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

Menée à l'aide de lignées cellulaires, de modèles murins et d'échantillons tumoraux ou d'échantillons de tissus adjacents normaux prélevés sur des patients atteints d'un cancer du foie, cette étude met en évidence un mécanisme par lequel l'acyl-coenzyme A synthétase ACSL6 favorise l'échappement immunitaire et la progression tumorale via l'activation de l'axe interleukine IL-18-facteur nucléaire NF-kappaB

Résumé en anglais

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. Ablation or S674A mutation of ACSL6 inhibits IL-18–mediated tumor progression and enhances the therapeutic efficacy of anti–PD-1.