GAS6 drives chemoresistance and immune escape in ovarian cancer

High-grade serous ovarian cancer (HGSOC) has poor prognosis owing to widespread platinum resistance and unsatisfactory efficacy of chemo-immunotherapy, so novel mechanisms of therapeutic failure are urgently required. The GAS6/AXL axis supports tumor survival and immunosuppression, yet how chemotherapy modulates GAS6 expression remains unclear. We demonstrate that chemotherapy elevates GAS6, which activates AXL to trigger NF-κB-mediated transcription of GDF-15. This GAS6-AXL-GDF-15 cascade drives intrinsic platinum resistance and tumor immune evasion. Blocking GDF-15 reverses chemoresistance; combined with anti-PD-1 antibody, it produces synergistic anti-tumor effects. Circulating GAS6 protein reflects activation of this signaling cascade and acts as a non-invasive predictive biomarker for combined GDF-15/PD-1 blockade. Collectively, we identify a chemotherapy-activated GAS6/AXL-NF-κB-GDF-15 pathway that mediates both chemoresistance and immune escape in HGSOC, supporting translational application of GDF-15 inhibitors plus immune checkpoint inhibitors for biomarker-stratified patients.