A Potent Oral Sialylation Inhibitor Augments the Immunotherapy in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) remains refractory to current immune checkpoint blockade (ICB) therapies, necessitating innovative therapeutic strategies. Emerging evidence implicates aberrant sialoglycan upregulation as a key mediator of immune evasion in PDAC. Herein, we report Y-320, a highly potent oral sialylation inhibitor discovered through high-throughput screening. Y-320 suppresses α-2,3/2,6-sialylation in PDAC cells (IC<sub>50</sub> ≈ 200 nM) with >300-fold higher activity than the known pan-inhibitor P-3F<sub>ax</sub>-Neu5Ac. Structural analyses reveal competitive occupation of multiple sialyltransferases' substrate-binding pockets as Y-320's action mechanism. <i>In vivo</i>, Y-320 significantly inhibits tumor growth and remodels the tumor immune microenvironment. Mechanistic studies establish that the therapeutic efficacy of Y-320 depends on the coordinated engagement between CD8<sup>+</sup> T cell and macrophage. Importantly, Y-320 synergizes with anti-PD-1 therapy to overcome ICB resistance in PDAC, demonstrating superior tumor suppression compared to monotherapies. Our findings demonstrate that Y-320 shows promise for use as a therapeutic agent for cancer and validates sialylation inhibition as a novel glycoimmune checkpoint strategy for PDAC and other immunotherapy-resistant malignancies.

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Publication Details

Journal
ACS Central Science
Published
2025-09-03
DOI
https://doi.org/10.1021/acscentsci.5c00939
Citations
3
Primary Topic
Glycosylation and Glycoproteins Research
Type
article
Field-Weighted Citation Impact
2.42

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article

A Potent Oral Sialylation Inhibitor Augments the Immunotherapy in Pancreatic Ductal Adenocarcinoma

Yiru Long, Jiahui Mou, Hao Yang, Zihao Dai et al.
3 citations
ACS Central Science
Glycosylation and Glycoproteins Research
2.42
article

A Potent Oral Sialylation Inhibitor Augments the Immunotherapy in Pancreatic Ductal Adenocarcinoma

Yiru Long, Jiahui Mou, Hao Yang, Zihao Dai, Pengfei Fang, Biao Yu, Likun Gong, Fang Bai, Runqiu Chen, Jing Wang, Yifan Li, Rong Zhang, Yachen Zhao, Feng Suo, Y Ye
article en
3 citations

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains refractory to current immune checkpoint blockade (ICB) therapies, necessitating innovative therapeutic strategies. Emerging evidence implicates aberrant sialoglycan upregulation as a key mediator of immune evasion in PDAC. Herein, we report Y-320, a highly potent oral sialylation inhibitor discovered through high-throughput screening. Y-320 suppresses α-2,3/2,6-sialylation in PDAC cells (IC<sub>50</sub> ≈ 200 nM) with >300-fold higher activity than the known pan-inhibitor P-3F<sub>ax</sub>-Neu5Ac. Structural analyses reveal competitive occupation of multiple sialyltransferases' substrate-binding pockets as Y-320's action mechanism. <i>In vivo</i>, Y-320 significantly inhibits tumor growth and remodels the tumor immune microenvironment. Mechanistic studies establish that the therapeutic efficacy of Y-320 depends on the coordinated engagement between CD8<sup>+</sup> T cell and macrophage. Importantly, Y-320 synergizes with anti-PD-1 therapy to overcome ICB resistance in PDAC, demonstrating superior tumor suppression compared to monotherapies. Our findings demonstrate that Y-320 shows promise for use as a therapeutic agent for cancer and validates sialylation inhibition as a novel glycoimmune checkpoint strategy for PDAC and other immunotherapy-resistant malignancies.

ACS Central ScienceVol. 11(10)
Chinese Academy of Sciences (CN), Fudan University (CN), ShanghaiTech University (CN), Shanghai Institute of Materia Medica (CN), Shanghai Institute of Organic Chemistry (CN), Institute for Advanced Study (DE), National Institute for Communicable Disease Control and Prevention (CN), State Key Laboratory of Chemical Engineering (CN), University of Chinese Academy of Sciences (CN), China Medical University (CN)
National Natural Science Foundation of China, Chinese Academy of Sciences, China Postdoctoral Science Foundation, University of Chinese Academy of Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, State Key Laboratory of Drug Research, National Key Research and Development Program of China, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Openalex Percentile: Top 10%
Glycosylation and Glycoproteins Research
2.42
DOIOpen Access PDFOpenAlex
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