Lanatoside C activates the E3 ligase STUB1 to inhibit FOXP3 transcriptional activity and promote antitumor immunity.

ABSTRACT: Regulatory T cells (Tregs) play critical roles in inhibiting antitumor immunity, which is dependent on FOXP3-mediated transcriptional activity. However, no Treg-specific therapeutics has been approved for clinical use. We performed a high-throughput screen of FDA-approved drugs for potential inhibitors of FOXP3 transcriptional activity. These efforts identified Lanatoside C (Lac), which potently inhibits FOXP3 activity by causing degradation of RUNX1, a FOXP3-associated component required for its transcriptional activity. Lac directly binds the E3 ligase STUB1, leading to increased polyubiquitination and proteasomal degradation of RUNX1. Lac inhibits Tregs activity and promotes antitumor immunity in a mouse primary lung cancer model. In addition, Lac synergizes with PD-1 inhibitor to shrin

SUBMITTER: Zhou Q 

PROVIDER: S-EPMC11904033 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature