Development of small molecule drugs targeting CAF-mediated IL-6 signaling in the tumor microenvironment

Abstract

The tumor microenvironment (TME) plays a central role in cancer progression through dynamic interactions between cancer cells and stromal components such as cancer-associated fibroblasts (CAFs). Among stromal components, CAF constitute a major cellular population that supports tumor growth by secreting cytokines and remodeling immune cell functions. Among CAF-derived cytokines, IL-6, a key inflammatory cytokine produced abundantly by activated CAFs, drives malignant behaviors through the JAK2/STAT3 and NF-κB signaling pathways that regulate cancer cell proliferation and immune modulation. In this study, FDA-approved compounds were screened to identify inhibitors of IL-6 secretion in cancer-stimulated CAFs, and NDT-PTU emerged as the most effective candidate without cytotoxicity. NDT-PTU markedly reduced IL-6 production and significantly attenuated the activation of JAK2/STAT3 and NF-κB signaling induced by cancer cell–conditioned medium. Moreover, conditioned media from cancer-stimulated CAFs promoted cancer cell proliferation and STAT3 activation, whereas these effects were substantially diminished when using CM derived from NDT-PTU–treated CAFs. In co-culture systems, cancer-stimulated CAFs induced monocyte to macrophage differentiation and promoted an M2-like macrophages phenotype, while NDT-PTU treatment effectively suppressed these effects. Collectively, these findings demonstrate that cancer-stimulated CAFs promote tumor progression and immune suppression through IL-6–dependent signaling, and highlight NDT-PTU as a promising repurposed small-molecule drug for modulating the TME.