YBX1 Confers immunosuppressive bone metastatic traits in non-small cell lung cancer

Abstract The spread of lung cancer to bone is a devastating complication often linked to resistance against immunotherapy, but the reasons for this connection are poorly understood. Here we show that the transcription factor YBX1 acts as a central regulator driving both bone metastasis and the formation of an immunosuppressive environment in non-small cell lung cancer (NSCLC). YBX1 achieves this by activating distinct signaling pathways (IL6 and CCL5, respectively). Mechanistically, YBX1 protein levels are controlled by glycosylation that marks it for autophagic degradation inside cells. Notably, reduced YBX1 glycosylation was observed in highly bone-metastatic NSCLC cells. Importantly, we identified a drug candidate, Icaritin, which boosts this sugar-modification, leading to YBX1 degradation. This dual action inhibits bone metastasis and re-sensitizes tumors to immune attack. Our work reveals YBX1 as a promising single target for combating bone spread and overcoming immunotherapy resistance.