Intracellular Interleukin-1α in Peritumoral Monocytes Induces IL8 Production and Inhibits Mitophagy to Promote Stemness and Metastasis of Hepatocellular Carcinoma

Abstract IL-1α is a potent inflammatory cytokine that is released by cell necrosis and activates IL-1R. More recently, IL-1α has been shown to have intracellular functions. In the current study, we investigated the expression and distinctive role of IL-1α in tumor progression. In hepatocellular carcinoma (HCC) patients, IL-1α levels were significantly upregulated in monocytes in peritumoral regions compared with nontumoral and intratumoral areas. A glycolytic switch mediated the upregulation of IL-1α via NF-κB signaling. The upregulated IL-1α was neither secreted by nor displayed on the cell surface of monocytes; instead, IL-1α translocated into the nucleus to induce the production of IL-8, which effectively enhanced cancer cell stemness and tumor metastasis. Additionally, IL-1α bound to mitochondria to inhibit mitophagy, inducing CA12 expression and macrophage accumulation via the mitochondrial reactive oxygen species-HIF-1α pathway. In accordance, IL-1α expression in peritumoral monocytes was negatively correlated with survival and positively associated with tumor metastasis in HCC patients. Targeting IL-1α+ monocytes or IL-8 effectively inhibited tumor progression and enhanced responsiveness to immune checkpoint blockade therapy in mouse HCC models. Overall, these results revealed an intracellular regulatory role of IL-1α in modifying the pro-tumor functions of monocytes within specific tumor microenvironments and pointed to both IL-1α and its downstream IL-8 as potential diagnostic and therapeutic targets for HCC.