在非小细胞肺癌（NSCLC）中，表皮生长因子受体（EGFR）的过度表达或异常激活与肿瘤进展和耐药性相关。 EGFR酪氨酸激酶抑制剂（TKI）是目前NSCLC的一线治疗药物。然而，患者不可避免地获得EGFR TKI耐药突变，从而导致疾病进展，因此迫切需要寻找新的治疗方法。在这里，我们报告D-甘露糖通过增强TFE3介导的溶酶体生物合成来上调溶酶体活性，从而增加EGFR的降解并显着下调其蛋白水平。因此，D-甘露糖在体外显着抑制野生型EGFR（WT-EGFR）和EGFR突变细胞（E746-A750缺失、L858R和T790M突变）的增殖、迁移和侵袭。口服 D-甘露糖可强烈抑制小鼠肿瘤生长，显示出与奥希替尼相似的效果。总而言之，这些数据表明 D-甘露糖可能代表 NSCLC 临床治疗的新策略。© 2023。作者，获得 Springer Nature Limited 的独家许可。

In non-small cell lung cancer (NSCLC), the overexpression or abnormal activation of epidermal growth factor receptor (EGFR) is associated with tumor progression and drug resistance. EGFR tyrosine kinase inhibitors (TKIs) are currently the first-line treatment of NSCLC. However, patients inevitably acquired EGFR TKIs resistance mutations, which led to disease progression, so it is urgent to find new treatment. Here, we report that D-mannose up-regulates lysosomal activity by enhancing TFE3-mediated lysosomal biogenesis, thereby increasing the degradation of EGFR and significantly down-regulating its protein level. Therefore, D-mannose significantly inhibited the proliferation, migration and invasion of wild-type EGFR (WT-EGFR) and EGFR mutant cells (E746-A750 deletion, L858R and T790M mutations) in vitro. Oral administration of D-mannose strongly inhibited tumor growth in mice, showing similar effects with osimertinib. Taken together, these data suggest that D-mannose may represent a new strategy for clinical treatment of NSCLC.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.