UFMylation: A supervisor of the HIF1α pathway and a potential therapeutic target for anti-PD-1 combination therapy in hypoxic tumors.

Abstract

Activation of hypoxia signaling has been identified as an innate resistance signature against anti-PD-1 therapy, suggesting its potential as a target for combination treatments. Here, we demonstrate that UFMylation modification of HIF1α stabilizes the protein by antagonizing its ubiquitination and proteasomal degradation under hypoxic conditions. Mechanistically, depletion of <i>UFL1</i> or defective UFMylation increases HIF1α binding to p53, promoting its degradation. Depletion of <i>UFL1</i> or <i>UBA5</i>, or defective UFMylation of HIF1α, destabilizes HIF1α, significantly inhibiting tumor growth and development in vitro and in xenograft mouse models. Defective UFMylation of HIF1α enhances the response to anti-PD-1 therapy in xenograft models. Clinically, UBA5 expression is upregulated in breast cancer tissues, and a selective UBA5 inhibitor reduces UFMylation activity and HIF1α protein levels, thereby enhancing anti-PD-1 combination therapy in mouse tumor models. Our findings highlight UFMylation as a critical posttranslational modification for the HIF1α pathway and a promising therapeutic target in hypoxic tumors.