The emergence of immune checkpoint blockade (ICB) therapy has brought revolutionary changes to cancer treatment. By using antibodies to block the "deceptive signals" sent by cancer cells using immune checkpoints, immune checkpoint blockade therapy can activate the host's immune system to attack cancer cells, thus bringing new hope for treatment for patients with various cancers. However, a thorny question has always troubled scientists, that is, why do some tumors become resistant to immune checkpoint blockade therapy?
Recently, in a research report entitled "Cytoplasmic WEE1 Promotes Resistance to PD-1 Blockade Through Hyperactivation of the HSP90A/TCL1/AKT Signaling Axis in NANOGhigh Tumors" published in the international journal Cancer Immunology Research, scientists from Korea University School of Medicine and other institutions found through research that a protein called WEE1 actually "rebelled" in the cytoplasm of cancer cells, thus becoming the mastermind behind immunotherapy resistance.
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Today, cancer has become the second leading cause of death in the world, with about 10 million people dying from cancer each year. Data show that the response rate of immune checkpoint blockade therapy in various cancers is only 20% to 40%, and drug resistance has become a major challenge limiting its widespread application. As scientists continue to deepen their research on the tumor immune microenvironment, they have found that in addition to the characteristics of cancer cells themselves, various factors in the immune microenvironment also play an important role in the drug resistance process. The "rebellious" behavior of WEE1 protein provides a new perspective for research in this field.
In the article, the researchers not only revealed the atypical carcinogenic mechanism of WEE1 protein in the cytoplasm, but also provided a new therapeutic strategy to overcome immune checkpoint blockade resistance. They analyzed transcriptome data of patient samples receiving PD-1 blockade therapy and tumor models resistant to immune checkpoint inhibitors. The results showed that WEE1 is significantly upregulated in resistant tumor cells and can give tumor cells characteristics similar to cancer stem cells and immune resistance phenotypes.
Figure 1. Model depicting the role of the NANOG/WEE1/AKT axis in resistance to anti–PD-1 therapy. (Kim S, et al., 2025)
WEE1 is a traditional cell cycle regulatory protein and tumor suppressor that usually functions in the cell nucleus and participates in DNA repair. However, when it is phosphorylated at the AKT-dependent S642 site, it will move from the cell nucleus to the cytoplasm. In the cytoplasm, WEE1 can continuously activate AKT by activating the HSP90A/TCL1A/AKT self-enhancement loop, thereby upregulating the expression of resistance factors (such as CYCLIN A and MCL-1), thereby promoting excessive proliferation of tumor cells and resistance to T cell killing. At the same time, downregulation of CXCL10 expression will lead to insufficient T cell infiltration, which further weakens the immune system's attack ability.
Excitingly, the researchers found that targeting WEE1 with clinically relevant inhibitors (such as adavosertib) can significantly enhance the sensitivity of NANOG+ resistant tumors to immune checkpoint blockade therapy. Anti-tumor immune responses can also be reactivated by disrupting the AKT-dependent WEE1/HSP90A/TCL1A/AKT self-enhancement loop. This discovery not only provides new ideas for the treatment of tumors resistant to immune checkpoint blockade, but also provides a reference for the study of other cell cycle regulatory proteins with similar dual functions (such as p21, p27 and CHK1). It is expected to expand the range of targets for immunotherapy.
The importance of this study lies in that it not only reveals the atypical carcinogenic mechanism of WEE1 in the cytoplasm, but also provides a new therapeutic strategy to overcome immune checkpoint blockade resistance. The expression level of WEE1 is expected to become a biomarker to predict whether a patient is suitable for combined immune checkpoint blockade therapy, thereby helping doctors to choose treatment options more accurately. In the future, researchers will further explore the mechanism of action of WEE1 in different types of tumors and develop more specific inhibitors for WEE1 to bring good news to more cancer patients.
Reference
Kim S, et al. Cytoplasmic WEE1 promotes resistance to PD-1 blockade through hyperactivation of the HSP90A/TCL1/AKT signaling axis in NANOGhigh tumors. Cancer Immunology Research, 2025, 13(6): 912-930.