PLEK2 (pleckstrin 2) functions as an oncogenic protein that promotes tumor progression across multiple cancer types through regulation of cellular proliferation, migration, and metabolic reprogramming. The protein contributes to AKT pathway activation and stabilization, serving as a key mediator in cancer cell survival and growth 12. Mechanistically, PLEK2 interacts with critical signaling molecules including c-Myc, where it prevents FBXW7-mediated ubiquitination and proteasome degradation, establishing a positive feedback loop that sustains oncogenic signaling 3. In colorectal cancer, PLEK2 cooperates with YTHDF2 to enhance TYMS mRNA stability through an m6A-dependent mechanism, contributing to fluorouracil resistance 4. The protein is transcriptionally regulated by the APC/β-catenin pathway in colorectal carcinoma and negatively regulated by androgen receptor in prostate cancer 51. Clinically, elevated PLEK2 expression correlates with poor prognosis across various cancers including head and neck squamous cell carcinoma, melanoma, and esophageal cancer, and predicts resistance to neoadjuvant immunotherapy 367. PLEK2 knockdown suppresses tumor growth and enhances immunotherapy efficacy in preclinical models, making it a promising therapeutic target 2.