2. Academic Validation
  3. Targeting LRBA triggers CTLA4 degradation and antitumor immunity for cancer immunotherapy

Targeting LRBA triggers CTLA4 degradation and antitumor immunity for cancer immunotherapy

  • Nat Commun. 2025 Dec 14. doi: 10.1038/s41467-025-67365-5.
Xiaolu Ge # 1,  Liang Yu # 2,  Lei Zhang 1,  Liqing Jia 3,  Mingjing Meng 1,  Jingquan He 4,  Fan Bu 5,  Yue Song 6,  Gaorui Sun 7,  Shiming Lv 7,  Desheng Mei 7,  Yutao Yang 8,  Dakang Xu 6,  Jingfa Zhang 9,  Shengping Zhang 10,  Chuangui Wang 10,  Deshui Jia 11,  Yongping Chen 12,  Yue Gao 13,  Baokun He 14
Affiliations

Affiliations

  • 1 Laboratory of Molecular Pharmacology and Drug Discovery, Institute of Chinese Materia Medica, The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine; Shanghai Key Laboratory of Pancreatic Disease, Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China.
  • 2 Department of Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China.
  • 3 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
  • 4 Department of Radiotherapy, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, 518033, China.
  • 5 Department of Neurology and Psychology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, 518033, China.
  • 6 Department of Medical Laboratory Science, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 7 Suzhou Guokuang Pharm Tech. Co., Ltd, Suzhou, Jiangsu, 215000, China.
  • 8 School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
  • 9 The International Eye Research Institute of The Chinese University of Hong Kong (Shenzhen); C-MER Dennis Lam & Partners Eye Center, C-MER International Eye Care Group, Hong Kong, 999077, China.
  • 10 Biomedical Translational Research Institute, School of Life Sciences and Medicine, Shandong University of Technology, Zibo, Shandong, 255049, China.
  • 11 Laboratory of Cancer Genomics and Biology, Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China.
  • 12 Noble Life Sciences Inc, Sykesville, Maryland, 21784, USA.
  • 13 Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China. gaoyue@bmi.ac.cn.
  • 14 Laboratory of Molecular Pharmacology and Drug Discovery, Institute of Chinese Materia Medica, The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine; Shanghai Key Laboratory of Pancreatic Disease, Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China. hbk3397@gzucm.edu.cn.
  • # Contributed equally.
PMID: 41390689 DOI: 10.1038/s41467-025-67365-5
Abstract

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+ 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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z