The central role of IL-17 in cancer stemness and immune evasion: A novel axis for overcoming immune checkpoint inhibitor resistance.

Immune-checkpoint inhibitors (ICIs) have revolutionised cancer therapy, yet primary and adaptive resistance remain formidable hurdles. Emerging evidence positions interleukin-17 (IL-17) at the nexus of cancer stemness, tumor-promoting inflammation and immune escape. IL-17 signalling enriches cancer stem-cell (CSC) populations by activating NF-κB/ERK and STAT3-HIF-1α cascades, thereby up-regulating stemness genes such as SOX2, OCT4 and ALDH1A1 and reprogramming cellular metabolism towards aerobic glycolysis. Concurrently, IL-17 orchestrates a multilayered immunosuppressive ecosystem: it expands myeloid-derived suppressor cells and tumor-associated neutrophils, induces regulatory T-cell maturation, and activates cancer-associated fibroblasts to deposit collagen, thereby building a physical "immune-excluded" barrier that impedes cytotoxic T-cell infiltration. Beyond indirect suppression, IL-17 directly up-regulates PD-L1 by repressing miR-15b via the p65/NRF1 axis and inhibiting autophagy through the ROS/Nrf2/p62 pathway, thereby closing an "IL-17-CSC-PD-L1" loop that locks tumours into an immune-evasive state. Preclinical models and early clinical observations demonstrate that dual blockade of IL-17 and PD-1/PD-L1 restores CD8⁺ T-cell function, dismantles stromal barriers and achieves superior tumor control compared with monotherapy, highlighting the translational promise of this combinatorial strategy. The article further catalogues approved and investigational IL-17/IL-17R antibodies, bispecific constructs, small molecules and nucleic-acid therapeutics, and discusses biomarker-guided patient stratification, microbiota modulation and nano-delivery systems as next-generation avenues to fine-tune IL-17 activity. Collectively, these insights identify IL-17 as a double-edged orchestrator whose context-dependent functions could be harnessed to surmount ICI resistance. Rationally designed, function-selective modulation of the IL-17 axis may unlock durable anti-tumor immunity for a wider spectrum of patients.