Hepatocellular carcinoma (HCC) is the fourth most common cancer worldwide and the second leading cause of cancer-related death. Clinically, HCC is often diagnosed at an advanced stage, leaving patients with limited treatment options. Recently, immune checkpoint blockade (ICB) therapy using monoclonal antibodies targeting PD-1, PD-L1, or CTLA-4 has emerged as a promising treatment approach for HCC. However, the unique liver environment significantly reduces HCC's response to ICB therapy, and resistance often develops, resulting in an overall benefit rate of only 15%-20%.
Combination therapy is a promising strategy to overcome PD-1/PD-L1 resistance and improve treatment response rates. However, clinical trials combining anti-PD-1/PD-L1 with other anti-cancer agents without strong mechanistic evidence have failed to demonstrate synergistic effects. Therefore, innovative combination therapies that incorporate not only anti-PD-1/PD-L1 immune checkpoint inhibitors but also biomarkers that can predict efficacy are urgently needed.
Researchers from Tongji Medical College of Huazhong University of Science and Technology in China recently published a research paper titled "VRK2 targeting potentiates anti-PD-1 immunotherapy in hepatocellular carcinoma through MYC destabilization" in Nature Communications. The study demonstrates that targeted inhibition of the VRK2 kinase can destabilize the MYC protein, thereby enhancing the efficacy of anti-PD-1 immunotherapy in hepatocellular carcinoma.
The MYC proto-oncogene, also known as c-Myc, is a transcription factor located in the cell nucleus that controls cell growth, death, differentiation, and metabolism. MYC dysregulation is a common driver of hepatocellular carcinoma, but the underlying mechanisms remain unclear. Although MYC remains an elusive therapeutic target, developing strategies to promote its degradation has emerged as a promising alternative treatment approach.
In this recent study, the research team discovered that targeted inhibition of the VRK2 kinase can suppress tumors by degrading the MYC protein and significantly enhance the efficacy of anti-PD-1 immunotherapy. Specifically, the study identified for the first time that VRK2 is a direct partner of MYC. VRK2 phosphorylates MYC at serines 281 and 293 (Ser281/293), preventing MYC from being ubiquitinated and degraded, thereby stabilizing and significantly increasing MYC protein levels within cancer cells.
Figure 1. Proposed model underlying the roles of VRK2-MYC-PD-L1 axis in promoting tumor progression and immune evasion in HCC. (Su C, et al., 2025)
Mechanistically, VRK2 phosphorylation competes for the same binding site with the SCF-FBXO24 ubiquitin ligase complex responsible for MYC degradation. When VRK2 wins, MYC is stabilized; when VRK2 is inhibited, MYC is marked for degradation. The stabilized MYC-VRK2 complex enhances transcriptional activation of tumor-promoting programs, including PD-L1 and VRK2 itself, thereby forming a self-reinforcing oncogenic loop that perpetuates cancer progression.
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In a hepatocellular carcinoma model, therapeutic inhibition of VRK2 reduced MYC protein levels, inhibited tumor progression, and synergized with anti-PD-1 immunotherapy. These results indicate that VRK2-mediated MYC stabilization is a key link between carcinogenesis and immune evasion, suggesting that VRK2 inhibition may be a potential strategy for MYC-driven hepatocellular carcinoma.
This study addresses the undruggable nature of MYC: the extreme difficulty of directly targeting the MYC protein. Instead, it provides a new strategy for indirectly targeting MYC-inhibiting MYC-stabilizing VRK2 to promote MYC degradation. This study also suggests a novel combination therapy: VRK2 inhibitors plus anti-PD-1 immunotherapy.
Reference
Su C, et al. VRK2 targeting potentiates anti-PD-1 immunotherapy in hepatocellular carcinoma through MYC destabilization. Nature Communications, 2025, 16(1): 9027.