Targeting ACSS2 disrupts metabolic-epigenetic crosstalk to restore apoptosis and temozolomide chemosensitivity in pancreatic neuroendocrine tumors.

Temozolomide (TMZ) based chemotherapy remains the standard frontline treatment for advanced pancreatic neuroendocrine tumors (PNETs). However, the therapeutic efficacy is frequently compromised by primary or acquired resistance, and the underlying mechanisms beyond MGMT expression remain poorly understood. In this study, we identify acetyl coenzyme A synthetase 2 (ACSS2) as a critical driver of TMZ resistance in PNETs through a metabolic epigenetic signaling axis. Integrated single-cell RNA sequencing and clinical cohort analyses reveal that ACSS2 is significantly upregulated in PNETs and positively correlates with a chemoresistant transcriptomic profile. Mechanistically, ACSS2 mediated acetate metabolism facilitates histone hyperacetylation, which directly promotes the transcription of BCL6, a potent transcriptional repressor. BCL6 in turn binds to the promoter of the master tumor suppressor TP53 and silences its expression, thereby bypassing TMZ induced G2/M arrest and suppressing apoptosis. Pharmacological inhibition or genetic ablation of the ACSS2/BCL6 axis restores P53 mediated DNA damage response and re-sensitizes PNET cells to TMZ. Notably, combined treatment with an ACSS2 inhibitor and anti-PD1/L1 immunotherapy demonstrates superior synergistic efficacy in patient derived organoids and immunocompetent Rip1-Tag2 mice. This study delineates a non-redundant metabolic epigenetic barrier to chemotherapy and suggests that targeting the ACSS2/BCL6/P53 axis represents a promising strategy to overcome chemoresistance in PNET patients.