Immune checkpoints are regulatory proteins that prevent the immune system from attacking healthy tissues. Some cancer cells exploit these checkpoints to avoid immune detection. Immune checkpoint blockade (ICB)—a therapy that uses antibodies to block these deceptive signals—can unleash the immune system to destroy cancer.
However, a major challenge in oncology remains: why do some tumors resist ICB?
In a landmark study, researchers from Korea University have discovered a surprising answer: the protein WEE1, traditionally known as a cell cycle regulator and tumor suppressor, can paradoxically drive immune resistance when located in the cytoplasm of cancer cells.
Highlighting the significance of this achievement, Professor Tae Woo Kim from the Department of Biochemistry and Molecular Biology at Korea University College of Medicine, Seoul, Republic of Korea reveals, “Our findings uncover a non-canonical oncogenic mechanism of cytoplasmic WEE1 and provide a proof of principle that targeting WEE1 is an appealing combinational strategy to overcome refractory tumor to ICB therapy.” This study was published in Volume 13, Issue 6 of Cancer Immunology Research journal on June 04, 2025.
RNA samples were obtained from patients with metastatic melanoma and non–small cell lung cancer who were undergoing ICB treatment. These patients were categorized as responders and non-responders, and their transcriptomic signatures were analyzed to understand WEE1 expression levels. The team found that WEE1 expression was significantly elevated in non-responders, correlating with poor prognosis, high tumor proliferation, and cancer stem cell (CSC)-like features.
Mechanistically, the transcription factor NANOG upregulates WEE1. Once phosphorylated by AKT, WEE1 relocates from the nucleus to the cytoplasm, where it activates the HSP90A–TCL1A–AKT loop, sustaining AKT hyperactivation.
Elucidating the molecular mechanism, Dr. Hyo-Jung Lee, the first author of the study, explains, “WEE1 is phosphorylated by AKT and then translocated in the cytosol, in which it phosphorylates HSP90A, consequently enhancing chaperon activity of HSP90A toward TCL1A, an AKT coactivator. Subsequently, stabilization of TCL1A results in an increase of its proteins levels, leading to amplification of the WEE1/HSP90A1/TCL1A/AKT auto-loop that promotes immune-refractory phenotypes and CSC-like properties of tumor cells.”
Importantly, this study reveals the paradoxical role of cytoplasmic WEE1. While its canonical function involves DNA repair and tumor suppression in the nucleus, its non-canonical cytoplasmic role promotes tumor progression and immune resistance. These findings underscore the potential of WEE1 expression levels as predictive biomarkers for selecting patients who may benefit from ICB combination therapies.
Discussing the therapeutic implications of WEEI inhibitors, Prof. Kim comments, “Importantly, inhibiting WEE1 with a clinically relevant drug, adavosertib (AZD1775), sensitizes NANOG+ immune-refractory tumors to ICB and reinvigorates antitumor immunity via abrogating the autoamplifying loop triggered by AKT-dependent cytoplasmic WEE1.”
This proof-of-concept study may also extend to other cell cycle regulators with similar dual functions, such as p21, p27, and CHK1, thereby broadening the landscape of therapeutic targets and paving the way for the development of novel treatment strategies.
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Reference
DOI: 10.1158/2326-6066.CIR-24-0379
About Korea University College of Medicine
Korea University College of Medicine is the medical school of Korea University. It is located in Seoul, South Korea. As one of the oldest medical schools in South Korea, it has been historically regarded as one of the country's top medical schools. The school was founded as Chosun Women's Medical Training Institute in 1928 by Rosetta Sherwood Hall. The institute was subsequently renamed several times and ultimately merged with Korea University to become Korea University College of Medicine. So far, the school has produced over 7,000 graduates, most of whom are working as prominent physicians and public health advocates worldwide.
Website: https://medicine.korea.ac.kr/en/index.do
About Professor Tae Woo Kim
Professor Tae Woo Kim received his Ph.D. from Korea University, Seoul, and completed postdoctoral training at Johns Hopkins University School of Medicine. He is a Professor in the Department of Biochemistry and Molecular Biology and is affiliated with the Department of Biomedical Science at Korea University College of Medicine. With over 30 years of experience in cancer immunology, Prof. Kim leads research on cancer immunotherapy, immune evasion, and vaccine development. He has authored over 120 peer-reviewed articles and holds seven patents, including a recent one for a screening method targeting NANOG-mediated cancers.
Email id: twkim0421@korea.ac.kr
About Dr. Hyo-Jung Lee
Dr. Hyo-Jung Lee received her B.S. from Kyungpook National University and completed her and Ph.D. at Korea University. She is currently serving as a Research Professor at Korea University. Her research focuses on uncovering the key drivers and mechanisms underlying resistance to various anti-cancer therapies, including immunotherapy, anti-angiogenic therapy, chemotherapy. In particular, she investigates components of the tumor microenvironment that contribute to therapeutic resistance and seeks to identify strategies to target these factors, with the ultimate goal of enhancing the efficacy of cancer treatments.
Email id: hjlee0704@korea.ac.kr
About Dr. Suyeon Kim
Dr. Suyeon Kim received her B.S. from The Catholic University of Korea and earned her M.S. and Ph.D. from Korea University. She is currently a Postdoctoral Research Fellow at Columbia University. Her research has focused on mechanisms of resistance to various anti-cancer therapies, including immune checkpoint blockade and targeted agents. She is particularly interested in the signaling pathways that regulate cell proliferation, the evolutionary dynamics of tumor cells, and how these processes contribute to the development of therapeutic resistance. She aims to uncover novel strategies that can overcome treatment resistance and improve the effectiveness of cancer therapies.
Email id: a204061@gmail.com
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