IGFBPs define distinct pro-tumorigenic CAF subtypes in lung cancer tumour-microenvironment

Cancer-associated fibroblasts (CAFs) play a significant role in influencing tumour outcomes; however, their heterogeneity and context-sensitive nature present a therapeutically challenging target. Here, we identify a group of Insulin-like growth factor binding proteins (IGFBPs), specifically IGFBP5, 6 and 7, as key regulators of CAF heterogeneity in lung cancer. Notably, these binding proteins are highly expressed in lung CAFs and independently modulate CAF phenotype. We demonstrate that tumour-derived cues, particularly TGFβ1 and IL6, affect IGFBP expression in CAFs. Transcriptome studies indicate that selectively knocking down these proteins directs CAFs towards different CAF subtypes. Functionally, CAFs with high levels of IGFBP5, 6, or 7 promote tumour growth in both ex vivo and in vivo settings and, critically, confer cisplatin resistance to tumour cells. Furthermore, the gene signatures associated with these proteins correlate with unfavourable prognosis. In conclusion, our study highlights the phenotypic plasticity of CAFs driven by these three distinct IGFBPs from the same family, consequently influencing the tumour microenvironment landscape.