Integrated single-cell and bulk RNA sequencing analysis reveals ACACA as a potential prognostic and immunotherapeutic biomarker across cancers

Haihua He¹Zhen Zhang²Leifeng Chen³Fushan Gao²Yuze Wu¹Lina Yi¹Fei Shao^4*Yibo Gao^5*Jie He^1*

• ¹Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
• ²Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
• ³Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
• ⁴Laboratory of Translational Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
• ⁵Central Laboratory & Shenzhen Key Laboratory of Epigenetics and Precision Medicine for Cancers, National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Shenzhen, China

Background: Acetyl-CoA carboxylase alpha (ACACA), a crucial rate-limiting enzyme governing de novo biosynthesis of fatty acids, drives oncogenic metabolic reprogramming in diverse malignancies. However, the multiomics investigation and immunological implications of ACACA across cancers remain unclear. Methods: We performed a comprehensive pan-cancer analysis of ACACA via transcriptomic, proteomic, and clinical data from The Cancer Genome Atlas (TCGA), Clinical Proteomic Tumor Analysis Consortium (CPTAC), and the Human Protein Atlas (HPA) databases. Then, single-cell RNA sequencing acquired from the Gene Expression Omnibus (GEO) database was employed to map the expression pattern of ACACA in the tumor microenvironment (TME). Subsequently, functional validation experiments were conducted in lung cancer and sarcoma cells. Results: High ACACA expression was associated with poor survival in various cancers, particularly those exhibiting dysregulated lipid metabolism. Immune profiling revealed that elevated ACACA expression was associated with low infiltration of CD8⁺ T cells and activated natural killer (NK) cells. Single-cell analysis of lung adenocarcinoma revealed that ACACA was expressed predominantly within malignant cells and contributed to an immunosuppressive microenvironment through migration inhibitory factor (MIF) signaling and the extracellular matrix (ECM) remodeling pathway. Furthermore, in vitro studies demonstrated that ACACA inhibition suppresses fatty acid synthesis and tumor growth in lung cancer and sarcoma cells.