This study reports on a hypoxia‐responsive nanoparticle loaded with a HIF‐2α inhibitor (belzutifan), and the ultrasonic sensitizer (Chlorin e6, Ce6), which can inhibit tumor hypoxia and autophagy signaling pathways, and downregulate PD‐L1 expression in tumor cells, leading to improved efficacy of αPD‐1. This evidence concerns the gene EPAS1 and neoplasm.