A Small Natural Molecule Targeting IL-23/IL-17 Axis Exerts Dual Effects on T-Cell Function and Breast Cancer Cell...

Background/Objectives: Chronic inflammation in the tumor microenvironment (TME) promotes immune evasion and metastasis in breast cancer, where the IL-23/IL-17 axis is a key mediator. We investigated the expression of IL-23 in breast cancer and identified a small natural molecule therapeutically targeting this axis. Methods: IL-23 expression and its clinicopathological significance were assessed in a Moroccan breast cancer cohort and the METABRIC dataset. A High-throughput virtual screening of Allium sativum L. compounds was conducted to target the IL-23/IL-17 axis. In vitro, the selected candidate, IL-23RI, was evaluated for its effects on IL-17A and IFNγ production in human PBMCs using flow cytometry, as well as on the migration of MCF-7 and MDA-MB-231 breast cancer cells using wound-healing assays. Results: IL-23 was found to be overexpressed in aggressive breast cancer subtypes and correlated with unfavorable clinicopathological features and a poor prognosis. Elevated IL-23 expression was associated with an immunosuppressive TME, characterized by increased inhibitory immune checkpoints and immunosuppressive chemokines. In silico, IL-23RI demonstrates a high binding affinity for the IL-23 receptor, with a docking score of -7.482 kcal/mol and a binding free energy of -48.80 kcal/mol, stabilized by five hydrogen bonds. In vitro, IL-23RI selectively suppressed IL-17A production by CD4⁺ T cells without affecting IFNγ secretion by both CD4⁺ and CD8⁺ T cells. Furthermore, IL-23RI significantly inhibited the migration of MCF-7 and MDA-MB-231 breast cancer cells. Conclusions: These findings establish the IL-23/IL-17 axis as a critical therapeutic target and present IL-23RI as a promising dual-function agent for breast cancer treatment, concurrently modulating immunity and inhibiting tumor cell migration.