Crkl, also known as CT10 regulator of kinase-like, is a cellular counterpart of the viral oncoprotein v-Crk. It is an adaptor protein containing SH2 and SH3 domains. Crkl is involved in multiple signaling pathways. For example, it can interact with BCR-ABL and TEL-ABL in leukemia, and is also associated with pathways like Hippo, PI3K/Akt, and JNK/JUN, playing important roles in cell proliferation, transformation, migration, invasion, and epithelial-mesenchymal transition in various cancers [2,3,4].

In hepatocellular carcinoma (HCC), CRKL overexpression nullifies anti-PD-1 treatment efficacy by mobilizing tumor-associated neutrophils (TANs), which block CD8+ T cell infiltration and function. Targeting CRKL using CRISPR-Cas9 gene editing effectively restores the efficacy of anti-PD-1 therapy in an orthotopic mouse model and a patient-derived organotypic tumor spheroid model [1]. In colorectal cancer and glioblastoma cells, gene knockdown and knockout of Crk and CrkL suppress tumor cell functions such as proliferation, migration, and in vivo tumor growth and metastasis [2]. In lung adenocarcinoma, depletion of CRKL blunts Hh-GLI2 pathway-mediated cell proliferation and invasion, and CRKL knockout cells are more sensitive to EGFR-TKI and chemotherapeutics [5].

In conclusion, Crkl plays crucial roles in cancer progression, including promoting tumor cell functions and mediating treatment resistance. Studies using gene knockout models in various cancer types, such as HCC, colorectal cancer, glioblastoma, and lung adenocarcinoma, have revealed its specific functions and potential as a therapeutic target, providing insights for the development of cancer treatment strategies.