Lanatoside C activates the E3 ligase STUB1 to inhibit FOXP3 transcriptional activity and promote antitumor immunity
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 shrink lung cancers driven by mutant KRAS in a mouse model. Our findings suggested that the FDA-approved Lac is a Tregs inhibitor and serves as a candidate drug for cancer patients by its own or in combination with existing therapeutics such as PD-1 inhibitors.
Authors
- Guandi Zeng (ORCID: https://orcid.org/0000-0002-9698-781X)
- Robert J. Guo (ORCID: https://orcid.org/0000-0001-9619-7095)
- Jinxia Liang
- Hong‐Bing Shu (ORCID: https://orcid.org/0000-0001-9102-3272)
- Pengju Feng (ORCID: https://orcid.org/0000-0002-5470-0403)
- Li Zhou (ORCID: https://orcid.org/0000-0003-1945-3491)
- Yongxin Mao
- Jin Liu (ORCID: https://orcid.org/0000-0003-1884-671X)
- Liang Chen (ORCID: https://orcid.org/0000-0001-7300-6604)
- Nan Li (ORCID: https://orcid.org/0000-0003-0188-0460)
- Lu Liu (ORCID: https://orcid.org/0000-0002-5489-405X)
- Zhuo Feng
- Bo Li (ORCID: https://orcid.org/0000-0002-1918-8854)
- Qian Zhou (ORCID: https://orcid.org/0009-0007-0845-2115)
- Tong Yang (ORCID: https://orcid.org/0009-0009-5124-923X)
Institutions
- Guangzhou University of Chinese Medicine (CN)
- Jinan University (CN)
- Guangdong Pharmaceutical University (CN)
- Wuhan University (CN)
- Laboratoire de Chémo-biologie synthétique et thérapeutique (FR)
- Zhongnan Hospital of Wuhan University (CN)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2025-02-20
- DOI
- https://doi.org/10.1038/s44321-025-00200-y
- Citations
- 1
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 0.80
Funders
- National Natural Science Foundation of China
- National Key Research and Development Program of China
- Basic and Applied Basic Research Foundation of Guangdong Province