ACSS2/AATF Drives Soluble FasL‐Mediated CD8 <sup>+</sup> T Cell Apoptosis in Pancreatic Neuroendocrine Tumors
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<sup>+</sup> 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.
Authors
- Shunrong Ji (ORCID: https://orcid.org/0000-0003-2556-3320)
- Qiangsheng Hu (ORCID: https://orcid.org/0000-0003-0373-2007)
- Desheng Jing (ORCID: https://orcid.org/0009-0005-4592-0403)
- Qin Dang (ORCID: https://orcid.org/0000-0002-2521-625X)
- Guixiong Fan (ORCID: https://orcid.org/0009-0004-3995-612X)
- Yi Qin (ORCID: https://orcid.org/0000-0001-9804-202X)
- Junfeng Xu (ORCID: https://orcid.org/0009-0002-0899-4874)
- Xianjun Yu (ORCID: https://orcid.org/0000-0002-6697-7143)
- Zheng Li
- Ting Wang (ORCID: https://orcid.org/0000-0001-6446-4056)
- Xiaowu Xu
- Borui Li (ORCID: https://orcid.org/0009-0003-8537-4457)
- Xuan Pan (ORCID: https://orcid.org/0000-0001-9161-4267)
- Ye Zeng (ORCID: https://orcid.org/0000-0003-1207-6486)
- Yan Wang (ORCID: https://orcid.org/0000-0001-6111-5379)
Institutions
- Tongji University (CN)
- Shanghai Medical College of Fudan University (CN)
- China Three Gorges University (CN)
- Fudan University Shanghai Cancer Center (CN)
- Shanghai Cancer Institute (CN)
- Shanghai Pulmonary Hospital (CN)
- First Affiliated Hospital of Wannan Medical College (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-08-12
- DOI
- https://doi.org/10.1002/advs.202506883
- Citations
- 2
- Primary Topic
- Neuroendocrine Tumor Research Advances
- Type
- article
- Field-Weighted Citation Impact
- 2.71
Funders
- Natural Science Foundation of Shanghai
- Shanghai Municipal Health Commission
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Fudan University
- Science and Technology Commission of Shanghai Municipality
- Shanghai Hospital Development Center