Immune checkpoints are regulatory proteins that stop the immune system from attacking wholesome tissues. Some most cancers cells exploit these checkpoints to keep away from immune detection. Immune checkpoint blockade (ICB)—a remedy that makes use of antibodies to dam these misleading indicators—can unleash the immune system to destroy most cancers.
Nonetheless, a significant problem in oncology stays: why do some tumors resist ICB?
In a landmark examine, researchers from Korea College have found a shocking reply: the protein WEE1, historically often called a cell cycle regulator and tumor suppressor, can paradoxically drive immune resistance when situated within the cytoplasm of most cancers cells.
Highlighting the importance of this achievement, Professor Tae Woo Kim from the Division of Biochemistry and Molecular Biology at Korea College School of Drugs, Seoul, Republic of Korea reveals, “Our findings uncover a non-canonical oncogenic mechanism of cytoplasmic WEE1 and supply a proof of precept that focusing on WEE1 is an interesting combinational technique to beat refractory tumor to ICB remedy.” This examine was printed within the Most cancers Immunology Analysis journal on June 4, 2025.
RNA samples have been obtained from sufferers with metastatic melanoma and non–small cell lung most cancers who have been present process ICB therapy. These sufferers have been categorized as responders and non-responders, and their transcriptomic signatures have been analyzed to grasp WEE1 expression ranges. The crew discovered that WEE1 expression was considerably elevated in non-responders, correlating with poor prognosis, excessive tumor proliferation, and most cancers stem cell (CSC)-like options.
Mechanistically, the transcription issue NANOG upregulates WEE1. As soon as phosphorylated by AKT, WEE1 relocates from the nucleus to the cytoplasm, the place it prompts the HSP90A–TCL1A–AKT loop, sustaining AKT hyperactivation.
Elucidating the molecular mechanism, Dr. Hyo-Jung Lee, the primary creator of the examine, explains, “WEE1 is phosphorylated by AKT after which translocated within the cytosol, by which it phosphorylates HSP90A, consequently enhancing chaperone exercise of HSP90A towards TCL1A, an AKT coactivator. Subsequently, the stabilization of TCL1A ends in a rise of its protein ranges, resulting in amplification of the WEE1/HSP90A1/TCL1A/AKT auto-loop that promotes immune-refractory phenotypes and CSC-like properties of tumor cells.”
Importantly, this examine reveals the paradoxical position of cytoplasmic WEE1. Whereas its canonical perform includes DNA restore and tumor suppression within the nucleus, its non-canonical cytoplasmic position promotes tumor development and immune resistance. These findings underscore the potential of WEE1 expression ranges as predictive biomarkers for choosing sufferers who could profit from ICB mixture therapies.
Discussing the therapeutic implications of WEE1 inhibitors, Prof. Kim feedback, “Importantly, inhibiting WEE1 with a clinically related drug, adavosertib (AZD1775), sensitizes NANOG+ immune-refractory tumors to ICB and reinvigorates antitumor immunity by way of abrogating the autoamplifying loop triggered by AKT-dependent cytoplasmic WEE1.”
This proof-of-concept examine can also prolong to different cell cycle regulators with comparable twin features, equivalent to p21, p27, and CHK1, thereby broadening the panorama of therapeutic targets and paving the best way for the event of novel therapy methods.
Extra info:
Suyeon Kim et al, Cytoplasmic WEE1 Promotes Resistance to PD-1 Blockade By way of Hyperactivation of the HSP90A/TCL1/AKT Signaling Axis in NANOGhigh Tumors, Most cancers Immunology Analysis (2025). DOI: 10.1158/2326-6066.CIR-24-0379
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Immunotherapy resistance linked to cytoplasmic WEE1 protein (2025, July 15)
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