ROR1 protein: a pseudokinase at the crossroads of cancer progression and therapy.

Pseudokinases, a subclass of the human kinome, play critical roles in cellular regulation despite their lack of enzymatic activity. Among these, the Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1) has emerged as a pivotal regulator in cancer biology. ROR1, initially identified for its role in embryonic development, is aberrantly expressed in various malignancies, including hematologic cancers and solid tumors, while being largely absent in normal adult tissues. Its unique expression profile, coupled with its role in tumor survival, metastasis, therapy resistance, and stemness, makes ROR1 an attractive therapeutic target. This review provides an in-depth analysis of the structural and functional attributes of ROR1, its interaction with oncogenic signaling pathways, and its implications in tumor progression. We also explore current therapeutic strategies, including monoclonal antibodies, antibody-drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, and small-molecule inhibitors, highlighting their clinical potential and limitations. Understanding the mechanistic underpinnings of ROR1-driven oncogenesis and overcoming therapeutic challenges will be crucial for developing effective anti-cancer strategies targeting this pseudokinase.