Wee1 Identified As A Key Driver Of Immune Resistance In Cancer

Immune checkpoints are regulatory proteins that forestall nan immune strategy from attacking patient tissues. Some crab cells utilization these checkpoints to debar immune detection. Immune checkpoint blockade (ICB)-a therapy that uses antibodies to artifact these deceptive signals-can unleash nan immune strategy to destruct cancer.

However, a awesome situation successful oncology remains: why do immoderate tumors defy ICB?

In a landmark study, researchers from Korea University person discovered a astonishing answer: nan macromolecule WEE1, traditionally known arsenic a compartment rhythm regulator and tumor suppressor, tin paradoxically thrust immune guidance erstwhile located successful nan cytoplasm of crab cells.

Highlighting nan value of this achievement, Professor Tae Woo Kim from nan Department of Biochemistry and Molecular Biology astatine Korea University College of Medicine, Seoul, Republic of Korea reveals, "Our findings uncover a non-canonical oncogenic system of cytoplasmic WEE1 and supply a impervious of rule that targeting WEE1 is an appealing combinational strategy to flooded refractory tumor to ICB therapy." This study was published successful Volume 13, Issue 6 of Cancer Immunology Research diary connected June 04, 2025.

RNA samples were obtained from patients pinch metastatic melanoma and non–small compartment lung crab who were undergoing ICB treatment. These patients were categorized arsenic responders and non-responders, and their transcriptomic signatures were analyzed to understand WEE1 look levels. The squad recovered that WEE1 look was importantly elevated successful non-responders, correlating pinch mediocre prognosis, precocious tumor proliferation, and crab stem compartment (CSC)-like features.

Mechanistically, nan transcription facet NANOG upregulates WEE1. Once phosphorylated by AKT, WEE1 relocates from nan nucleus to nan cytoplasm, wherever it activates nan HSP90A–TCL1A–AKT loop, sustaining AKT hyperactivation.

Elucidating nan molecular mechanism, Dr. Hyo-Jung Lee, nan first writer of nan study, explains, "WEE1 is phosphorylated by AKT and past translocated successful nan cytosol, successful which it phosphorylates HSP90A, result enhancing chaperon activity of HSP90A toward TCL1A, an AKT coactivator. Subsequently, stabilization of TCL1A results successful an summation of its proteins levels, starring to amplification of nan WEE1/HSP90A1/TCL1A/AKT auto-loop that promotes immune-refractory phenotypes and CSC-like properties of tumor cells."

Importantly, this study reveals nan paradoxical domiciled of cytoplasmic WEE1. While its canonical usability involves DNA repair and tumor suppression successful nan nucleus, its non-canonical cytoplasmic domiciled promotes tumor progression and immune resistance. These findings underscore nan imaginable of WEE1 look levels arsenic predictive biomarkers for selecting patients who whitethorn use from ICB operation therapies.

Discussing nan therapeutic implications of WEEI inhibitors, Prof. Kim comments, "Importantly, inhibiting WEE1 pinch a clinically applicable drug, adavosertib (AZD1775), sensitizes NANOG+ immune-refractory tumors to ICB and reinvigorates antitumor immunity via abrogating nan autoamplifying loop triggered by AKT-dependent cytoplasmic WEE1."

This proof-of-concept study whitethorn besides widen to different compartment rhythm regulators pinch akin dual functions, specified arsenic p21, p27, and CHK1, thereby broadening nan scenery of therapeutic targets and paving nan measurement for nan improvement of caller curen strategies.