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

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.