem R, Rosati B, Lu K, Maimouni S, Jiang YP, Montoya V, Van Der Velden A, Zong WX, Lin RZ. Propionyl-CoA carboxylase subunit B regulates anti-tumor T cells in a pancreatic cancer mouse model. eLife 2025; 13:RP96925. [PMID: 40067762 PMCID: PMC11896608 DOI: 10.7554/elife.96925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/15/2025] Open
Abstract
Most human pancreatic ductal adenocarcinoma (PDAC) are not infiltrated with cytotoxic T cells and are highly resistant to immunotherapy. Over 90% of PDAC have oncogenic KRAS mutations, and phosphoinositide 3-kinases (PI3Ks) are direct effectors of KRAS. Our previous study demonstrated that ablation of Pik3ca in KPC (KrasG12D; Trp53R172H; Pdx1-Cre) pancreatic cancer cells induced host T cells to infiltrate and completely eliminate the tumors in a syngeneic orthotopic implantation mouse model. Now, we show that implantation of Pik3ca-/- KPC (named αKO) cancer cells induces clonal enrichment of cytotoxic T cells infiltrating the pancreatic tumors. To identify potential molecules that can regulate the activity of these anti-tumor T cells, we conducted an in vivo genome-wide gene-deletion screen using αKO cells implanted in the mouse pancreas. The result shows that deletion of propionyl-CoA carboxylase subunit B gene (Pccb) in αKO cells (named p-αKO) leads to immune evasion, tumor progression, and death of host mice. Surprisingly, p-αKO tumors are still infiltrated with clonally enriched CD8+ T cells but they are inactive against tumor cells. However, blockade of PD-L1/PD1 interaction reactivated these clonally enriched T cells infiltrating p-αKO tumors, leading to slower tumor progression and improve survival of host mice. These results indicate that Pccb can modulate the activity of cytotoxic T cells infiltrating some pancreatic cancers and this understanding may lead to improvement in immunotherapy for this difficult-to-treat cancer.
Collapse
Affiliation(s)
- Han V Han
- Department of Physiology and Biophysics, Stony Brook University, Stony BrookNew YorkUnited States
- Department of Biomedical Engineering, Stony Brook University, Stony BrookNew YorkUnited States
| | - Richard Efem
- Department of Physiology and Biophysics, Stony Brook University, Stony BrookNew YorkUnited States
| | - Barbara Rosati
- Department of Physiology and Biophysics, Stony Brook University, Stony BrookNew YorkUnited States
| | - Kevin Lu
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers-The State University of New JerseyPiscatawayUnited States
| | - Sara Maimouni
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers-The State University of New JerseyPiscatawayUnited States
| | - Ya-Ping Jiang
- Department of Physiology and Biophysics, Stony Brook University, Stony BrookNew YorkUnited States
| | - Valeria Montoya
- Department of Microbiology and Immunology, Renaissance School of Medicine at Stony Brook University, Stony BrookNew YorkUnited States
- Center for Infectious Diseases, Renaissance School of Medicine at Stony Brook University, Stony BrookNew YorkUnited States
| | - Ando Van Der Velden
- Center for Infectious Diseases, Renaissance School of Medicine at Stony Brook University, Stony BrookNew YorkUnited States
| | - Wei-Xing Zong
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers-The State University of New JerseyPiscatawayUnited States
| | - Richard Z Lin
- Department of Physiology and Biophysics, Stony Brook University, Stony BrookNew YorkUnited States
- Northport Veteran Affair Medical Center, NorthportNew YorkUnited States
| |
Collapse
|
20
|
Guan F, Wang R, Yi Z, Luo P, Liu W, Xie Y, Liu Z, Xia Z, Zhang H, Cheng Q. Tissue macrophages: origin, heterogenity, biological functions, diseases and therapeutic targets. Signal Transduct Target Ther 2025; 10:93. [PMID: 40055311 PMCID: PMC11889221 DOI: 10.1038/s41392-025-02124-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 11/01/2024] [Accepted: 12/15/2024] [Indexed: 05/04/2025] Open
Abstract
Macrophages are immune cells belonging to the mononuclear phagocyte system. They play crucial roles in immune defense, surveillance, and homeostasis. This review systematically discusses the types of hematopoietic progenitors that give rise to macrophages, including primitive hematopoietic progenitors, erythro-myeloid progenitors, and hematopoietic stem cells. These progenitors have distinct genetic backgrounds and developmental processes. Accordingly, macrophages exhibit complex and diverse functions in the body, including phagocytosis and clearance of cellular debris, antigen presentation, and immune response, regulation of inflammation and cytokine production, tissue remodeling and repair, and multi-level regulatory signaling pathways/crosstalk involved in homeostasis and physiology. Besides, tumor-associated macrophages are a key component of the TME, exhibiting both anti-tumor and pro-tumor properties. Furthermore, the functional status of macrophages is closely linked to the development of various diseases, including cancer, autoimmune disorders, cardiovascular disease, neurodegenerative diseases, metabolic conditions, and trauma. Targeting macrophages has emerged as a promising therapeutic strategy in these contexts. Clinical trials of macrophage-based targeted drugs, macrophage-based immunotherapies, and nanoparticle-based therapy were comprehensively summarized. Potential challenges and future directions in targeting macrophages have also been discussed. Overall, our review highlights the significance of this versatile immune cell in human health and disease, which is expected to inform future research and clinical practice.
Collapse
Affiliation(s)
- Fan Guan
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Ruixuan Wang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Zhenjie Yi
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Wanyao Liu
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Yao Xie
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Zaoqu Liu
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhiwei Xia
- Department of Neurology, Hunan Aerospace Hospital, Hunan Normal University, Changsha, China.
| | - Hao Zhang
- Department of Neurosurgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
| |
Collapse
|
21
|
Song X, Pan Z, Zhang Y, Yang W, Zhang T, Wang H, Chen Y, Yu X, Ding H, Li R, Ge P, Xu L, Dong G, Jiang F. Excessive MYC Orchestrates Macrophages induced Chromatin Remodeling to Sustain Micropapillary-Patterned Malignancy in Lung Adenocarcinoma. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2403851. [PMID: 39899538 PMCID: PMC11948069 DOI: 10.1002/advs.202403851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 01/15/2025] [Indexed: 02/05/2025]
Abstract
Current understanding of micropapillary (MP)-subtype lung adenocarcinoma (LUAD) remains confined to biological activities and genomic landscapes. Unraveling the major regulatory programs underlying MP patterned malignancy offers opportunities to identify more feasible therapeutic targets for patients with MP LUAD. This study shows that patients with MP subtype LUAD have aberrant activation of the MYC pathway compared to patients with other subtypes. In vitro and xenograft mouse model studies reveal that MP pattern in malignancy cannot be solely due to aberrant MYC expression but requires the involvement of M2-like macrophages. Excessively expressed MYC leads to the accumulation of M2-like macrophages from the bone marrow, which secretes TGFβ, to induce the expression of FOSL2 in tumor cells, thereby remodeling chromatin accessibility at promoter regions of MP-pattern genes to promote the MYC-mediated de novo transcriptional regulation of these genes. Additionally, the MP-pattern in malignancy can be effectively alleviated by disrupting the TGFβ-FOSL2 axis. These findings reveal new functions for the M2-like macrophage-TGFβ-FOSL2 axis in MYC-overexpressing MP-subtype LUAD, identifying targetable vulnerabilities in this pathway.
Collapse
Affiliation(s)
- Xuming Song
- Department of Thoracic SurgeryNanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer ResearchNanjing210009P. R. China
- Jiangsu Key Laboratory of Molecular and Translational Cancer ResearchCancer Institute of Jiangsu ProvinceNanjing210000P. R. China
- The Fourth Clinical College of Nanjing Medical UniversityNanjing210000P. R. China
| | - Zehao Pan
- Department of Thoracic SurgeryNanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer ResearchNanjing210009P. R. China
- Jiangsu Key Laboratory of Molecular and Translational Cancer ResearchCancer Institute of Jiangsu ProvinceNanjing210000P. R. China
- The Fourth Clinical College of Nanjing Medical UniversityNanjing210000P. R. China
| | - Yi Zhang
- Jiangsu Key Laboratory of Molecular and Translational Cancer ResearchCancer Institute of Jiangsu ProvinceNanjing210000P. R. China
- Department of PathologyNanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer ResearchNanjing210009P. R. China
| | - Wenmin Yang
- Department of Thoracic SurgeryNanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer ResearchNanjing210009P. R. China
- Jiangsu Key Laboratory of Molecular and Translational Cancer ResearchCancer Institute of Jiangsu ProvinceNanjing210000P. R. China
- Department of PathologyNanjing Drum Tower hospitalNanjing210008P.R. China
| | - Te Zhang
- Department of Thoracic SurgeryNanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer ResearchNanjing210009P. R. China
- Jiangsu Key Laboratory of Molecular and Translational Cancer ResearchCancer Institute of Jiangsu ProvinceNanjing210000P. R. China
- Department of Biochemistry and Molecular GeneticsFeinberg School of MedicineNorthwestern UniversityChicagoIllinois60201USA
| | - Hui Wang
- Department of Thoracic SurgeryNanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer ResearchNanjing210009P. R. China
- Jiangsu Key Laboratory of Molecular and Translational Cancer ResearchCancer Institute of Jiangsu ProvinceNanjing210000P. R. China
- The Fourth Clinical College of Nanjing Medical UniversityNanjing210000P. R. China
| | - Yuzhong Chen
- Department of Thoracic SurgeryNanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer ResearchNanjing210009P. R. China
- Jiangsu Key Laboratory of Molecular and Translational Cancer ResearchCancer Institute of Jiangsu ProvinceNanjing210000P. R. China
- The Fourth Clinical College of Nanjing Medical UniversityNanjing210000P. R. China
| | - Xinnian Yu
- Department of Thoracic SurgeryNanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer ResearchNanjing210009P. R. China
- Jiangsu Key Laboratory of Molecular and Translational Cancer ResearchCancer Institute of Jiangsu ProvinceNanjing210000P. R. China
- The Fourth Clinical College of Nanjing Medical UniversityNanjing210000P. R. China
| | - Hanlin Ding
- Department of Thoracic SurgeryNanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer ResearchNanjing210009P. R. China
- Jiangsu Key Laboratory of Molecular and Translational Cancer ResearchCancer Institute of Jiangsu ProvinceNanjing210000P. R. China
- The Fourth Clinical College of Nanjing Medical UniversityNanjing210000P. R. China
| | - Rutao Li
- Jiangsu Key Laboratory of Molecular and Translational Cancer ResearchCancer Institute of Jiangsu ProvinceNanjing210000P. R. China
- Department of Thoracic SurgeryThe Fourth Affiliated Hospital of Soochow UniversityNanjing215000P. R. China
| | - Pengfei Ge
- Department of Thoracic SurgeryNanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer ResearchNanjing210009P. R. China
- Jiangsu Key Laboratory of Molecular and Translational Cancer ResearchCancer Institute of Jiangsu ProvinceNanjing210000P. R. China
- The Fourth Clinical College of Nanjing Medical UniversityNanjing210000P. R. China
| | - Lin Xu
- Department of Thoracic SurgeryNanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer ResearchNanjing210009P. R. China
- Jiangsu Key Laboratory of Molecular and Translational Cancer ResearchCancer Institute of Jiangsu ProvinceNanjing210000P. R. China
- Collaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjing211116P. R. China
| | - Gaochao Dong
- Department of Thoracic SurgeryNanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer ResearchNanjing210009P. R. China
- Jiangsu Key Laboratory of Molecular and Translational Cancer ResearchCancer Institute of Jiangsu ProvinceNanjing210000P. R. China
| | - Feng Jiang
- Department of Thoracic SurgeryNanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer ResearchNanjing210009P. R. China
- Jiangsu Key Laboratory of Molecular and Translational Cancer ResearchCancer Institute of Jiangsu ProvinceNanjing210000P. R. China
| |
Collapse
|
22
|
Tripathi S, Sharma Y, Kumar D. Unveiling the link between chronic inflammation and cancer. Metabol Open 2025; 25:100347. [PMID: 39876904 PMCID: PMC11772974 DOI: 10.1016/j.metop.2025.100347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 01/05/2025] [Accepted: 01/06/2025] [Indexed: 01/31/2025] Open
Abstract
The highly nuanced transition from an inflammatory process to tumorigenesis is of great scientific interest. While it is well known that environmental stimuli can cause inflammation, less is known about the oncogenic modifications that chronic inflammation in the tissue microenvironment can bring about, as well as how these modifications can set off pro-tumorigenic processes. It is clear that no matter where the environmental factors come from, maintaining an inflammatory microenvironment encourages carcinogenesis. In addition to encouraging angiogenesis and metastatic processes, sustaining the survival and proliferation of malignant transformed cells, and possibly altering the efficacy of therapeutic agents, inflammation can negatively regulate the antitumoral adaptive and innate immune responses. Because chronic inflammation has multiple pathways involved in tumorigenesis and metastasis, it has gained recognition as a marker of cancer and a desirable target for cancer therapy. Recent advances in our knowledge of the molecular mechanisms that drive cancer's progression demonstrate that inflammation promotes tumorigenesis and metastasis while suppressing anti-tumor immunity. In many solid tumor types, including breast, lung, and liver cancer, inflammation stimulates the activation of oncogenes and impairs the body's defenses against the tumor. Additionally, it alters the microenvironment of the tumor. As a tactical approach to cancer treatment, these findings have underscored the importance of targeting inflammatory pathways. This review highlights the role of inflammation in cancer development and metastasis, focusing on its impact on tumor progression, immune suppression, and therapy resistance. It examines current anti-inflammatory strategies, including NSAIDs, cytokine modulators, and STAT3 inhibitors, while addressing their potential and limitations. The review emphasizes the need for further research to unravel the complex mechanisms linking inflammation to cancer progression and identify molecular targets for specific cancer subtypes.
Collapse
Affiliation(s)
- Siddhant Tripathi
- Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University, Pune, Maharashtra, 411038, India
| | - Yashika Sharma
- Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University, Pune, Maharashtra, 411038, India
| | - Dileep Kumar
- Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| |
Collapse
|
23
|
Feng Z, Wang L, Yang J, Li T, Liao X, Kang Y, Xiao F, Zhang W. Sepsis: the evolution of molecular pathogenesis concepts and clinical management. MedComm (Beijing) 2025; 6:e70109. [PMID: 39991626 PMCID: PMC11847631 DOI: 10.1002/mco2.70109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 11/29/2024] [Accepted: 01/07/2025] [Indexed: 02/25/2025] Open
Abstract
The mortality rate of sepsis is approximately 22.5%, accounting for 19.7% of the total global mortality. Since Lewis Thomas proposed in 1972 that "it is our response that makes the disease (sepsis)" rather than the invading microorganisms, numerous drugs have been developed to suppress the "overwhelming" inflammatory response, but none of them has achieved the desired effect. Continued failure has led investigators to question whether deaths in septic patients are indeed caused by uncontrolled inflammation. Here, we review the history of clinical trials based on evolving concepts of sepsis pathogenesis over the past half century, summarize the factors that led to the failure of these historical drugs and the prerequisites for the success of future drugs, and propose the basic principles of preclinical research to ensure successful clinical translation. The strategy of targeting inflammatory factors are like attempting to eliminate invaders by suppressing the host's armed forces, which is logically untenable. Sepsis may not be that complex; rather, sepsis may be the result of a failure to fight microbes when the force of an invading pathogen overwhelms our defenses. Thus, strengthening the body's defense forces instead of suppressing them may be the correct strategy to overcome sepsis.
Collapse
Affiliation(s)
- Zhongxue Feng
- Institute of Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Lijun Wang
- Institute of Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Jing Yang
- Institute of Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Tingting Li
- Institute of Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Xuelian Liao
- Department of Critical Care MedicineWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Yan Kang
- Institute of Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Fei Xiao
- Department of Intensive Care Unit of Gynecology and ObstetricsWest China Second University Hospital, Sichuan UniversityChengduSichuanChina
| | - Wei Zhang
- Institute of Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital, Sichuan UniversityChengduSichuanChina
| |
Collapse
|
24
|
Tan H, Cai M, Wang J, Yu T, Xia H, Zhao H, Zhang X. Harnessing Macrophages in Cancer Therapy: from Immune Modulators to Therapeutic Targets. Int J Biol Sci 2025; 21:2235-2257. [PMID: 40083710 PMCID: PMC11900799 DOI: 10.7150/ijbs.106275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Accepted: 02/14/2025] [Indexed: 03/16/2025] Open
Abstract
Macrophages, as the predominant phagocytes, play an essential role in pathogens defense and tissue homeostasis maintenance. In the context of cancer, tumor-associated macrophages (TAMs) have evolved into cunning actors involved in angiogenesis, cancer cell proliferation and metastasis, as well as the construction of immunosuppressive microenvironment. Once properly activated, macrophages can kill tumor cells directly through phagocytosis or attack tumor cells indirectly by stimulating innate and adaptive immunity. Thus, the prospect of targeting TAMs has sparked significant interest and emerged as a promising strategy in immunotherapy. In this review, we summarize the diverse roles and underlying mechanisms of TAMs in cancer development and immunity and highlight the TAM-based therapeutic strategies such as inhibiting macrophage recruitment, inhibiting the differentiation reprogramming of TAMs, blocking phagocytotic checkpoints, inducing trained macrophages, as well as the potential of engineered CAR-armed macrophages in cancer therapy.
Collapse
Affiliation(s)
- Huabing Tan
- Department of Infectious Diseases, Hepatology Institute, Renmin Hospital, Shiyan Key Laboratory of Virology, Hubei University of Medicine, Shiyan, Hubei Province, China
- General internal medicine, Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Meihe Cai
- Department of Traditional Chinese Medicine, Zhushan Renmin Hospital, Zhushan, 442200, China
| | | | - Tao Yu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Houjun Xia
- Center for Cancer Immunology, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Huanbin Zhao
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Present: Division of Pharmaceutical Sciences, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Xiaoyu Zhang
- Department of Gastrointestinal Surgery, Huai'an Second People's Hospital, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, China
| |
Collapse
|
25
|
Lehtonen H, Jokela H, Hofmann J, Tola L, Mehmood A, Ginhoux F, Becher B, Greter M, Yegutkin GG, Salmi M, Gerke H, Rantakari P. Early precursor-derived pituitary gland tissue-resident macrophages play a pivotal role in modulating hormonal balance. Cell Rep 2025; 44:115227. [PMID: 39841599 DOI: 10.1016/j.celrep.2024.115227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 11/26/2024] [Accepted: 12/30/2024] [Indexed: 01/24/2025] Open
Abstract
The pituitary gland is the central endocrine regulatory organ producing and releasing hormones that coordinate major body functions. The physical location of the pituitary gland at the base of the brain, though outside the protective blood-brain barrier, leads to an unexplored special immune environment. Using single-cell transcriptomics, fate mapping, and imaging, we characterize pituitary-resident macrophages (pitMØs), revealing their heterogeneity and spatial specialization. Microglia-like macrophages (ml-MACs) are enriched in the posterior pituitary, while other pitMØs in the anterior pituitary exhibit close interactions with hormone-secreting cells. Importantly, all pitMØs originate from early yolk sac progenitors and maintain themselves through self-renewal, independent of bone marrow-derived monocytes. Macrophage depletion experiments unveil the role of macrophages in regulating intrapituitary hormonal balance through extracellular ATP-mediated intercellular signaling. Altogether, these findings provide information on pituitary gland macrophages and advance our understanding of immune-endocrine system crosstalk.
Collapse
Affiliation(s)
- Henna Lehtonen
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; Institute of Biomedicine, University of Turku, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland
| | - Heli Jokela
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; Institute of Biomedicine, University of Turku, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland
| | - Julian Hofmann
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; Institute of Biomedicine, University of Turku, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland
| | - Lauriina Tola
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; Institute of Biomedicine, University of Turku, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland
| | - Arfa Mehmood
- Institute of Biomedicine, University of Turku, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland
| | - Florent Ginhoux
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore; INSERM U1015, Gustave Roussy Cancer Campus, Villejuif 94800, France; Translational Immunology Institute, SingHealth Duke-NUS, Singapore 169856, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Burkhard Becher
- Institute of Experimental Immunology, University of Zürich, 8057 Zurich, Switzerland
| | - Melanie Greter
- Institute of Experimental Immunology, University of Zürich, 8057 Zurich, Switzerland
| | - Gennady G Yegutkin
- InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland; MediCity Research Laboratory, University of Turku, 20520 Turku, Finland
| | - Marko Salmi
- Institute of Biomedicine, University of Turku, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland; MediCity Research Laboratory, University of Turku, 20520 Turku, Finland
| | - Heidi Gerke
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; Institute of Biomedicine, University of Turku, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland
| | - Pia Rantakari
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; Institute of Biomedicine, University of Turku, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland.
| |
Collapse
|
26
|
Garvin-Jiménez E, Casanova-Acebes M. It takes two to TAM-go. Gut 2025:gutjnl-2024-334506. [PMID: 39919827 DOI: 10.1136/gutjnl-2024-334506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Accepted: 01/28/2025] [Indexed: 02/09/2025]
Affiliation(s)
- Eduardo Garvin-Jiménez
- Cancer Immunity Laboratory. Molecular Oncology Programme, Centro Nacional de Investigaciones Oncologicas Carlos III, Madrid, Spain
| | - María Casanova-Acebes
- Cancer Immunity Laboratory. Molecular Oncology Programme, Centro Nacional de Investigaciones Oncologicas Carlos III, Madrid, Spain
| |
Collapse
|
27
|
Jin R, Neufeld L, McGaha TL. Linking macrophage metabolism to function in the tumor microenvironment. NATURE CANCER 2025; 6:239-252. [PMID: 39962208 DOI: 10.1038/s43018-025-00909-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 12/10/2024] [Indexed: 02/28/2025]
Abstract
Macrophages are present at high frequency in most solid tumor types, and their relative abundance negatively correlates with therapy responses and survival outcomes. Tissue-resident macrophages are highly tuned to integrate tissue niche signals, and multiple factors within the idiosyncratic tumor microenvironment (TME) drive macrophages to polarization states that favor immune suppression, tumor growth and metastasis. These diverse functional states are underpinned by extensive and complex rewiring of tumor-associated macrophage (TAM) metabolism. In this Review, we link distinct and specific macrophage functional states within the TME to major, phenotype-sustaining metabolic programs and discuss the metabolic impact of macrophage-modulating therapeutic interventions.
Collapse
Affiliation(s)
- Robbie Jin
- Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Immunology, Temerty Faculty of Medicine, the University of Toronto, Toronto, Ontario, Canada
| | - Luke Neufeld
- Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Immunology, Temerty Faculty of Medicine, the University of Toronto, Toronto, Ontario, Canada
| | - Tracy L McGaha
- Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
- Department of Immunology, Temerty Faculty of Medicine, the University of Toronto, Toronto, Ontario, Canada.
| |
Collapse
|
28
|
Aksoy SA, Earl J, Grahovac J, Karakas D, Lencioni G, Sığırlı S, Bijlsma MF. Organoids, tissue slices and organotypic cultures: Advancing our understanding of pancreatic ductal adenocarcinoma through in vitro and ex vivo models. Semin Cancer Biol 2025; 109:10-24. [PMID: 39730107 DOI: 10.1016/j.semcancer.2024.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 12/14/2024] [Accepted: 12/19/2024] [Indexed: 12/29/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses of all common solid cancers. For the large majority of PDAC patients, only systemic therapies with very limited efficacy are indicated. In addition, immunotherapies have not brought the advances seen in other cancer types. Several key characteristics of PDAC contribute to poor treatment outcomes, and in this review, we will discuss how these characteristics are best captured in currently available ex vivo or in vitro model systems. For instance, PDAC is hallmarked by a highly desmoplastic and immune-suppressed tumor microenvironment that impacts disease progression and therapy resistance. Also, large differences in tumor biology exist between and within tumors, complicating treatment decisions. Furthermore, PDAC has a very high propensity for locally invasive and metastatic growth. The use of animal models is often not desirable or feasible and several in vitro and ex vivo model systems have been developed, such as organotypic cocultures and tissue slices, among others. However, the absence of a full host organism impacts the ability of these models to accurately capture the characteristics that contribute to poor outcomes in PDAC. We will discuss the caveats and advantages of these model systems in the context of PDAC's key characteristics and provide recommendations on model choice and the possibilities for optimization. These considerations should be of use to researchers aiming to study PDAC in the in vitro setting.
Collapse
Affiliation(s)
- Secil Ak Aksoy
- Bursa Uludag University, Faculty of Medicine, Department of Medical Microbiology, Bursa, Turkey
| | - Julie Earl
- Ramón y Cajal Health Research Institute (IRYCIS), Biomodels and Biomodels Platform Hospital Ramón y Cajal-IRYCIS, Carretera Colmenar Km 9,100, Madrid 28034, Spain; The Biomedical Research Network in Cancer (CIBERONC), Av. Monforte de Lemos, 3-5. Pabellón 11. Planta 0, Madrid 28029, Spain
| | - Jelena Grahovac
- Experimental Oncology Department, Institute for Oncology and Radiology of Serbia, Belgrade, Serbia
| | - Didem Karakas
- Acibadem Mehmet Ali Aydinlar University, Department of Medical Biotechnology, Graduate School of Health Sciences, Istanbul, Turkey
| | - Giulia Lencioni
- Department of Biology, University of Pisa, Pisa, Italy; Fondazione Pisana per la Scienza, San Giuliano Terme, Pisa, Italy
| | - Sıla Sığırlı
- Acibadem Mehmet Ali Aydinlar University, Department of Medical Biotechnology, Graduate School of Health Sciences, Istanbul, Turkey
| | - Maarten F Bijlsma
- Amsterdam UMC Location University of Amsterdam, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands.
| |
Collapse
|
29
|
Wang CA, Hou YC, Hong YK, Tai YJ, Shen C, Hou PC, Fu JL, Wu CL, Cheng SM, Hwang DY, Su YY, Shan YS, Tsai SJ. Intercellular TIMP-1-CD63 signaling directs the evolution of immune escape and metastasis in KRAS-mutated pancreatic cancer cells. Mol Cancer 2025; 24:25. [PMID: 39825392 PMCID: PMC11742192 DOI: 10.1186/s12943-024-02207-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 12/24/2024] [Indexed: 01/20/2025] Open
Abstract
BACKGROUND AND AIMS Oncogenic KRAS mutations are present in approximately 90% of pancreatic ductal adenocarcinoma (PDAC). However, Kras mutation alone is insufficient to transform precancerous cells into metastatic PDAC. This study investigates how KRAS-mutated epithelial cells acquire the capacity to escape senescence or even immune clearance, thereby progressing to advanced PDAC. METHODS Single-cell RNA sequencing and analysis of primary PDAC tumors were conducted. Genetically engineered pancreas-specific Kras-mutated, dual specificity phosphatase-2 (Dusp2) knockout mouse models were established. Human and mouse primary pancreatic cancer cell lines were used for in vitro assessment of cancer characteristics. Tumor progression was studied via pancreas orthotopic and portal vein injection in the immune-competent mice. Clinical relevance was validated by digital spatial transcriptomic analysis of PDAC tumors. RESULTS Kras mutation induces the formation of pancreatic intraepithelial neoplasia (PanIN), these lesions also exhibit significant apoptotic signals. Single-cell RNA sequencing identified a subset of ERKactiveDUSP2low cells continuing to expand from early to advanced stage PDAC. In vitro and in vivo studies reveal that early infiltrating macrophage-derived tissue inhibitor of metallopeptidase 1 (TIMP-1) is the key factor in maintaining the ERKactiveDUSP2low cell population in a CD63-dependent manner. The ERKactiveDUSP2low cancer cells further exacerbate macrophage-mediated cancer malignancy, including loss of epithelial trait, increased lymphangiogenesis, and immune escape. Digital spatial profiling analysis of PDAC samples demonstrates the colocalization of TIMP-1high macrophages and CD63high cancer cells. The presence of TIMP-1high macrophages and CD63high epithelial cells correlates with poor prognosis in PDAC. CONCLUSIONS Our study reveals the vicious cycle between early infiltrating macrophages and pancreatic cancer cells, providing a mechanistic insight into the dynamic regulation directing pancreatic cancer progression.
Collapse
Affiliation(s)
- Chu-An Wang
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ya-Chin Hou
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Division of General Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Kai Hong
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Yu-Jing Tai
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chieh Shen
- Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Pei-Chi Hou
- Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Jhao-Lin Fu
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Cheng-Lin Wu
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Siao Muk Cheng
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
| | - Daw-Yang Hwang
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
| | - Yung-Yeh Su
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Center for Cancer Research,, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yan-Shen Shan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- Division of General Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
| | - Shaw-Jenq Tsai
- Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- Department of Biomedical Sciences, National Chung Cheng University, No.168, Sect. 1, University Rd., Minhsiung, Chiayi, 621301, Taiwan.
| |
Collapse
|
30
|
Li J, Xiao C, Li C, He J. Tissue-resident immune cells: from defining characteristics to roles in diseases. Signal Transduct Target Ther 2025; 10:12. [PMID: 39820040 PMCID: PMC11755756 DOI: 10.1038/s41392-024-02050-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 09/28/2024] [Accepted: 11/04/2024] [Indexed: 01/19/2025] Open
Abstract
Tissue-resident immune cells (TRICs) are a highly heterogeneous and plastic subpopulation of immune cells that reside in lymphoid or peripheral tissues without recirculation. These cells are endowed with notably distinct capabilities, setting them apart from their circulating leukocyte counterparts. Many studies demonstrate their complex roles in both health and disease, involving the regulation of homeostasis, protection, and destruction. The advancement of tissue-resolution technologies, such as single-cell sequencing and spatiotemporal omics, provides deeper insights into the cell morphology, characteristic markers, and dynamic transcriptional profiles of TRICs. Currently, the reported TRIC population includes tissue-resident T cells, tissue-resident memory B (BRM) cells, tissue-resident innate lymphocytes, tissue-resident macrophages, tissue-resident neutrophils (TRNs), and tissue-resident mast cells, but unignorably the existence of TRNs is controversial. Previous studies focus on one of them in specific tissues or diseases, however, the origins, developmental trajectories, and intercellular cross-talks of every TRIC type are not fully summarized. In addition, a systemic overview of TRICs in disease progression and the development of parallel therapeutic strategies is lacking. Here, we describe the development and function characteristics of all TRIC types and their major roles in health and diseases. We shed light on how to harness TRICs to offer new therapeutic targets and present burning questions in this field.
Collapse
Affiliation(s)
- Jia Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chu Xiao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chunxiang Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| |
Collapse
|
31
|
Chen Y, Chen X, Zhang Y, Wang M, Yang M, Wang R, Yan X, Shao S, Xin H, Hu Q, Wei W, Ping Y. Macrophage-specific in vivo RNA editing promotes phagocytosis and antitumor immunity in mice. Sci Transl Med 2025; 17:eadl5800. [PMID: 39813319 DOI: 10.1126/scitranslmed.adl5800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 07/09/2024] [Accepted: 12/18/2024] [Indexed: 01/18/2025]
Abstract
Macrophages play a central role in antitumor immunity, making them an attractive target for gene therapy strategies. However, macrophages are difficult to transfect because of nucleic acid sensors that can trigger the degradation of foreign plasmid DNA. Here, we developed a macrophage-specific editing (MAGE) system by which compact plasmid DNA encoding a CasRx editor can be delivered to macrophages by a poly(β-amino ester) (PBAE) carrier to bypass the DNA sensor and enable RNA editing in vitro and in vivo. We identified a four-arm branched PBAE with 1-(2-aminoethyl)-4-methylpiperazine end-capping (PBAE29) that enables highly efficient macrophage transfection. PBAE29-mediated transfection of cultured macrophages stimulated less inflammatory cytokine production and inflammasome activation compared with traditional lipofectamine or electroporation-mediated plasmid delivery. Transfection efficiency was further improved by delivering CasRx by minicircle plasmid. The MAGE system incorporated a layer of carboxylated-mannan coating to target macrophage mannose receptors and a macrophage-specific promoter for enhanced selectivity. The delivery of CasRx with guide RNA targeting the transcripts for sialic acid-binding immunoglobulin similar to lectin 10 and signal regulatory protein alpha expression resulted in effective protein knockdown, improving macrophage phagocytosis. The MAGE system also showed efficacy in targeting macrophages in vivo, stimulating antitumor immune responses and reducing tumor volume in murine tumor models, including patient-derived pancreatic adenocarcinoma xenografts in humanized mice. In sum, the MAGE system presents a promising platform for in vivo macrophage-specific delivery of RNA editing tools that can be applied as a cancer therapy.
Collapse
Affiliation(s)
- Yuxuan Chen
- College of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China
| | - Xiaohong Chen
- College of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, MOE Joint International Research Laboratory of Pancreatic Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Yao Zhang
- College of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China
| | - Meng Wang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, MOE Joint International Research Laboratory of Pancreatic Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Minqi Yang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, MOE Joint International Research Laboratory of Pancreatic Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Ruiji Wang
- College of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China
| | - Xiaojie Yan
- College of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China
| | - Shiyi Shao
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, MOE Joint International Research Laboratory of Pancreatic Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Huhu Xin
- College of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China
| | - Qida Hu
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, MOE Joint International Research Laboratory of Pancreatic Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Wei Wei
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China
- School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuan Ping
- College of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China
| |
Collapse
|
32
|
Liu K, Li Y, Shen M, Xu W, Wu S, Yang X, Zhang B, Lin N. Epigenetic Regulation of Stromal and Immune Cells and Therapeutic Targets in the Tumor Microenvironment. Biomolecules 2025; 15:71. [PMID: 39858465 PMCID: PMC11764280 DOI: 10.3390/biom15010071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 12/19/2024] [Accepted: 01/04/2025] [Indexed: 01/27/2025] Open
Abstract
The tumor microenvironment (TME) plays a pivotal role in neoplastic initiation and progression. Epigenetic machinery, governing the expression of core oncogenes and tumor suppressor genes in transformed cells, significantly contributes to tumor development at both primary and distant sites. Recent studies have illuminated how epigenetic mechanisms integrate external cues and downstream signals, altering the phenotype of stromal cells and immune cells. This remolds the area surrounding tumor cells, ultimately fostering an immunosuppressive microenvironment. Therefore, correcting the TME by targeting the epigenetic modifications holds substantial promise for cancer treatment. This review synthesizes recent research that elucidates the impact of specific epigenetic regulations-ranging from DNA methylation to histone modifications and chromatin remodeling-on stromal and immune cells within the TME. Notably, we highlight their functional roles in either promoting or restricting tumor progression. We also discuss the potential applications of epigenetic agents for cancer treatment, envisaging their ability to normalize the ecosystem. This review aims to assist researchers in understanding the dynamic interplay between epigenetics and the TME, paving the way for better epigenetic therapy.
Collapse
Affiliation(s)
- Kang Liu
- College of Pharmaceutical Sciences, Hangzhou First People’s Hospital, Zhejiang Chinese Medical University, Hangzhou 311402, China; (K.L.); (Y.L.); (M.S.); (W.X.); (S.W.); (X.Y.)
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou 310006, China
| | - Yue Li
- College of Pharmaceutical Sciences, Hangzhou First People’s Hospital, Zhejiang Chinese Medical University, Hangzhou 311402, China; (K.L.); (Y.L.); (M.S.); (W.X.); (S.W.); (X.Y.)
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou 310006, China
| | - Minmin Shen
- College of Pharmaceutical Sciences, Hangzhou First People’s Hospital, Zhejiang Chinese Medical University, Hangzhou 311402, China; (K.L.); (Y.L.); (M.S.); (W.X.); (S.W.); (X.Y.)
- Department of Drug Clinical Trial Institution, Huzhou Central Hospital, Huzhou 313000, China
| | - Wei Xu
- College of Pharmaceutical Sciences, Hangzhou First People’s Hospital, Zhejiang Chinese Medical University, Hangzhou 311402, China; (K.L.); (Y.L.); (M.S.); (W.X.); (S.W.); (X.Y.)
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou 310006, China
| | - Shanshan Wu
- College of Pharmaceutical Sciences, Hangzhou First People’s Hospital, Zhejiang Chinese Medical University, Hangzhou 311402, China; (K.L.); (Y.L.); (M.S.); (W.X.); (S.W.); (X.Y.)
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou 310006, China
| | - Xinxin Yang
- College of Pharmaceutical Sciences, Hangzhou First People’s Hospital, Zhejiang Chinese Medical University, Hangzhou 311402, China; (K.L.); (Y.L.); (M.S.); (W.X.); (S.W.); (X.Y.)
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou 310006, China
| | - Bo Zhang
- College of Pharmaceutical Sciences, Hangzhou First People’s Hospital, Zhejiang Chinese Medical University, Hangzhou 311402, China; (K.L.); (Y.L.); (M.S.); (W.X.); (S.W.); (X.Y.)
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou 310006, China
| | - Nengming Lin
- College of Pharmaceutical Sciences, Hangzhou First People’s Hospital, Zhejiang Chinese Medical University, Hangzhou 311402, China; (K.L.); (Y.L.); (M.S.); (W.X.); (S.W.); (X.Y.)
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou 310006, China
- Westlake Laboratory of Life Sciences and Biomedicine of Zhejiang Province, Westlake University, Hangzhou 310024, China
| |
Collapse
|
33
|
Perez-Penco M, Byrdal M, Lara de la Torre L, Ballester M, Khan S, Siersbæk M, Lecoq I, Madsen CO, Kjeldsen JW, Svane IM, Hansen M, Donia M, Johansen JS, Olsen LR, Grøntved L, Chen IM, Arnes L, Holmström MO, Andersen MH. The antitumor activity of TGFβ-specific T cells is dependent on IL-6 signaling. Cell Mol Immunol 2025; 22:111-126. [PMID: 39653766 PMCID: PMC11685413 DOI: 10.1038/s41423-024-01238-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 11/10/2024] [Indexed: 01/01/2025] Open
Abstract
Although interleukin (IL)-6 is considered immunosuppressive and tumor-promoting, emerging evidence suggests that it may support antitumor immunity. While combining immune checkpoint inhibitors (ICIs) and radiotherapy in patients with pancreatic cancer (PC) has yielded promising clinical results, the addition of an anti-IL-6 receptor (IL-6R) antibody has failed to elicit clinical benefits. Notably, a robust TGFβ-specific immune response at baseline in PC patients treated solely with ICIs and radiotherapy correlated with improved survival. Recent preclinical studies demonstrated the efficacy of a TGFβ-based immune modulatory vaccine in controlling PC tumor growth, underscoring the important role of TGFβ-specific immunity in PC. Here, we explored the importance of IL-6 for TGFβ-specific immunity in PC. In a murine model of PC, coadministration of the TGFβ-based immune modulatory vaccine with an anti-IL-6R antibody rendered the vaccine ineffective. IL-6R blockade hampered the development of vaccine-induced T-cells and tumoral T-cell infiltration. Furthermore, it impaired the myeloid population, resulting in increased tumor-associated macrophage infiltration and an enhanced immunosuppressive phenotype. In PC patients, in contrast to those receiving only ICIs and radiotherapy, robust TGFβ-specific T-cell responses at baseline did not correlate with improved survival in patients receiving ICIs, radiotherapy and IL-6R blockade. Peripheral blood immunophenotyping revealed that IL-6R blockade altered the T-cell and monocytic compartments, which was consistent with the findings in the murine model. Our data suggest that the antitumor efficacy of TGFβ-specific T cells in PC depends on the presence of IL-6 within the tumor. Consequently, caution should be exercised when employing IL-6R blockade in patients receiving cancer immunotherapy.
Collapse
Affiliation(s)
- Maria Perez-Penco
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Mikkel Byrdal
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Lucia Lara de la Torre
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Marta Ballester
- Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Shawez Khan
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Majken Siersbæk
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
| | - Inés Lecoq
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
- IO Biotech ApS, Copenhagen, Denmark
| | - Cecilie Oelvang Madsen
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Julie Westerlin Kjeldsen
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
- Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Inge Marie Svane
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
- Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Morten Hansen
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Marco Donia
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Julia Sidenius Johansen
- Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lars Rønn Olsen
- Department of Health Technology, Technical University of Denmark, Lyngby, Denmark
| | - Lars Grøntved
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
| | | | - Luis Arnes
- Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Morten Orebo Holmström
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Mads Hald Andersen
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
| |
Collapse
|
34
|
Illingworth EJ, Rychlik KA, Maertens A, Sillé FCM. Sex-specific transcriptomic effects of low-dose inorganic arsenic exposure on bone marrow-derived macrophages. Toxicology 2025; 510:153988. [PMID: 39515575 PMCID: PMC12023008 DOI: 10.1016/j.tox.2024.153988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 10/19/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024]
Abstract
Both tissue-resident macrophages and monocytes recruited from the bone marrow that transform into tissue-resident cells play critical roles in mediating homeostasis as well as in the pathology of inflammatory diseases. Inorganic arsenic (iAs) is the most common drinking water contaminant worldwide and represents a major public health concern. There are numerous diseases caused by iAs exposure in which macrophages are involved, including cardiovascular disease, cancer, and increased risk of (respiratory) infectious diseases. Notably, prenatal iAs exposure is also associated with negative birth outcomes and developmental immunotoxicity (DIT) contributing to long-term adverse outcomes of these immune-related diseases. Therefore, understanding the effects of iAs exposure on macrophages, particularly during immune development or tissue injury and inflammation, can help us better grasp the full range of arsenic immunotoxicity and better design therapeutic targets for iAs-induced diseases particularly in exposed populations. In contrast to prior published studies which often only focused on the effect of iAs on mature macrophages after development, in this study, we analyzed the transcriptome of M0-, M1- and M2-polarized male and female murine bone marrow-derived macrophages (BMDMs) which were exposed to iAs during the differentiation phase, as a model to study iAs (developmental) immunotoxicity. We identified differentially expressed genes by iAs in a sex- and stimulation-dependent manner and used bioinformatics tools to predict protein-protein interactions, transcriptional regulatory networks, and associated biological processes. Overall, our data suggest that M1-stimulated, especially female-derived, BMDMs are most susceptible to iAs exposure during differentiation. Most notably, we observed significant downregulation of major proinflammatory transcription factors, like IRF8, and its downstream targets, as well as genes encoding proteins involved in pattern recognition and antigen presentation, such as TLR7, TLR8, and H2-D1, potentially providing causal insight regarding the role of (early-life) arsenic exposure in perturbing immune responses to infectious diseases. We also observed significant downregulation of genes involved in processes crucial to coordinating a proinflammatory response including leukocyte migration, differentiation, and cytokine and chemokine production and response. Finally, we discovered that 24 X-linked genes were dysregulated in iAs-exposed female stimulation groups compared to only 3 across the iAs-exposed male stimulation groups. These findings elucidate the potential mechanisms underlying the sex-differential iAs-associated immune-related disease risk.
Collapse
Affiliation(s)
- Emily J Illingworth
- Department of Environmental Health and Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - Kristal A Rychlik
- Department of Environmental Health and Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA; Public Health Program, School of Health Professions, Mayborn College of Health Sciences, University of Mary Hardin-Baylor, Belton, TX, USA
| | - Alexandra Maertens
- Department of Environmental Health and Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - Fenna C M Sillé
- Department of Environmental Health and Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
| |
Collapse
|
35
|
Jaune-Pons E, Wang X, Mousavi F, Klassen Z, El Kaoutari A, Berger K, Johnson C, Martin MB, Aggarwal S, Brar S, Khalid M, Ryan JF, Shooshtari P, Mathison AJ, Dusetti N, Urrutia R, Lomberk G, Pin CL. EZH2 deletion does not affect acinar regeneration but restricts progression to pancreatic cancer in mice. JCI Insight 2024; 10:e173746. [PMID: 39739419 PMCID: PMC11948588 DOI: 10.1172/jci.insight.173746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 12/16/2024] [Indexed: 01/02/2025] Open
Abstract
Enhancer of zeste homologue 2 (EZH2) is part of the Polycomb Repressor Complex 2, which promotes trimethylation of lysine 27 on histone 3 (H3K27me3) and gene repression. EZH2 is overexpressed in many cancers, and studies in mice attributed both prooncogenic and tumor suppressive functions to EZH2 in pancreatic ductal adenocarcinoma (PDAC). EZH2 deletion enhances de novo KRAS-driven neoplasia following pancreatic injury, while increased EZH2 expression in patients with PDAC is correlated to poor prognosis, suggesting a context-dependant effect for EZH2 in PDAC progression. In this study, we examined EZH2 in pre- and early neoplastic stages of PDAC. Using an inducible model to delete the SET domain of EZH2 in adult acinar cells (EZH2ΔSET), we showed that loss of EZH2 activity did not prevent acinar cell regeneration in the absence of oncogenic KRAS (KRASG12D) nor did it increase PanIN formation following KRASG12D activation in adult mice. Loss of EZH2 did reduce recruitment of inflammatory cells and, when combined with a more aggressive PDAC model, promoted widespread PDAC progression and remodeling of the tumor microenvironment. This study suggests that expression of EZH2 in adult acinar cells restricts PDAC initiation and progression by affecting both the tumor microenvironment and acinar cell differentiation.
Collapse
Affiliation(s)
- Emilie Jaune-Pons
- Department of Physiology and Pharmacology and
- Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
- Verspeeten Family Cancer Centre, London, Ontario, Canada
| | - Xiaoyi Wang
- Department of Physiology and Pharmacology and
- Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
- Verspeeten Family Cancer Centre, London, Ontario, Canada
| | - Fatemeh Mousavi
- Department of Physiology and Pharmacology and
- Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
- Verspeeten Family Cancer Centre, London, Ontario, Canada
| | - Zachary Klassen
- Department of Physiology and Pharmacology and
- Verspeeten Family Cancer Centre, London, Ontario, Canada
| | - Abdessamad El Kaoutari
- Centre de Recherche en Cancérologie de Marseille (CRCM), Unité 1068, Institut National de la Santé et de la Recherche Médicale, Marseille, France
| | - Kurt Berger
- Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
- Department of Pediatrics and
| | - Charis Johnson
- Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Mickenzie B. Martin
- Department of Physiology and Pharmacology and
- Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
- Verspeeten Family Cancer Centre, London, Ontario, Canada
| | | | - Sukhman Brar
- Verspeeten Family Cancer Centre, London, Ontario, Canada
| | | | - Joanna F. Ryan
- Department of Physiology and Pharmacology and
- Verspeeten Family Cancer Centre, London, Ontario, Canada
| | - Parisa Shooshtari
- Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
- Verspeeten Family Cancer Centre, London, Ontario, Canada
- Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Angela J. Mathison
- Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Department of Surgery, Division of Research, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Nelson Dusetti
- Centre de Recherche en Cancérologie de Marseille (CRCM), Unité 1068, Institut National de la Santé et de la Recherche Médicale, Marseille, France
| | - Raul Urrutia
- Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Department of Surgery, Division of Research, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Gwen Lomberk
- Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Christopher L. Pin
- Department of Physiology and Pharmacology and
- Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
- Verspeeten Family Cancer Centre, London, Ontario, Canada
- Department of Pediatrics and
| |
Collapse
|
36
|
Slusny B, Zimmer V, Nasiri E, Lutz V, Huber M, Buchholz M, Gress TM, Roth K, Bauer C. Optimized Spheroid Model of Pancreatic Cancer Demonstrates Influence of Macrophage-T Cell Interaction for Intratumoral T Cell Motility. Cancers (Basel) 2024; 17:51. [PMID: 39796680 PMCID: PMC11718817 DOI: 10.3390/cancers17010051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 12/19/2024] [Accepted: 12/20/2024] [Indexed: 01/13/2025] Open
Abstract
BACKGROUND Most spheroid models use size measurements as a primary readout parameter; some models extend analysis to T cell infiltration or perform caspase activation assays. However, to our knowledge, T cell motility analysis is not regularly included as an endpoint in imaging studies on cancer spheroids. METHODS Here, we intend to demonstrate that motility analysis of macrophages and T cells is a valuable functional endpoint for studies on molecular interventions in the tumor microenvironment. In particular, T cell migration analysis represents the final step of effector function, as T cells engage with targets cells upon cytotoxic interaction, which is represented by an arrest within the spheroid volume. Therefore, T cell arrest is a novel readout parameter of T cell effector function in spheroids. RESULTS Here, we demonstrate that incubation of macrophages with nigericin for NLRP3 activation increases T cell velocity, but results in decreased T cellular arrest. This is paralleled by reduced rejection kinetics of pancreatic cancer spheroids in the presence of antigen-dependent T cells and nigericin-treated macrophages. Our model demonstrates consistent changes in T cell motility upon coculturing of T cells and tumors cells with macrophages, including influences of molecular interventions such as NLRP3 activation. CONCLUSIONS Motility analysis using a spheroid model of pancreatic cancer is a more sophisticated alternative to in vitro cytotoxicity assays measuring spheroid size. Ultimately, an optimized spheroid model might replace at least some aspects of animal experiments investigating T cell effector function.
Collapse
Affiliation(s)
- Benedikt Slusny
- Department of Gastroenterology, Endocrinology, Infectious Diseases and Metabolism, University Hospital Marburg, 35043 Marburg, Germany; (B.S.); (E.N.); (M.B.); (T.M.G.)
| | - Vanessa Zimmer
- Department of Gastroenterology, Endocrinology, Infectious Diseases and Metabolism, University Hospital Marburg, 35043 Marburg, Germany; (B.S.); (E.N.); (M.B.); (T.M.G.)
| | - Elena Nasiri
- Department of Gastroenterology, Endocrinology, Infectious Diseases and Metabolism, University Hospital Marburg, 35043 Marburg, Germany; (B.S.); (E.N.); (M.B.); (T.M.G.)
| | - Veronika Lutz
- Institute of Systems Immunology, Center for Tumor Biology and Immunology, Philipps University Marburg, 35043 Marburg, Germany (M.H.)
| | - Magdalena Huber
- Institute of Systems Immunology, Center for Tumor Biology and Immunology, Philipps University Marburg, 35043 Marburg, Germany (M.H.)
| | - Malte Buchholz
- Department of Gastroenterology, Endocrinology, Infectious Diseases and Metabolism, University Hospital Marburg, 35043 Marburg, Germany; (B.S.); (E.N.); (M.B.); (T.M.G.)
| | - Thomas M. Gress
- Department of Gastroenterology, Endocrinology, Infectious Diseases and Metabolism, University Hospital Marburg, 35043 Marburg, Germany; (B.S.); (E.N.); (M.B.); (T.M.G.)
| | - Katrin Roth
- Core Facility Cellular Imaging, Center for Tumor Biology and Immunology, Philipps University Marburg, 35043 Marburg, Germany;
| | - Christian Bauer
- Department of Gastroenterology, Endocrinology, Infectious Diseases and Metabolism, University Hospital Marburg, 35043 Marburg, Germany; (B.S.); (E.N.); (M.B.); (T.M.G.)
- Department of Gastroenterology, DonauIsar Klinikum Deggendorf, MedizinCampus Niederbayern, 94469 Deggendorf, Germany
| |
Collapse
|
37
|
Zhao L, Wang Z, Tan Y, Ma J, Huang W, Zhang X, Jin C, Zhang T, Liu W, Yang YG. IL-17A/CEBPβ/OPN/LYVE-1 axis inhibits anti-tumor immunity by promoting tumor-associated tissue-resident macrophages. Cell Rep 2024; 43:115039. [PMID: 39643970 DOI: 10.1016/j.celrep.2024.115039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 10/18/2024] [Accepted: 11/18/2024] [Indexed: 12/09/2024] Open
Abstract
Tumor-associated macrophages (TAMs) are a critical component of the immunosuppressive tumor microenvironment, comprising monocyte-derived macrophages (MDM-TAMs) and tissue-resident macrophages (TRM-TAMs). Here, we discovered that TRM-TAMs mediate the pro-tumor effects of interleukin (IL)-17A and that IL-17A-driven tumor progression requires tumor cell production of osteopontin (OPN). Mechanistically, we identified CEBPβ as a transcription factor downstream of IL-17A in tumor cells and LYVE-1 as an OPN receptor on TRM-TAMs. IL-17A stimulates tumor cell production of OPN, and OPN/LYVE-1 signaling activates the JNK/c-Jun pathway, leading to the proliferation of immunosuppressive LYVE-1+ TRM-TAMs. Unlike its effect on LYVE-1+ TRM-TAMs, OPN interacts with α4β1 to promote the chemotaxis of LYVE-1- MDM-TAMs toward tumors. IL-17A neutralization, OPN inactivation in tumor cells, or LYVE-1 deletion in macrophages inhibited TAMs and enhanced anti-tumor immune responses and anti-PDL1 therapy. Thus, the IL-17A/CEBPβ/OPN/LYVE-1 axis offers a mechanism suppressing anti-tumor immune responses and, hence, an effective therapeutic target for cancer.
Collapse
Affiliation(s)
- Lei Zhao
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China
| | - Zonghan Wang
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China
| | - Yuying Tan
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China
| | - Jianan Ma
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China
| | - Wei Huang
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China
| | - Xiaoying Zhang
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China
| | - Chunhui Jin
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China; Department of Pathology, The First Hospital of Jilin University, Changchun, China
| | - Ting Zhang
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China
| | - Wentao Liu
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China.
| | - Yong-Guang Yang
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China; International Center of Future Science, Jilin University, Changchun, China.
| |
Collapse
|
38
|
Finan JM, Guo Y, Goodyear SM, Brody JR. Challenges and Opportunities in Targeting the Complex Pancreatic Tumor Microenvironment. JCO ONCOLOGY ADVANCES 2024; 1:e2400050. [PMID: 39735733 PMCID: PMC11670921 DOI: 10.1200/oa-24-00050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 10/16/2024] [Accepted: 11/04/2024] [Indexed: 12/31/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths with a 5-year survival rate of 13%. Surgical resection remains the only curative option as systemic therapies offer limited benefit. Poor response to chemotherapy and immunotherapy is due, in part, to the dense stroma and heterogeneous tumor microenvironment (TME). Opportunities to target the PDAC stroma may increase the effectiveness of existing or novel therapies. Current strategies targeting the stromal compartment within the PDAC TME primarily focus on degrading extracellular matrix or inhibiting stromal cell activity, angiogenesis, or hypoxic responses. In addition, extensive work has attempted to use immune targeting strategies to improve clinical outcomes. Preclinically, these strategies show promise, especially with the ability to alter the tumor ecosystem; however, when translated to the clinic, most of these trials have failed to improve overall patient outcomes. In this review, we catalog the heterogenous elements of the TME and discuss the potential of combination therapies that target the heterogeneity observed in the TME between patients and how molecular stratification could improve responses to targeted and combination therapies.
Collapse
Affiliation(s)
- Jennifer M. Finan
- Department of Surgery, Oregon Health & Science University, Portland, OR
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR
| | - Yifei Guo
- Department of Surgery, Oregon Health & Science University, Portland, OR
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR
| | - Shaun M. Goodyear
- Division of Hematology and Oncology, School of Medicine, Oregon Health & Science University, Portland, OR
| | - Jonathan R. Brody
- Department of Surgery, Oregon Health & Science University, Portland, OR
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR
| |
Collapse
|
39
|
Topham B, Hock B, Phillips E, Wiggins G, Currie M. The Role of Innate Priming in Modifying Tumor-associated Macrophage Phenotype. FRONT BIOSCI-LANDMRK 2024; 29:418. [PMID: 39735978 DOI: 10.31083/j.fbl2912418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 08/07/2024] [Accepted: 08/19/2024] [Indexed: 12/31/2024]
Abstract
Tumor-associated macrophages (TAMs) are innate immune cells that exert far reaching influence over the tumor microenvironment (TME). Depending on cues within the local environment, TAMs may promote tumor angiogenesis, cancer cell invasion and immunosuppression, or, alternatively, inhibit tumor progression via neoantigen presentation, tumoricidal reactive oxygen species generation and pro-inflammatory cytokine secretion. Therefore, TAMs have a pivotal role in determining tumor progression and response to therapy. TAM phenotypes are driven by cytokines and physical cues produced by tumor cells, adipocytes, fibroblasts, pericytes, immune cells, and other cells within the TME. Research has shown that TAMs can be primed by environmental stimuli, adding another layer of complexity to the environmental context that determines TAM phenotype. Innate priming is a functional consequence of metabolic and epigenetic reprogramming of innate cells by a primary stimulant, resulting in altered cellular response to future secondary stimulation. Innate priming offers a novel target for development of cancer immunotherapy and improved prognosis of disease, but also raises the risk of exacerbating existing inflammatory pathologies. This review will discuss the mechanisms underlying innate priming including metabolic and epigenetic modification, its relevance to TAMs and tumor progression, and possible clinical implications for cancer treatment.
Collapse
Affiliation(s)
- Ben Topham
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, 8011 Christchurch, Aotearoa New Zealand
| | - Barry Hock
- Haematology Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, 8011 Christchurch, Aotearoa New Zealand
| | - Elisabeth Phillips
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, 8011 Christchurch, Aotearoa New Zealand
| | - George Wiggins
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, 8011 Christchurch, Aotearoa New Zealand
| | - Margaret Currie
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, 8011 Christchurch, Aotearoa New Zealand
| |
Collapse
|
40
|
Kzhyshkowska J, Shen J, Larionova I. Targeting of TAMs: can we be more clever than cancer cells? Cell Mol Immunol 2024; 21:1376-1409. [PMID: 39516356 PMCID: PMC11607358 DOI: 10.1038/s41423-024-01232-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 10/12/2024] [Indexed: 11/16/2024] Open
Abstract
АBSTRACT: With increasing incidence and geography, cancer is one of the leading causes of death, reduced quality of life and disability worldwide. Principal progress in the development of new anticancer therapies, in improving the efficiency of immunotherapeutic tools, and in the personification of conventional therapies needs to consider cancer-specific and patient-specific programming of innate immunity. Intratumoral TAMs and their precursors, resident macrophages and monocytes, are principal regulators of tumor progression and therapy resistance. Our review summarizes the accumulated evidence for the subpopulations of TAMs and their increasing number of biomarkers, indicating their predictive value for the clinical parameters of carcinogenesis and therapy resistance, with a focus on solid cancers of non-infectious etiology. We present the state-of-the-art knowledge about the tumor-supporting functions of TAMs at all stages of tumor progression and highlight biomarkers, recently identified by single-cell and spatial analytical methods, that discriminate between tumor-promoting and tumor-inhibiting TAMs, where both subtypes express a combination of prototype M1 and M2 genes. Our review focuses on novel mechanisms involved in the crosstalk among epigenetic, signaling, transcriptional and metabolic pathways in TAMs. Particular attention has been given to the recently identified link between cancer cell metabolism and the epigenetic programming of TAMs by histone lactylation, which can be responsible for the unlimited protumoral programming of TAMs. Finally, we explain how TAMs interfere with currently used anticancer therapeutics and summarize the most advanced data from clinical trials, which we divide into four categories: inhibition of TAM survival and differentiation, inhibition of monocyte/TAM recruitment into tumors, functional reprogramming of TAMs, and genetic enhancement of macrophages.
Collapse
Affiliation(s)
- Julia Kzhyshkowska
- Department of Innate Immunity and Tolerance, Institute of Transfusion Medicine and Immunology, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer, 1-3, 68167, Mannheim, Germany.
- German Red Cross Blood Service Baden-Württemberg - Hessen, Friedrich-Ebert Str. 107, 68167, Mannheim, Germany.
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, 634050, Lenina av.36, Tomsk, Russia.
- Bashkir State Medical University of the Ministry of Health of Russia, 450000, Teatralnaya Street, 2a, Ufa, Russia.
| | - Jiaxin Shen
- Department of Innate Immunity and Tolerance, Institute of Transfusion Medicine and Immunology, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer, 1-3, 68167, Mannheim, Germany
- Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Irina Larionova
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, 634050, Lenina av.36, Tomsk, Russia
- Bashkir State Medical University of the Ministry of Health of Russia, 450000, Teatralnaya Street, 2a, Ufa, Russia
- Laboratory of Molecular Therapy of Cancer, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009, Kooperativnyi st, Tomsk, Russia
| |
Collapse
|
41
|
Tang Y, Shi T, Lin S, Fang T. Current status of research on the mechanisms of tumor-associated macrophages in esophageal cancer progression. Front Oncol 2024; 14:1450603. [PMID: 39678502 PMCID: PMC11638059 DOI: 10.3389/fonc.2024.1450603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 09/27/2024] [Indexed: 12/17/2024] Open
Abstract
Esophageal carcinoma (EC) is one of the most common tumors in China and seriously affects patient survival and quality of life. In recent years, increasing studies have shown that the tumor microenvironment is crucial in promoting tumor progression and metastasis. Tumor-associated macrophages (TAM) are key components of the tumor immune microenvironment and promote both tumor growth and antitumor immunity. Much evidence suggests that TAMs are closely associated with esophageal tumors. However, understanding of the clinical value and mechanism of action of TAM in esophageal cancer remains limited. Therefore, we reviewed the status of research on the role and mechanism of action of TAM in EC progression and summarized its potential clinical application value to provide a theoretical basis for the clinical treatment of EC.
Collapse
Affiliation(s)
- Yuchao Tang
- Department of Gastroenterology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Tingting Shi
- Department of Gastroenterology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Shu Lin
- Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
- Group of Neuroendocrinology, Garvan Institute of Medical Research, Sydney, Australia
| | - Taiyong Fang
- Department of Gastroenterology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| |
Collapse
|
42
|
Arleo A, Montagner A, Giovannini C, Suzzi F, Piscaglia F, Gramantieri L. Multifaceted Aspects of Dysfunctional Myelopoiesis in Cancer and Therapeutic Perspectives with Focus on HCC. Biomolecules 2024; 14:1496. [PMID: 39766202 PMCID: PMC11673139 DOI: 10.3390/biom14121496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 11/14/2024] [Accepted: 11/20/2024] [Indexed: 01/04/2025] Open
Abstract
Myelopoiesis provides for the formation and continued renewal of cells belonging primarily to the innate immune system. It is a highly plastic process that secures the response to external and internal stimuli to face acute and changing needs. Infections and chronic diseases including cancer can modulate it by producing several factors, impacting proliferation and differentiation programs. While the lymphocytic compartment has attracted major attention due to the role of adaptive immunity in anticancer immune response, in recent years, research has found convincing evidence that confirms the importance of innate immunity and the key function played by emergency myelopoiesis. Due to cancer's ability to manipulate myelopoiesis to its own advantage, the purpose of this review is to outline myelopoiesis processes within the tumor microenvironment and suggest possible therapeutic lines of research to restore the physiological functioning of the host's immune system, with a special outlook on hepatocellular carcinoma (HCC).
Collapse
Affiliation(s)
- Andrea Arleo
- Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy; (A.M.); (C.G.); (F.S.); (F.P.)
| | - Annapaola Montagner
- Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy; (A.M.); (C.G.); (F.S.); (F.P.)
| | - Catia Giovannini
- Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy; (A.M.); (C.G.); (F.S.); (F.P.)
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Fabrizia Suzzi
- Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy; (A.M.); (C.G.); (F.S.); (F.P.)
| | - Fabio Piscaglia
- Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy; (A.M.); (C.G.); (F.S.); (F.P.)
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Laura Gramantieri
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| |
Collapse
|
43
|
Murrey MW, Ng IT, Pixley FJ. The role of macrophage migratory behavior in development, homeostasis and tumor invasion. Front Immunol 2024; 15:1480084. [PMID: 39588367 PMCID: PMC11586339 DOI: 10.3389/fimmu.2024.1480084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 10/23/2024] [Indexed: 11/27/2024] Open
Abstract
Tumor-associated macrophages (TAMs) recapitulate the developmental and homeostatic behaviors of tissue resident macrophages (TRMs) to promote tumor growth, invasion and metastasis. TRMs arise in the embryo and colonize developing tissues, initially to guide tissue morphogenesis and then to form complex networks in adult tissues to constantly search for threats to homeostasis. The macrophage growth factor, colony-stimulating factor-1 (CSF-1), which is essential for TRM survival and differentiation, is also responsible for the development of the unique motility machinery of mature macrophages that underpins their ramified morphologies, migratory capacity and ability to degrade matrix. Two CSF-1-activated kinases, hematopoietic cell kinase and the p110δ catalytic isoform of phosphatidylinositol 3-kinase, regulate this machinery and selective inhibitors of these proteins completely block macrophage invasion. Considering tumors co-opt the invasive capacity of TAMs to promote their own invasion, these proteins are attractive targets for drug development to inhibit tumor progression to invasion and metastasis.
Collapse
Affiliation(s)
| | | | - Fiona J. Pixley
- Macrophage Biology and Cancer Laboratory, School of Biomedical Sciences, The University of Western Australia, Crawley, WA, Australia
| |
Collapse
|
44
|
Chi J, Gao Q, Liu D. Tissue-Resident Macrophages in Cancer: Friend or Foe? Cancer Med 2024; 13:e70387. [PMID: 39494816 PMCID: PMC11533131 DOI: 10.1002/cam4.70387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 10/15/2024] [Accepted: 10/20/2024] [Indexed: 11/05/2024] Open
Abstract
INTRODUCTION Macrophages are essential in maintaining homeostasis, combating infections, and influencing the process of various diseases, including cancer. Macrophages originate from diverse lineages: Notably, tissue-resident macrophages (TRMs) differ from hematopoietic stem cells and circulating monocyte-derived macrophages based on genetics, development, and function. Therefore, understanding the recruited and TRM populations is crucial for investigating disease processes. METHODS By searching literature databses, we summarized recent relevant studies. Research has shown that tumor-associated macrophages (TAMs) of distinct origins accumulate in tumor microenvironment (TME), with TRM-derived TAMs closely resembling gene signatures of normal TRMs. RESULTS Recent studies have revealed that TRMs play a crucial role in cancer progression. However, organ-specific effects complicate TRM investigations. Nonetheless, the precise involvement of TRMs in tumors is unclear. This review explores the multifaceted roles of TRMs in cancer, presenting insights into their origins, proliferation, the latest research methodologies, their impact across various tumor sites, their potential and strategies as therapeutic targets, interactions with other cells within the TME, and the internal heterogeneity of TRMs. CONCLUSIONS We believe that a comprehensive understanding of the multifaceted roles of TRMs will pave the way for targeted TRM therapies in the treatment of cancer.
Collapse
Affiliation(s)
- Jianhua Chi
- Department of Obstetrics and GynecologyNational Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and MetastasisTongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Qinglei Gao
- Department of Obstetrics and GynecologyNational Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and MetastasisTongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Dan Liu
- Department of Obstetrics and GynecologyNational Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and MetastasisTongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| |
Collapse
|
45
|
Fan H, Liang X, Tang Y. Neuroscience in peripheral cancers: tumors hijacking nerves and neuroimmune crosstalk. MedComm (Beijing) 2024; 5:e784. [PMID: 39492832 PMCID: PMC11527832 DOI: 10.1002/mco2.784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/25/2024] [Accepted: 09/25/2024] [Indexed: 11/05/2024] Open
Abstract
Cancer neuroscience is an emerging field that investigates the intricate relationship between the nervous system and cancer, gaining increasing recognition for its importance. The central nervous system governs the development of the nervous system and directly affects brain tumors, and the peripheral nervous system (PNS) shapes the tumor microenvironment (TME) of peripheral tumors. Both systems are crucial in cancer initiation and progression, with recent studies revealing a more intricate role of the PNS within the TME. Tumors not only invade nerves but also persuade them through remodeling to further promote malignancy, creating a bidirectional interaction between nerves and cancers. Notably, immune cells also contribute to this communication, forming a triangular relationship that influences protumor inflammation and the effectiveness of immunotherapy. This review delves into the intricate mechanisms connecting the PNS and tumors, focusing on how various immune cell types influence nerve‒tumor interactions, emphasizing the clinical relevance of nerve‒tumor and nerve‒immune dynamics. By deepening our understanding of the interplay between nerves, cancer, and immune cells, this review has the potential to reshape tumor biology insights, inspire innovative therapies, and improve clinical outcomes for cancer patients.
Collapse
Affiliation(s)
- Hua‐Yang Fan
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial SurgeryWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Xin‐Hua Liang
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial SurgeryWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Ya‐Ling Tang
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Oral PathologyWest China Hospital of StomatologySichuan UniversityChengduChina
| |
Collapse
|
46
|
Kerneur C, Foucher E, Guillén Casas J, Colazet M, Le KS, Fullana M, Bergot E, Audemard C, Drapeau M, Louche P, Gorvel L, Rouvière MS, Boucherit N, Audebert S, Magrini E, Carnevale S, de Gassart A, Madakamutil L, Mantovani A, Garlanda C, Agaugué S, Cano CE, Olive D. BTN2A1 targeting reprograms M2-like macrophages and TAMs via SYK and MAPK signaling. Cell Rep 2024; 43:114773. [PMID: 39325623 DOI: 10.1016/j.celrep.2024.114773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 06/05/2024] [Accepted: 09/03/2024] [Indexed: 09/28/2024] Open
Abstract
Tumor-associated macrophages (TAMs), often adopting an immunosuppressive M2-like phenotype, correlate with unfavorable cancer outcomes. Our investigation unveiled elevated expression of the butyrophilin (BTN)2A1 in M2-like TAMs across diverse cancer types. We developed anti-BTN2A1 monoclonal antibodies (mAbs), and notably, one clone demonstrated a robust inhibitory effect on M2-like macrophage differentiation, inducing a shift toward an M1-like phenotype both in vitro and ex vivo in TAMs from patients with cancer. Macrophages treated with this anti-BTN2A1 mAb exhibited enhanced support for T cell proliferation and interferon-gamma (IFNγ) secretion. Mechanistically, BTN2A1 engagement induced spleen tyrosine kinase (SYK) recruitment, leading to sequential SYK and extracellular signal-regulated kinase (ERK) phosphorylation. Inhibition of SYK or ERK phosphorylation abolished M2 reprogramming upon BTN2A1 engagement. Our findings, derived from an analysis of macrophages from healthy donors and human tumors, underscore the pivotal role of BTN2A1 in immunosuppressive macrophage differentiation and function, offering potential applications in cancer immunotherapy.
Collapse
Affiliation(s)
- Clément Kerneur
- ImCheck Therapeutics, R&D Department, 13009 Marseille, France; Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, 13009 Marseille, France
| | - Etienne Foucher
- ImCheck Therapeutics, R&D Department, 13009 Marseille, France
| | | | - Magali Colazet
- ImCheck Therapeutics, R&D Department, 13009 Marseille, France
| | - Kieu-Suong Le
- ImCheck Therapeutics, R&D Department, 13009 Marseille, France
| | - Marie Fullana
- ImCheck Therapeutics, R&D Department, 13009 Marseille, France
| | - Elise Bergot
- ImCheck Therapeutics, R&D Department, 13009 Marseille, France
| | | | - Marion Drapeau
- ImCheck Therapeutics, R&D Department, 13009 Marseille, France
| | - Pauline Louche
- ImCheck Therapeutics, R&D Department, 13009 Marseille, France
| | - Laurent Gorvel
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, 13009 Marseille, France
| | - Marie-Sarah Rouvière
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, 13009 Marseille, France
| | - Nicolas Boucherit
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, 13009 Marseille, France
| | - Stéphane Audebert
- Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille Protéomique, Marseille, France
| | - Elena Magrini
- IRCCS, Humanitas Research Hospital, 20089 Rozzano, Italy
| | | | - Aude de Gassart
- ImCheck Therapeutics, R&D Department, 13009 Marseille, France
| | | | - Alberto Mantovani
- IRCCS, Humanitas Research Hospital, 20089 Rozzano, Italy; Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Milan, Italy; William Harvey Research Institute, Queen Mary University, London EC1M 6BQ, UK
| | | | - Sophie Agaugué
- ImCheck Therapeutics, R&D Department, 13009 Marseille, France
| | - Carla E Cano
- ImCheck Therapeutics, R&D Department, 13009 Marseille, France.
| | - Daniel Olive
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, 13009 Marseille, France.
| |
Collapse
|
47
|
Ghebremedhin A, Athavale D, Zhang Y, Yao X, Balch C, Song S. Tumor-Associated Macrophages as Major Immunosuppressive Cells in the Tumor Microenvironment. Cancers (Basel) 2024; 16:3410. [PMID: 39410029 PMCID: PMC11475569 DOI: 10.3390/cancers16193410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 10/02/2024] [Accepted: 10/05/2024] [Indexed: 10/20/2024] Open
Abstract
Within the tumor microenvironment, myeloid cells constitute a dynamic immune population characterized by a heterogeneous phenotype and diverse functional activities. In this review, we consider recent literature shedding light on the increasingly complex biology of M2-like immunosuppressive tumor-associated macrophages (TAMs), including their contribution to tumor cell invasion and metastasis, stromal remodeling (fibrosis and matrix degradation), and immune suppressive functions, in the tumor microenvironment (TME). This review also delves into the intricate signaling mechanisms underlying the polarization of diverse macrophage phenotypes, and their plasticity. We also review the development of promising therapeutic approaches to target these populations in cancers. The expanding knowledge of distinct subsets of immunosuppressive TAMs, and their contributions to tumorigenesis and metastasis, has sparked significant interest among researchers regarding the therapeutic potential of TAM depletion or phenotypic modulation.
Collapse
Affiliation(s)
| | - Dipti Athavale
- Coriell Institute for Medical Research, 403 Haddon Ave., Camden, NJ 08103, USA
| | - Yanting Zhang
- Coriell Institute for Medical Research, 403 Haddon Ave., Camden, NJ 08103, USA
- Department Biomedical Sciences, Cooper Medical School of Rowan University, 401 Broadway, Camden, NJ 08103, USA
| | - Xiaodan Yao
- Coriell Institute for Medical Research, 403 Haddon Ave., Camden, NJ 08103, USA
| | - Curt Balch
- Coriell Institute for Medical Research, 403 Haddon Ave., Camden, NJ 08103, USA
- Department Biomedical Sciences, Cooper Medical School of Rowan University, 401 Broadway, Camden, NJ 08103, USA
| | - Shumei Song
- Coriell Institute for Medical Research, 403 Haddon Ave., Camden, NJ 08103, USA
- Department Biomedical Sciences, Cooper Medical School of Rowan University, 401 Broadway, Camden, NJ 08103, USA
- MD Anderson Cancer Center at Cooper, Cooper University Hospital, 2 Cooper Plaza, Camden, NJ 08103, USA
- Departments of Surgery, Cooper University Hospital, 1 Cooper Plaza, Camden, NJ 08103, USA
| |
Collapse
|
48
|
Yang J, Xu T, Wang H, Wang L, Cheng Y. Mechanisms of Berberine in anti-pancreatic ductal adenocarcinoma revealed by integrated multi-omics profiling. Sci Rep 2024; 14:22929. [PMID: 39358545 PMCID: PMC11446930 DOI: 10.1038/s41598-024-74943-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 09/30/2024] [Indexed: 10/04/2024] Open
Abstract
This study integrates pharmacology databases with bulk RNA-seq and scRNA-seq to reveal the latent anti-PDAC capacities of BBR. Target genes of BBR were sifted through TargetNet, CTD, SwissTargetPrediction, and Binding Database. Based on the GSE183795 dataset, DEG analysis, GSEA, and WGCNA were sequentially run to build a disease network. Through sub-network filtration acquired PDAC-related hub genes. A PPI network was established using the shared genes. Degree algorithm from cytoHubba screened the key cluster in the network. Analysis of differential mRNA expression and ROC curves gauged the diagnostic performance of clustered genes. CYBERSORT uncovered the potential role of the key cluster on PDAC immunomodulation. ScRNA-seq analysis evaluated the distribution and expression profile of the key cluster at the single-cell level, assessing enrichment within annotated cell subpopulations to delineate the target distribution of BBR in PDAC. We identified 425 drug target genes and 771 disease target genes, using 57 intersecting genes to construct the PPI network. CytoHubba anchored the top 10 highest contributing genes to be the key cluster. mRNA expression levels and ROC curves confirmed that these genes showed good robustness for PDAC. CYBERSORT revealed that the key cluster influenced immune pathways predominantly associated with Macrophages M0, CD8 T cells, and naïve B cells. ScRNA-seq analysis clarified that BBR mainly acted on epithelial cells and macrophages in PDAC tissues. BBR potentially targets CDK1, CCNB1, CTNNB1, CDK2, TOP2A, MCM2, RUNX2, MYC, PLK1, and AURKA to exert therapeutic effects on PDAC. The mechanisms of action appear to significantly involve macrophage polarization-related immunological responses.
Collapse
Affiliation(s)
- Jia Yang
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tingting Xu
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hongwei Wang
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lei Wang
- Shanghai Putuo District People's Hospital, Shanghai, China
| | - Yanmei Cheng
- Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| |
Collapse
|
49
|
Huang D, Jiao X, Huang S, Liu J, Si H, Qi D, Pei X, Lu D, Wang Y, Li Z. Analysis of the heterogeneity and complexity of murine extraorbital lacrimal gland via single-cell RNA sequencing. Ocul Surf 2024; 34:60-95. [PMID: 38945476 DOI: 10.1016/j.jtos.2024.06.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 06/22/2024] [Accepted: 06/26/2024] [Indexed: 07/02/2024]
Abstract
PURPOSE The lacrimal gland is essential for maintaining ocular surface health and avoiding external damage by secreting an aqueous layer of the tear film. However, a healthy lacrimal gland's inventory of cell types and heterogeneity remains understudied. METHODS Here, 10X Genome-based single-cell RNA sequencing was used to generate an unbiased classification of cellular diversity in the extraorbital lacrimal gland (ELG) of C57BL/6J mice. From 43,850 high-quality cells, we produced an atlas of cell heterogeneity and defined cell types using classic marker genes. The possible functions of these cells were analyzed through bioinformatics analysis. Additionally, the CellChat was employed for a preliminary analysis of the cell-cell communication network in the ELG. RESULTS Over 37 subclasses of cells were identified, including seven types of glandular epithelial cells, three types of fibroblasts, ten types of myeloid-derived immune cells, at least eleven types of lymphoid-derived immune cells, and five types of vascular-associated cell subsets. The cell-cell communication network analysis revealed that fibroblasts and immune cells play a pivotal role in the dense intercellular communication network within the mouse ELG. CONCLUSIONS This study provides a comprehensive transcriptome atlas and related database of the mouse ELG.
Collapse
Affiliation(s)
- Duliurui Huang
- Department of Ophthalmology, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Xinwei Jiao
- Henan Eye Institute, Henan Eye Hospital and Henan Key Laboratory of Ophthalmology and Visual Science, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, 450000, China
| | - Shenzhen Huang
- Henan Eye Institute, Henan Eye Hospital and Henan Key Laboratory of Ophthalmology and Visual Science, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, 450000, China
| | - Jiangman Liu
- Department of Ophthalmology, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Hongli Si
- Department of Ophthalmology, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Di Qi
- Henan Eye Institute, Henan Eye Hospital and Henan Key Laboratory of Ophthalmology and Visual Science, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, 450000, China
| | - Xiaoting Pei
- Henan Eye Institute, Henan Eye Hospital and Henan Key Laboratory of Ophthalmology and Visual Science, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, 450000, China
| | - Dingli Lu
- Henan Eye Institute, Henan Eye Hospital and Henan Key Laboratory of Ophthalmology and Visual Science, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, 450000, China
| | - Yimian Wang
- Division of Medicine, Faculty of Medical Sciences, University College London, Gower Street, London, WC1E 6BT, UK
| | - Zhijie Li
- Department of Ophthalmology, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan, China; Henan Eye Institute, Henan Eye Hospital and Henan Key Laboratory of Ophthalmology and Visual Science, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, 450000, China.
| |
Collapse
|
50
|
Li X, Hou W, Xiao C, Yang H, Zhao C, Cao D. Panoramic tumor microenvironment in pancreatic ductal adenocarcinoma. Cell Oncol (Dordr) 2024; 47:1561-1578. [PMID: 39008192 DOI: 10.1007/s13402-024-00970-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/28/2024] [Indexed: 07/16/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is notorious for its resistance to various treatment modalities. The genetic heterogeneity of PDAC, coupled with the presence of a desmoplastic stroma within the tumor microenvironment (TME), contributes to an unfavorable prognosis. The mechanisms and consequences of interactions among different cell types, along with spatial variations influencing cellular function, potentially play a role in the pathogenesis of PDAC. Understanding the diverse compositions of the TME and elucidating the functions of microscopic neighborhoods may contribute to understanding the immune microenvironment status in pancreatic cancer. As we delve into the spatial biology of the microscopic neighborhoods within the TME, aiding in deciphering the factors that orchestrate this intricate ecosystem. This overview delineates the fundamental constituents and the structural arrangement of the PDAC microenvironment, highlighting their impact on cancer cell biology.
Collapse
Affiliation(s)
- Xiaoying Li
- Department of Abdominal Oncology, Division of Abdominal Tumor Multimodality Treatment, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610017, People's Republic of China
| | - Wanting Hou
- Department of Abdominal Oncology, Division of Abdominal Tumor Multimodality Treatment, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610017, People's Republic of China
| | - Chaoxin Xiao
- State Key Laboratory of Biotherapy and Cancer Center, West China HospitaL, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, Sichuan, 610017, People's Republic of China
| | - Heqi Yang
- Department of Abdominal Oncology, Division of Abdominal Tumor Multimodality Treatment, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610017, People's Republic of China
| | - Chengjian Zhao
- State Key Laboratory of Biotherapy and Cancer Center, West China HospitaL, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, Sichuan, 610017, People's Republic of China
| | - Dan Cao
- Department of Abdominal Oncology, Division of Abdominal Tumor Multimodality Treatment, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610017, People's Republic of China.
| |
Collapse
|