CRKL is an adaptor protein that mediates intracellular signal transduction downstream of receptor tyrosine kinases 1. It functions as a scaffolding protein that facilitates signaling through the ERK1/2 and Ras pathways 2, and interacts with multiple proteins including VASP at its SH3N domain to regulate cell migration and invasion 3. In cancer contexts, CRKL is frequently amplified or overexpressed and promotes tumor cell proliferation, transformation, migration, invasion, and chemotherapy resistance 2. Specifically, CRKL amplification drives acral melanoma through synergy with posterior HOX13 gene programs to amplify IGF signaling in limb melanocytes 4. In hepatocellular carcinoma, CRKL overexpression confers anti-PD-1 immunotherapy resistance by inhibiting APC-mediated β-catenin degradation, leading to enhanced VEGFα and CXCL1 expression that promotes immunosuppressive tumor-associated neutrophil infiltration, blocking CD8+ T cell function 5. Beyond cancer, CRKL haploinsufficiency contributes to 22q11.2 deletion syndrome pathogenesis when the gene is deleted 6. As a therapeutic target, CRKL knockout or inhibition restores immunotherapy efficacy and suppresses tumor growth 5, positioning CRKL inhibitors as potential combination therapies with immunotherapy or kinase inhibitors 7.