Abstract Bone metastasis in lung cancer is frequently associated with immunotherapy resistance, yet its underlying mechanisms remain elusive. Here, we demonstrate that the transcription factor YBX1 orchestrates both bone metastasis and immunosuppressive microenvironment formation in non-small cell lung cancer (NSCLC) through IL6 and CCL5 signaling, respectively. Mechanistically, YBX1 protein stability is regulated by glycosylation-dependent mitophagy, wherein O-GlcNAc transferase (OGT)-mediated glycosylation at T271 enhances its mitochondrial membrane localization and subsequent autophagic degradation. Notably, reduced YBX1 glycosylation was observed in highly bone-metastatic NSCLC cells. Through drug screening, we identified Icaritin(iac) as a small molecule that potentiates YBX1 glycosylation, accelerates its degradation, and consequently suppresses bone metastasis while reversing immunosuppression. Our findings unveil YBX1 as a dual-functional therapeutic target for simultaneously inhibiting NSCLC bone metastasis and sensitizing tumors to immunotherapy. Citation Format: Yongsheng Wang, Liyun Miao. Ybx1 correlates with an immunosuppressive microenvironment in bone-metastatic lung adenocarcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6161.
WANG et al. (2026) studied this question.