ARNTL-mediated INO80-DHX15 axis reprograms the glycolytic metabolism and augments the progression of endometrial carcinoma.

Immune evasion is a major mechanism responsible for tumor cell survival and dissemination. This study aims to explore key molecules involved in immunosuppression and metastasis of endometrial carcinoma (EC). Primary and metastatic tumors were collected from four patients with EC for array analysis. Metastatic tumors exhibited increased macrophage infiltration, while decreased CD8⁺ T cell infiltration, and aryl hydrocarbon receptor nuclear translocator-like (ARNTL) was identified as a key factor involved. High ARNTL expression was linked to poor tumor differentiation, advanced stage, and increased metastasis in another cohort of 300 EC patients. ARNTL knockout (ARNTL-KO) in EC cells reduced cell proliferation, migration, and invasion, and increased cell death in vitro, and it blocked the tumorigenicity and metastatic activity of cells in mice. The ARNTL-KO EC cells reduced the M2 polarization of macrophages and induced CD8⁺ T cell proliferation both in vitro and in vivo. ARNTL activated the transcription of INO80 complex ATPase subunit (INO80), a chromatin remodeler, which further promoted the transcription of DEAH-box helicase 15 (DHX15) through histone acetylation modifications. Overexpression of either INO80 or DHX15 increased glycolytic activity and immunosuppression in ARNTL-KO EC cells. Collectively, this study suggests that the ARNTL-mediated INO80-DHX15 axis induces glycolysis and immunosuppression during EC progression.