Intracellular IL1α in Peritumoral Monocytes Induces IL8 Production and Inhibits Mitophagy to Promote Stemness and Metastasis of Hepatocellular Carcinoma

IL1α is a potent inflammatory cytokine that is released by cell necrosis and activates IL1R. More recently, IL1α has been shown to have intracellular functions. In the current study, we investigated the expression and distinctive role of IL1α in tumor progression. In patients with hepatocellular carcinoma (HCC), IL1α levels were significantly upregulated in monocytes in peritumoral regions compared with nontumoral and intratumoral areas. A glycolytic switch mediated the upregulation of IL1α via NF-κB signaling. The upregulated IL1α was neither secreted by nor displayed on the cell surface of monocytes; instead, IL1α translocated into the nucleus to induce the production of IL8, which effectively enhanced cancer cell stemness and tumor metastasis. Additionally, IL1α bound to mitochondria to inhibit mitophagy, inducing CA12 expression and macrophage accumulation via the mitochondrial reactive oxygen species-hypoxia-inducible factor-1α pathway. In accordance, IL1α expression in peritumoral monocytes was negatively correlated with survival and positively associated with tumor metastasis in patients with HCC. Targeting IL1α+ monocytes or IL8 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 IL1α in modifying the protumor functions of monocytes within specific tumor microenvironments and pointed to both IL1α and its downstream IL8 as potential diagnostic and therapeutic targets for HCC. SIGNIFICANCE: Glycolysis upregulates intracellular IL1α that reprograms peritumoral monocytes by translocating into the nucleus to induce prometastatic IL8 production or binding to mitochondria to stimulate prosurvival CA12 expression.