Overexpression of hypoxia-inducible factors led to tumor angiogenesis and tumor progression. However, unlike HIF-1α, the role of EPAS1/HIF-2α in papillary thyroid carcinoma (PTC) was unknown. Here, we aimed to investigate the role of EPAS1/HIF-2α in PTC.EPAS1/HIF-2α expression of fresh frozen tumor samples and adjacent tissues in Tongji Hospital of 46 PTC patients was detected by RT-PCR. Gene expression datasets of PTC patients were gained from The Cancer Genome Atlas (TCGA) database. The Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis (GSEA) were used to explore the potential biological function of EPAS1/HIF-2α. The effect of EPAS1/HIF-2α on immune microenvironment of PTC was analyzed in R package "estimate". The sensitivity to various targeted drugs was quantified in R package "pRRophetic", while the sensitivity to immunotherapy was estimated based on TCIA website.We found higher EPAS1/HIF-2α mRNA expression in PTC was associated with lower N stage, M stage, and better progression-free time (PFS) and disease-free time (DFS). Further, biological function analysis indicated that EPAS1/HIF-2α was mainly involved in PI3K-Akt signaling pathway. EPAS1/HIF-2α expression was positively related with CD8+ T cell infiltration and negatively related to PD-L1 expression and tumor mutation burden. Patients with low EPAS1/HIF-2α expression were more than likely to get a profit from Sorafenib, Dabrafenib, Cetuximab, Bosutinib, and immune checkpoint blockade.Our results suggested that EPAS1/HIF-2α played an unanticipated tumor-suppressive role in PTC. EPAS1/HIF-2α contributed to anti-tumor immunity by promoting CD8+ T cell infiltration and inhibiting PD-L1 expression in PTC.© 2023 Zhang et al.