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Gastrointestinal cancers are highly aggressive malignancies with significant mortality rates. Recent research emphasizes the critical role of the tumor microenvironment (TME) in these cancers, which includes cancer-associated fibroblasts (CAFs), a key component of the TME that have diverse origins, including fibroblasts, mesenchymal stem cells, and endothelial cells. Several markers, such as and , have been identified to label CAFs, and some specific markers may serve as potential therapeutic targets. In this review article, we summarize the literature on the multifaceted role of CAFs in tumor progression, including their effects on angiogenesis, immune suppression, invasion, and metastasis. In addition, we highlight the use of single-cell transcriptomics to understand CAF heterogeneity and their interactions within the TME. Moreover, we discuss the dynamic interplay between CAFs and the immune system, which contributes to immunosuppression in the TME, and the potential for CAF-targeted therapies and combination approaches with immunotherapy to improve cancer treatment outcomes.
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http://dx.doi.org/10.3390/ijms242216505 | DOI Listing |
J Immunother Cancer
September 2025
Pharmaceutical Sciences, Washington State University, Spokane, Washington, USA
Prostate cancer (PC) is notoriously known for exhibiting an immunologically cold phenotype in the tumor immune microenvironment (TIME), leading to the need for interventions to enhance immunotherapy efficacy. Recent findings by Zhao in the identified stromal monoamine oxidase A (MAOA), a key enzyme that degrades monoamine neurotransmitters and plays a role in the neuroendocrine system, as a critical regulator of the immune response to PC. Altering MAOA levels in myofibroblastic cancer-associated fibroblasts, either genetically or pharmacologically, can reprogram PC's TIME to modulate CD8 T cell-mediated cytotoxicity through the WNT5A-Ca²-NFATC1 signaling axis, highlighting the stromal influences on CD8 T cell cytotoxic activity within the TIME.
View Article and Find Full Text PDFBiochim Biophys Acta Rev Cancer
September 2025
Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350001, China; Fujian Abdominal Surgery Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350001, China; National Regional Medical Cente
Pancreatic ductal adenocarcinoma (PDAC) exhibits persistent resistance to immunotherapy, with a 5-year survival rate around 10 %. The CD39-CD73-adenosine axis emerges as a critical mediator of immune evasion in PDAC, generating pathologically elevated adenosine concentrations that systematically suppress anti-tumor immunity. This purinergic pathway operates through sequential ATP hydrolysis by CD39 and CD73 ectonucleotidases, producing adenosine that engages four G-protein-coupled receptors (A1, A2A, A2B, A3) to orchestrate comprehensive immunosuppression.
View Article and Find Full Text PDFFunct Integr Genomics
September 2025
Department of Plastic Surgery, the First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China.
Keloid scarring and Metabolic Syndrome (MS) are distinct conditions marked by chronic inflammation and tissue dysregulation, suggesting shared pathogenic mechanisms. Identifying common regulatory genes could unveil novel therapeutic targets. Methods.
View Article and Find Full Text PDFVirchows Arch
September 2025
Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Lung adenocarcinoma (LUAD) associated with usual interstitial pneumonia (UIP) harbours distinct features compared to lung adenocarcinoma without UIP. Therefore, we aimed to characterise the tumour microenvironment of LUAD with UIP by focusing on cancer-associated fibroblasts (CAFs) and stromal composition. Immunohistochemistry was performed on 32 LUAD samples (16 each with and without UIP) to evaluate CAF marker expression and lymphocyte infiltration.
View Article and Find Full Text PDFInt J Pharm
September 2025
CINBIO, Immunology Group, Universidade de Vigo 36310 Vigo, Spain; Instituto de Investigación Sanitaria Galicia Sur (IIS Galicia Sur), SERGAS-UVIGO, 36312 Vigo, Spain. Electronic address:
Pancreatic ductal adenocarcinoma (PDAC) remains a highly aggressive malignancy with poor therapeutic outcomes due to its desmoplastic tumor microenvironment (TME), hindering drug and activated immune cell penetration. Cancer-associated fibroblasts (CAFs) are central in supporting tumor growth and forming a protective stroma. We propose a novel dual-therapy targeting the Hippo pathway and histone deacetylation, both involved in tumor progression, resistance, and stromal interactions, to overcome PDAC therapeutic resistance.
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