Targeted degradation of DDR1 by proteolytic targeting chimera reverses immune exclusion for tumor immunotherapy

The formation of immune exclusion microenvironment restricts the infiltration of immune cells into the core of tumors. The extracellular domain of the discoidin domain receptor tyrosine kinase 1 (DDR1) protein plays a pivotal role in this process by aligning collagen fibers to remodel the extracellular matrix (ECM), thereby excluding immune cells. Targeted degradation of DDR1 represents a promising approach to suppress the catalytic functions of the protein and remodel the extracellular matrix of DDR1-related tumors. Here, we report the discovery of a selective DDR1 degrader (DP 1), using the proteolysis targeting chimera (PROTAC) approach. Compound DP 1 exhibited potent DDR1 degradation ability with DC₅₀ values reaching nanomolar range across various cell lines. The degradation of DDR1 effectively blocked the downstream signaling pathways, leading to further inhibition of tumor cell migration and invasion. More importantly, the in vivo studies highlighted the therapeutic potential of DDR1 degradation, indicated by the administration of DP 1 could facilitate the infiltration of immune cells into the tumor core which was associated with enhanced tumor apoptosis. In summary, we report a novel DDR1-targeting degrader with efficacious anti-tumor activity and excellent safety profile. Our studies offer a new perspective for cancer immunotherapy by targeting the immune-exclusion microenvironment.