Targeting YES1 enhances the efficacy of chemotherapy, targeted therapy and onco-immunotherapy.

YES1 (Yamaguchi sarcoma virus homolog 1), a non-receptor tyrosine kinase of the SRC family (SFK), has been abnormally amplified or mutated in several types of solid tumors. The alteration of YES1 impacted multiple biological processes, including promoting tumor progression and metastasis, especially, producing cancer therapy resistance via bypass pathways. Thus, YES1 can serve as a druggable target to overcome drug resistance and suppress tumor growth. Due to toxicity and lack of selectivity, several SFK-targeted agents in clinical trials were limited for further investigation. Recently, the emerging role of YES1-selective inhibitors and the promising approach of combinational therapy have exhibited synergistic anti-tumor effects. Herein, we summarize the multiple mechanisms of YES1-driving tumor progression and resistance, focusing on YES1 inhibitors in combination with other therapies. We also discuss the oncogenic mechanism of the YES1-YAP1 pathway, EGFR-YES1 crosstalk, the roles of YES1 in the tumor microenvironment, and the synthetic lethal effect of YES1 inhibitors. Taken together, available evidences strongly suggest that targeting YES1 could be a promising sensitization strategy for cancer treatment and improve the patient's quality of life.