IDO1 Inhibition Promotes Activation of Tumor-intrinsic STAT3 Pathway and Induces Adverse Tumor-protective Effects

Abstract Pharmacological inhibition of IDO1 exhibits great promise as a strategy in cancer therapy. However, the failure of phase III clinical trials has raised the pressing need to understand the underlying reasons for this outcome. To gain comprehensive insights into the reasons behind the clinical failure of IDO1 inhibitors, it is essential to investigate the entire tumor microenvironment rather than focusing solely on individual cells or relying on knockout techniques. In this study, we conducted single-cell RNA sequencing to determine the overall response to apo-IDO1 inhibitor administration. Interestingly, although apo-IDO1 inhibitors were found to significantly activate intratumoral immune cells (mouse colon cancer cell CT26 transplanted in BALB/C mice), such as T cells, macrophages, and NK cells, they also stimulated the infiltration of M2 macrophages. Moreover, these inhibitors prompted monocytes and macrophages to secrete elevated levels of IL-6, which in turn activated the JAK2/STAT3 signaling pathway in tumor cells. Consequently, this activation enables tumor cells to survive even in the face of heightened immune activity. These findings underscore the unforeseen adverse effects of apo-IDO1 inhibitors on tumor cells and highlight the potential of combining IL-6/JAK2/STAT3 inhibitors with apo-IDO1 inhibitors to improve their clinical efficacy.