ACSS2/AATF Drives Soluble FasL-Mediated CD8+ T Cell Apoptosis in Pancreatic Neuroendocrine Tumors

  • Adv Sci (Weinh). 2025 Aug 12:e06883. doi: 10.1002/advs.202506883.
Qin Dang  1  2  3  4  5 ,  Ting Wang  1  2  3  4  5 ,  Yan Wang  1  2  3  4  5 ,  Zeng Ye  1  2  3  4  5 ,  Borui Li  6  7 ,  Xuan Pan  8 ,  Zheng Li  1  2  3  4  5 ,  Guixiong Fan  1  2  3  4  5 ,  Desheng Jing  1  2  3  4  5 ,  Junfeng Xu  1  2  3  4  5 ,  Qiangsheng Hu  9 ,  Shunrong Ji  1  2  3  4  5 ,  Xiaowu Xu  1  2  3  4  5 ,  Xianjun Yu  1  2  3  4  5 ,  Yi Qin  1  2  3  4  5
Affiliations
  • 1. Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
  • 2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • 3. Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.
  • 4. Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai, 200032, China.
  • 5. Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
  • 6. Department of Hepatopancreatobilary Surgery, the First College of Clinical Medical Science, Three Gorges University, Yichang, Hubei, 443001, China.
  • 7. The People's Hospital of China Three Gorges University, Yichang, Hubei, 443001, China.
  • 8. Department of Hepatobiliary Surgery, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China.
  • 9. Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China.
PMID: 40791180 DOI: 10.1002/advs.202506883
Abstract

Besides the traditional carbon sources, Acetyl coenzyme A has recently been shown to be generated from acetate in various cancers, which subsequently promotes tumor growth and immune escape. However, the mechanism of Acetyl coenzyme A availability in pancreatic neuroendocrine Tumors (PNETs) remains largely unknown. Herein, the metabolic-epigenetic modification driven by acetyl coenzyme A synthase 2 (ACSS2) and its effect on the Fas/FasL system in PNETs is investigated. ACSS2 is highly expressed in PNETs and significantly correlated with patient prognosis. Mechanistically, ACSS2 activity or acetate supplementation induces histone H3/H4 hyperacetylated in PNET cells. This epigenetic modification recruits the transcription factor AATF to co-regulate FasL transcription, specifically enhancing soluble FasL secretion. Secreted FasL binds Fas receptors on CD8+ T cells, activating Caspase-8/3 cascades to trigger T-cell Apoptosis and promote immune evasion. Notably, the finding indicated the non-redundant and synergistic effects of ACSS2 and AATF in modulating FasL expression, which might support emerging strategies for immunotherapy of PNETs.

Keywords
AATF; ACSS2; Acetyl‐CoA; Fas/FasL pathway; pancreatic neuroendocrine tumors.
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