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

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.