Prostatic fibroblast reprogramming by Interleukin-30 activates prostate cancer metastasis programs.

Prostate cancer (PC) progression and mortality are largely driven by therapeutic resistance, increasingly linked to dynamic tumor-stroma interactions. However, the molecular basis of cancer-fibroblast crosstalk remains incompletely understood, particularly the contribution of Interleukin (IL)-30, an emerging regulator of PC aggressiveness. Here, we demonstrate that IL30 produced by PC cells reprograms stromal fibroblasts via IL6Rα/gp130 signaling, activating AKT and TGF-β/BMP pathways to drive their proliferation and differentiation into pro-angiogenic cancer-associated fibroblasts (CAFs). Reciprocally, these fibroblasts amplify IL30-mediated tumor aggressiveness by enhancing oncogenic transcriptional programs and by promoting cancer cell migration. Notably, while fibroblast co-culture suppresses epithelial-mesenchymal transition (EMT)-associated genes in PC cells, including NOTCH1, SNAI1/2 and ZEB1, IL30 overexpression overrides this effect, inducing EMT regulators alongside key PC-associated genes, such as IL6, LGALS4, HAL, and SHBG, whose expression correlates with IL30 levels in clinical bone metastasis datasets. Using a two-organ-on-chip platform linking PC-fibroblast spheroids to a bone marrow-like niche, we show that fibroblasts enhance PC cell migration and colonization of the bone marrow microenvironment, effects potentiated by IL30 overexpression and largely abrogated by its genetic depletion. Collectively, these findings identify an IL30-driven tumor-stroma signaling axis that promotes microenvironmental remodeling and metastatic progression, highlighting a potential therapeutic target to counteract PC progression and treatment resistance.