Targeting LRBA triggers CTLA4 degradation and antitumor immunity for cancer immunotherapy
The lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency causes severe autoimmune diseases and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) loss in humans. However, the impact of LRBA on antitumor immunity remains understudied. Here we show the important role of LRBA in antitumor immunity and develop small molecules targeting LRBA for cancer immunotherapy. Interestingly, LRBA is negatively associated with antitumor immunity in human patients and mouse models. Using high-throughput screening and subsequent hit optimization, we discover a small molecule LC427 that facilitates the lysosomal degradation of CTLA4 and bolsters survival of activated T cells by binding directly to LRBA and inhibiting the LRBA-CTLA4 interaction. Orally administrated LC427 increases tumor-infiltrating CD8<sup>+</sup> T cells and displays effective antitumor activity in multiple mouse tumor models. Notably, LC427 does not induce immune-related adverse events observed with immune checkpoint inhibitors in colitis models. Our study demonstrates that targeting LRBA offers an effective strategy for cancer immunotherapy.
Authors
- Yue Song
- Yue Gao (ORCID: https://orcid.org/0000-0003-1131-5326)
- Jingquan He (ORCID: https://orcid.org/0000-0002-9341-8750)
- Yutao Yang (ORCID: https://orcid.org/0000-0002-6835-2964)
- Chuangui Wang (ORCID: https://orcid.org/0000-0002-1213-946X)
- Xiaolu Ge (ORCID: https://orcid.org/0000-0002-5533-7749)
- Deshui Jia (ORCID: https://orcid.org/0000-0002-2784-126X)
- Guowei Sun
- Baokun He
- Jingfa Zhang (ORCID: https://orcid.org/0000-0003-0601-4342)
- Desheng Mei
- Shi-Ming Lv
- Liqing Jia (ORCID: https://orcid.org/0000-0003-1734-6043)
- Lei Zhang (ORCID: https://orcid.org/0000-0003-2424-7019)
- Yongping Chen (ORCID: https://orcid.org/0000-0002-9418-7552)
- Dakang Xu (ORCID: https://orcid.org/0000-0003-2415-4920)
- Liang Yu (ORCID: https://orcid.org/0009-0007-3922-3454)
- Shengping Zhang (ORCID: https://orcid.org/0000-0003-4088-2768)
- Mingjing Meng
Institutions
- Guangzhou University of Chinese Medicine (CN)
- Shandong University of Technology (CN)
- Shanghai Jiao Tong University (CN)
- Capital Medical University (CN)
- Hong Kong Eye Hospital (CN)
- Shanghai Children's Medical Center (CN)
- Fudan University Shanghai Cancer Center (CN)
- National Institutes of Pharmaceutical Research and Development (China) (CN)
- Shanghai Cancer Institute (CN)
- Shanghai Institute of Materia Medica (CN)
- Chinese University of Hong Kong, Shenzhen (CN)
- Suzhou Research Institute (CN)
- Noble Life Sciences (United States) (US)
- Shanghai First People's Hospital (CN)
- Massachusetts Eye Research and Surgery Institute (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-14
- DOI
- https://doi.org/10.1038/s41467-025-67365-5
- Primary Topic
- Immunodeficiency and Autoimmune Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China