Association of expression of m6A-modified ACLY immunotherapy resistance and poor survival in head and neck cancer.

e18094 Background: N6-methyladenosine (m6A) is the most common internal RNA modification and plays a significant role in post-transcriptional gene regulation in cancer. Although metabolic reprogramming and m6A dysregulation are major characteristics of head and neck squamous cell carcinoma (HNSCC), the effects of m6A modification on metabolic enzyme–encoding genes, particularly on their function and immune responses, remain unexplored. Therefore, this study aimed to focus on the expression, prognostic significance, and m6A modification of ATP citrate lyase (ACLY), particularly their relationship to immunotherapy efficacy. Methods: The evaluation of ACLY expression, clinicopathological associations, and survival outcomes used transcriptomic and clinical data from the TCGA-HNSCC cohort. In silico MeRIP-seq data were used to assess m6A modification sites on ACLY mRNA and their correlation with m6A regulatory proteins. Independent HNSCC cohorts and experimental expression analyses were employed for validation. Functional enrichment, pathway analysis, immune cell infiltration profiling, and analyses of immune checkpoint–related gene signatures were performed to explore the biological and immunological roles of ACLY. Predictive immunotherapy response analyses were conducted to assess sensitivity to immune checkpoint blockade. Results: Compared with normal tissues, ACLY expression was significantly higher in HNSCC tumor tissues and correlated with advanced clinicopathological features and reduced overall survival. Conserved m6A modification sites in the ACLY transcript and a strong positive association with m6A regulators indicated m6A-dependent regulation. Altered ACLY expression was associated with changes in lipid and glucose metabolism, activation of oncogenic immune-related pathways, the presence of an immunosuppressive tumor microenvironment, and low predicted responsiveness to immune checkpoint inhibitor therapy. Conclusions: In conclusion, the present study demonstrates that m6A-modified ACLY is a key metabolic regulator associated with poor prognosis and resistance to immunotherapy in HNSCC, making it a candidate for both a prognostic biomarker and a therapeutic target.