ACLY palmitoylation reprograms macrophages histone acetylation rewiring to repress hepatocellular carcinoma

The tumor microenvironment (TME) domesticates macrophage function by decreasing chromatin accessibility. The activation and nuclear translocation of ATP-citrate lyase (ACLY) convert citrate to acetyl-CoA, providing a substrate necessary for histone acetylation. However, the underlying mechanisms in macrophage remodeling are poorly understood. Here, we found that saturated fatty acids (sFA), especially palmitic acid (PA), were lower in TAMs of patients with hepatocellular carcinoma (HCC). Scd1 knockout promoted PA accumulation, resulting in both primary and metastatic liver cancer retardation and overall survival improvement. Mechanisms indicated that ACLY-C893 palmitoylation via PA maintained tetramer stability against CUL3-mediated degradation, facilitating histone acetylation of M1-related genes. Notably, both dietary PA with Scd1^KO macrophage infusion and TAM-targeted in vivo PA/shSCD1 reprogramming improved the TME to repress HCC progression. Collectively, our research highlights the crucial role of ACLY palmitoylation in the connection between macrophage FA metabolism and histone acetylation reprogramming, which sheds light on the strategy of macrophage-based HCC immunotherapy.