The extracellular matrix (ECM) plays a pivotal role in maintaining tissue architecture and regulating cellular behavior. Recent insights have highlighted Discoidin Domain Receptors (DDRs) as critical mediators in cancer progression and therapeutic resistance. This editorial synthesizes the current understanding of DDR1 and DDR2, unique members of the receptor tyrosine kinase family activated by collagen, focusing on their distinct roles in cell-ECM interactions and cancer biology. We explore emerging therapeutic strategies targeting DDRs, with particular emphasis on differential approaches to DDR1 and DDR2 degradation. Additionally, we examine the complex relationship between DDR inhibition, degradation, and knockout phenotypes, presenting the novel DDR1 degrader LLC355 as a case study. By integrating findings from recent molecular investigations and clinical studies, we propose a comprehensive framework for DDRtargeted therapies in cancer treatment, highlighting their potential to overcome immune evasion mechanisms and enhance the efficacy of existing therapies.