ACSL6-activated IL-18R1–NF-κB promotes IL-18–mediated tumor immune evasion and tumor progression

Aberrant activation of IL-18 signaling regulates tumor immune evasion and progression. However, the underlying mechanism remains unclear. Here, we report that long-chain acyl-CoA synthase 6 (ACSL6) is highly expressed in liver cancer and correlated with poor prognosis. ACSL6 promotes tumor growth, metastasis, and immune evasion mediated by IL-18, independent of its metabolic enzyme activity. Mechanistically, upon IL-18 stimulation, ACSL6 is phosphorylated by ERK2 at S674 and recruits IL-18RAP to interact with IL-18R1, thereby reinforcing the IL-18R1–IL-18RAP heterodimer and triggering NF-κB–dependent gene expression to facilitate tumor development. Furthermore, the up-regulation of CXCL1 and CXCL5 by ACSL6 promotes tumor-associated neutrophil and tumor-associated macrophage recruitment, thereby inhibiting cytotoxic CD8 + T cell infiltration. Ablation or S674A mutation of ACSL6 potentiated anti–PD-1 therapeutic efficacy by increasing the effector activity of intertumoral CD8 + T cells. We revealed that ACSL6 is a potential adaptor that activates IL-18–NF-κB axis–mediated tumor immune evasion and provides valuable insights for developing effective immunotherapy strategies for cancer.