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

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

  • Cancer Lett. 2026 May 1:645:218406. doi: 10.1016/j.canlet.2026.218406.
Qin Dang 1,  Liangju Peng 1,  Yinrong Niu 1,  Xuan Pan 2,  Zeng Ye 1,  Ting Wang 1,  Yan Wang 1,  Jiahao Wu 1,  Zheng Li 1,  Heli Gao 1,  Miaoyan Wei 1,  Qiangsheng Hu 3,  Guixiong Fan 1,  Desheng Jing 1,  Junfeng Xu 1,  Shunrong Ji 4,  Xianjun Yu 5,  Xiaowu Xu 6,  Yi Qin 7
Affiliations

Affiliations

  • 1 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China.
  • 2 Department of Hepatobiliary Surgery, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, China.
  • 3 Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of, Medicine, Shanghai, China.
  • 4 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China. Electronic address: [email protected].
  • 5 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China. Electronic address: [email protected].
  • 6 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China. Electronic address: [email protected].
  • 7 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China. Electronic address: [email protected].
PMID: 41786280 DOI: 10.1016/j.canlet.2026.218406
Abstract

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.

Keywords

ACSS2; Acetyl-CoA; BCL6; Pancreatic neuroendocrine tumors; TMZ.

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