Targeting Prolyl 3-hydroxylase 1 inhibits pancreatic cancer progression and macrophage immunity

Sep 23, 2026

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Pancreatic ductal adenocarcinoma remains difficult to treat, with limited therapeutic options and poor prognosis. This study identifies Prolyl 3-hydroxylase 1 as a key regulator of PDAC progression and macrophage-related immunity using transcriptome sequencing, proteomics, and engineered mouse models. Mechanistically, the effect involves Polo-like kinase 1 and PLK1-mediated β-catenin signaling. Restoring P3H1 or PLK1 reverses β-catenin defects, promotes tumor proliferation changes, and increases macrophage infiltration. Pharmacological PLK1 inhibition enhances chemotherapy response in mice, reducing tumor burden and suggesting a promising therapeutic strategy.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages22

Reading Time55 min

AccessFree to download

Abstract

Background

Mechanistic findings

Therapeutic implications

Article [https://doi.org/10.1038/s41467-026-70452-w](https://doi.org/10.1038/s41467-026-70452-w) Targeting Prolyl 3-hydroxylase 1 inhibits pancreatic cancer progression and macrophage immunity Received: 15 April 2025 | Accepted: 24 February 2026 | | --- | | | | Check for updates | Panzhu Bai1,5, Chengmin Liu1,5, Changying Fu2,5, Renwei Cai 1, Yanyan Ding1, Meiling Quan1, Yuhao Ye1, Ziyang Zhang1, Yuan Li2, Yanfen Xu2, Siqi Guo1, Binbin Li1, Guizhen Li1, Wudi Yu1, Dalu Wang1, Ming Jiang3, Yi Deng1, Sicong He1, Chuanyue Wu 4, Ruijun Tian 2 & Ying Sun 1 Pancreatic ductal adenocarcinoma remains one of the most formidable challenges in oncology, with limited treatment options and a poor prognosis. Understanding the key pathways affecting cancer progression is crucial for the development of therapeutic strategies. Here, we reveal a pivotal role of Prolyl 3-hydroxylase 1 in pancreatic ductal adenocarcinoma using transcriptome sequencing, proteomic analyses and engineered mouse model. Mechanistically, our ﬁndings indicate that this effect is, at least in part, through the regulation of Polo-like kinase 1 and Polo-like kinase 1-mediated β-catenin signaling. Restoration of either Prolyl 3-hydroxylase 1 or Polo-like kinase 1 expression in Prolyl 3-hydroxylase 1-deﬁcient cells reverses the defects of β -catenin signaling, facilitates tumor cell proliferation and elicits macrophage inﬁltration. In addition, pharmacological inhibition of Polo-like kinase 1 strongly increases the therapeutic efﬁcacy of chemotherapeutic response against pancreatic ductal adenocarcinoma, alleviating tumor burden in mice. Our ﬁndings suggest a promising therapeutic strategy for treating pancreatic ductal adenocarcinoma. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide with over 467,005 death cases in 20221. More concerningly, it is estimated that PDAC will surpass colorectal cancer by 2040 as the second leading cause of cancer-related death2,3. The overall 5-year survival rate for pancreatic cancer is approximately 10%, primarily due to the absence of reliable biomarkers for early detection, the lack of effective late-stage treatments and widespread resistance to chemotherapy4,5. Despite revolutionized advances in immunotherapy and targeted treatments improving outcomes in various cancers, these approaches have achieved limited success in PDAC6. Gemcitabinebased chemotherapy has been the primary chemotherapeutic treatment for pancreatic cancer patients since 1997, and current clinical guidelines still recommend either gemcitabine alone or in combination therapies7,8. Unfortunately, combination chemotherapy generally results in only short-term, partial remission in newly diagnosed PDAC patients9. Given these limitations, there is an urgent need to identify novel therapeutic targets and to develop more effective and durable treatment strategies for PDAC. 1Department of Systems Biology, School of Life Sciences, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen, China. 2Shenzhen Key Laboratory of Functional Proteomics, Department of Chemistry and Research Center for Chemical Biology and Omics Analysis, College of Science, Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen, China. 3Center for Genetic Medicine, the Fourth Afﬁliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. 4Department of Pathology, School of Medicine and University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA. 5These authors contributed equally: Panzhu Bai, Chengmin Liu, Changying Fu. e-mail: [tianrj@sustech.edu.cn](tianrj@sustech.edu.cn); [suny@sustech.edu.cn](suny@sustech.edu.cn) PDAC has a unique tumor immune microenvironment (TIME) with numerous immunosuppressive factors10. These factors include i

FAQs

What therapeutic strategy is suggested by the inhibition experiments?

Pharmacological inhibition of Polo-like kinase 1 strongly increases the efficacy of chemotherapeutic response against pancreatic ductal adenocarcinoma in mice. This alleviates tumor burden and supports combining PLK1 inhibition with chemotherapy as a potential strategy.

Sep 23, 2026

Uploaded by Angel