2. Academic Validation
  3. Nuclear mitochondrial acetyl-CoA acetyltransferase 1 orchestrates natural killer cell-dependent antitumor immunity in colorectal cancer

Nuclear mitochondrial acetyl-CoA acetyltransferase 1 orchestrates natural killer cell-dependent antitumor immunity in colorectal cancer

  • Signal Transduct Target Ther. 2025 Apr 28;10(1):138. doi: 10.1038/s41392-025-02221-y.
Chen Wei # 1,  Kun Liao # 1,  Hao-Jie Chen # 1,  Zi-Xuan Xiao # 1,  Qi Meng # 1,  Ze-Kun Liu 1,  Yun-Xin Lu 1,  Hui Sheng 1,  Hai-Yu Mo 1,  Qi-Nian Wu 1,  Yi Han 1,  Zhao-Lei Zeng 1 2,  Xin-Yuan Guan 3,  Hui-Yan Luo 1 2,  Huai-Qiang Ju 4 5,  Rui-Hua Xu 6 7
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China.
  • 2 Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, PR China.
  • 3 Department of Clinical Oncology, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, PR China.
  • 4 Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China. [email protected].
  • 5 Department of Clinical Oncology, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, PR China. [email protected].
  • 6 Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, PR China. [email protected].
  • 7 Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, PR China. [email protected].
  • # Contributed equally.
PMID: 40289129 DOI: 10.1038/s41392-025-02221-y
Abstract

Tumor metabolism often interferes with the immune microenvironment. Although natural killer (NK) cells play pivotal roles in antitumor immunity, the connection between NK cells and tumor metabolism remains unclear. Our systematic analysis of multiomics data and survival data from colorectal Cancer (CRC) patients uncovered a novel association between mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) and NK cell infiltration that influences disease progression. ACAT1, a metabolic enzyme involved in reversible conversion of acetoacetyl-CoA to two molecules of acetyl-CoA, exhibits nuclear protein acetylation activity through its translocation. Under immune stimulation, mitochondrial ACAT1 can be phosphorylated at serine 60 (S60) and enters the nucleus; however, this process is hindered in nutrient-poor tumor microenvironments. Nuclear ACAT1 directly acetylates lysine 146 of p50 (NFKB1), attenuating its DNA binding and transcriptional repression activity and thereby increasing the expression of immune-related factors, which in turn promotes NK cell recruitment and activation to suppress colorectal Cancer growth. Furthermore, significant associations are found among low nuclear ACAT1 levels, decreased S60 phosphorylation, and reduced NK cell infiltration, as well as poor prognosis in CRC. Our findings reveal an unexpected function of ACAT1 as a nuclear acetyltransferase and elucidate its role in NK cell-dependent antitumor immunity through p50 acetylation.

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