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  3. Ablation of the adhesion G protein-coupled receptor ADGRL1 activates anti-tumor immune response via cDC1-T cell hub formation

Ablation of the adhesion G protein-coupled receptor ADGRL1 activates anti-tumor immune response via cDC1-T cell hub formation

  • Cell Rep. 2026 Jun 23;45(6):117409. doi: 10.1016/j.celrep.2026.117409.
Guangqian Cheng 1,  Junning Wu 2,  Yanmiao Wang 2,  Qiaoming Li 2,  Jun Yang 2,  Ling V Sun 2,  Yang Wang 2,  Wei Zhang 3,  Yiwei Li 4,  Yuetong Wang 5,  Steven X Hou 6
Affiliations

Affiliations

  • 1 Department of Cell and Developmental Biology at School of Life Sciences, State Key Laboratory of Genetics and Development of Complex Phenotypes, Children's Hospital, Zhongshan Hospital, Fudan University, Shanghai 200438, China; Zhejiang University-Lishui Joint Innovation Center for Life and Health, College of Life Sciences, Zhejiang University, Hangzhou 310027, China.
  • 2 Department of Cell and Developmental Biology at School of Life Sciences, State Key Laboratory of Genetics and Development of Complex Phenotypes, Children's Hospital, Zhongshan Hospital, Fudan University, Shanghai 200438, China.
  • 3 Changhai Hospital, Naval Medical University, Shanghai 200438, China.
  • 4 Fudan University Shanghai Cancer Center and Cancer Institute, Shanghai 200032, China. Electronic address: [email protected].
  • 5 Department of Cell and Developmental Biology at School of Life Sciences, State Key Laboratory of Genetics and Development of Complex Phenotypes, Children's Hospital, Zhongshan Hospital, Fudan University, Shanghai 200438, China. Electronic address: [email protected].
  • 6 Department of Cell and Developmental Biology at School of Life Sciences, State Key Laboratory of Genetics and Development of Complex Phenotypes, Children's Hospital, Zhongshan Hospital, Fudan University, Shanghai 200438, China. Electronic address: [email protected].
PMID: 42172123 DOI: 10.1016/j.celrep.2026.117409
Abstract

Immune-like coordinated cell death (CCD) indirectly eliminates target cells via immune activation, bypassing intrinsic programmed cell death. Using RNAi screening in a Drosophila tumor model, we identified a series of genes capable of inducing CCD. Here, we characterize adhesion G protein-coupled receptor ADGRL1 as a key mediator that activates anti-tumor immunity by facilitating cDC1-CD8+ T cell hub formation, as revealed by single-cell transcriptomics. Mechanistically, ADGRL1 ablation activates type I interferon signaling and promotes JAK/STAT1-dependent Decorin secretion, mediated by disrupting the GSK3β/β-catenin pathway. Clinical and database analyses validate ADGRL1 as a promising therapeutic target, and its deletion synergizes with PD-1 blockade to strongly suppress tumor growth. Furthermore, via virtual small molecule screening combined with DARTS (drug affinity responsive target stability), we identify an ADGRL1-targeting compound that demonstrates antitumor efficacy in vivo. Together, our findings reveal an immunoregulatory role for ADGRL1 and highlight its therapeutic potential in Cancer treatment.

Keywords

ADGRL1; CP: cancer; CP: immunology; anti-tumor immunity; cDC1-CD8(+) T cell hub; coordinated cell death.

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