Histone lactylation-driven feedback loop modulates cholesterol-linked immunosuppression in pancreatic cancer

Jing Yang; Xiaoning Yu; Mingming Xiao; He Xu; Zhen Tan; Yubin Lei; Yanmei Guo; Wei Wang; Jin Xu; Si Shi; Xianjun Yu

doi:10.1136/gutjnl-2024-334361

Histone lactylation-driven feedback loop modulates cholesterol-linked immunosuppression in pancreatic cancer

Gut. 2025 Jun 4:gutjnl-2024-334361. doi: 10.1136/gutjnl-2024-334361. Online ahead of print.

Authors

Jing Yang^#^{1

2

3

4

5}, Xiaoning Yu^#^{1

2

3

4

5}, Mingming Xiao^#^{1

2

3

4

5}, He Xu⁶, Zhen Tan⁷, Yubin Lei⁸, Yanmei Guo⁹, Wei Wang^{1

2

3

4

5}, Jin Xu^{1

2

3

4

5}, Si Shi^{10

2

3

4

5}, Xianjun Yu^{10

2

3

4

5}

Affiliations

¹ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
² Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China.
³ Shanghai Pancreatic Cancer Institute, Shanghai, China.
⁴ Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai, China.
⁵ Pancreatic Center Institute, Fudan University, Shanghai, China.
⁶ Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, China.
⁷ Department of Hepatobiliary Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.
⁸ Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China.
⁹ Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China.
¹⁰ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China yuxianjun@fudanpci.org shisi@fudanpci.org.

^# Contributed equally.

PMID: 40467104
DOI: 10.1136/gutjnl-2024-334361

Abstract

Background: Pancreatic cancer exhibits limited clinical responses to immunotherapy, highlighting the need for new strategies to counteract its immunosuppressive microenvironment. Although metabolic reprogramming and epigenetic changes contribute to malignancy, the impact of lactate-driven histone lactylation on the tumour microenvironment (TME) has not been fully explored.

Objective: This study aims to investigate the role of histone lactylation in pancreatic cancer, focusing on its effects on cholesterol metabolism and antitumour immunity.

Designs: Global lactylome profiling was conducted to identify novel epigenetic mechanisms driven by lactate-induced histone lactylation. Mechanisms were investigated via RNA sequencing, CUT&Tag, immunoprecipitation-mass spectrometry and GST-pull down. Mass cytometry by time-of-flight, in vitro co-culture system, orthotopic pancreatic cancer models and flow cytometry were used to explore Acetyl-CoA acetyltransferase (ACAT2) functions. A proteolysis-targeting chimaera (PROTAC) was developed to degrade ACAT2.

Results: Global lactylome profiling revealed that lactate-driven histone lactylation, particularly H3K18la, promotes the transcriptional activation of ACAT2. ACAT2 acetylates mitochondrial carrier homolog 2 (MTCH2), stabilising it and disrupting oxidative phosphorylation, which increases lactate production and fuels a positive feedback loop in pancreatic cancer. This loop facilitates the delivery of cholesterol via small extracellular vesicles (sEVs), polarising tumour-associated macrophages toward an immunosuppressive M2 phenotype. Additionally, the PROTAC targeting ACAT2 enhanced the efficacy of immune checkpoint blockade therapy in vivo.

Conclusions: Our findings highlight the critical role of the H3K18la/ACAT2/sEV-cholesterol axis in TME reprogramming. Targeting this pathway may improve anti-PD-1 therapy response in pancreatic cancer, providing a novel therapeutic strategy by linking histone lactylation, cholesterol metabolic reprogramming and immune modulation.

Keywords: GENE TARGETING; IMMUNE RESPONSE; LIPID METABOLISM; MACROPHAGES; PANCREATIC CANCER.