A moonlighting function of tumoral interleukin-1β precursor promotes metastasis via RACK1-mediated actin remodeling

Interleukin-1β (IL-1β) is a key inflammatory mediator in cancer. Its precursor, Pro-IL-1β, is conventionally considered inactive. Here we demonstrate that head and neck squamous cell carcinoma (HNSCC) cells exhibit significantly elevated Pro-IL-1β expression, driven by super-enhancer-mediated transcription of the IL1B gene. We show that intracellular Pro-IL-1β promotes tumor invasion and metastasis independent of IL-1β processing. Mechanistically, Pro-IL-1β binds RACK1 and inhibits its UBE2T-mediated ubiquitination, thereby stabilizing RACK1 and activating RhoA signaling to induce actin cytoskeleton remodeling and pseudopodia formation. Genetic inhibition of RACK1 abolishes Pro-IL-1β-induced metastasis. Clinically, RACK1 protein levels correlate with Pro-IL-1β expression in HNSCC specimens. Furthermore, we identify the natural compound Q3MG as a direct binder of Pro-IL-1β; it promotes lysosomal degradation of Pro-IL-1β and suppresses metastatic progression both in vitro and in vivo. Our study reveals a non-canonical, moonlighting function of Pro-IL-1β in tumor progression and highlights Q3MG as a promising therapeutic agent against metastatic cancer. Interleukin-1β (IL-1β) is a proinflammatory factor related to cancer progression that is synthesized as a precursor named pro-interleukin-1β (Pro-IL-1β). Here, the authors discover that Pro-IL-1β presents a IL-1β-independent pro-metastatic function through RACK1 regulation and modulation of actin cytoskeleton remodeling.