Work

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

Year: 2025

Type: article

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.

Source: Advanced Science

DOI: 10.1002/advs.202506883