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

In the current study, we found that IL-1a levels were significantly upregulated in peritumoral monocytes compared to nontumor and intratumor counterparts, and glycolytic switch mediated the upregulation of IL-1a via NF-?B signaling. The upregulated IL-1a was neither secreted by nor displayed on cell surface of monocytes. Rather, IL-1a translocated into nuclei to induce the production of IL-8, which effectively enhanced cancer cell stemness and tumor metastasis. Substantial amounts of IL-1a bound to mitochondria to inhibit mitophagy, inducing CA12 expression and macrophages accumulation via ROS-HIF-1a pathway. In accordance, IL-1a levels in peritumoral monocytes were positively correlated with both survival and tumor metastasis of HCC patients. Targeting IL-1a+ monocytes or IL-8 could effectively inhibited tumor progression and enhanced tumor responsiveness to immune checkpoint blockade therapy in mice in vivo. Our results revealed an intracellular regulatory role of IL-1a in modifying the pro-tumor functions of monocytes within specific tumor microenvironments, and pointed to both IL-1a and its downstream IL-8 as potential diagnostic and therapeutic targets for human HCC. Overall design: To delineate the pro-tumor functions of IL-1a, PBMC-derived monocytes from 2 donors were transfected with siIL1A or siNC, then cells were treated with TSN.