Chronic Stress Stimulates Protumor Macrophage Polarization to Propel Lung Cancer Progression

Chronic psychological stress is closely linked to malignant disorders, with novel modulators potentially mitigating tumor progression by regulating interactions between neoplastic cells and immune cells. This study identified lncRNA HIF1A-AS3 as a key driver of stress-induced lung cancer progression. Chronic stress models in mice with implanted lung cancer cells revealed significant upregulation of HIF1A-AS3 in stressed groups and human lung cancer tissues. Functional studies showed HIF1A-AS3 promotes cancer cell proliferation and invasion by activating HIF-1ɑ translation through interaction with YBX1, forming a positive feedback loop where HIF-1ɑ enhances HIF1A-AS3 transcription. Additionally, HIF1A-AS3 drove macrophage M2 polarization and reduced phagocytosis under hypoxia. Targeting the HIF1A-AS3/HIF-1ɑ loop effectively counteracted stress-induced lung cancer progression in vivo, highlighting its potential as a diagnostic and therapeutic target for stress-exacerbated lung cancer.