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STK25 Loss Augments Anti-PD-1 Therapy Efficacy by Regulating PD-L1 Stability in Colorectal Cancer
Xiaowen Qiao1, Pu Xing1,2, Hao Hao1
1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
Abstract:
Tumor immune evasion is intricately linked to malignant tumor progression and contributes to the failure of anti-cancer immunotherapy. Serine/threonine protein kinase 25 (STK25) has been previously implicated in the progression of various neoplastic diseases. However, the function of STK25 in the colorectal cancer (CRC) microenvironment remains unclear. Here, it is demonstrated that STK25 global knockout (STK25-/-) mice and STK25-knockout tumor-bearing mice exhibited enhanced effectiveness of anti-PD-1 immunotherapy, which leads to significant tumor suppression with increased recruitment of CD8+ T cells. Mechanistically, STK25 deficiency increased PD-L1 protein levels by regulating PD-L1 K48-linked ubiquitination in a NEDD4-dependent manner. Moreover, CRC patients with low STK25 expression are more responsive to immune checkpoint blockade (ICB) therapy compared to those with high STK25 levels. Taken together, the findings reveal a critical role of STK25 for regulating PD-L1 protein stability in tumor immune evasion, and suggest that targeting STK25 may provide a potential approach to increase sensitivity to the ICB treatment in patients with CRC.
Insights
Targeting Serine/threonine protein kinase 25 (STK25) enhances anti-PD-1 immunotherapy effectiveness in colorectal cancer. STK25 deficiency boosts CD8+ T cell recruitment and PD-L1 degradation, improving treatment response.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Tumor immune evasion hinders anti-cancer immunotherapy efficacy.
- Serine/threonine protein kinase 25 (STK25) is implicated in neoplastic diseases, but its role in colorectal cancer (CRC) is unknown.
Purpose of the Study:
- To investigate the function of STK25 in the colorectal cancer microenvironment.
- To determine STK25's role in regulating tumor immune evasion and immunotherapy response.
Main Methods:
- Utilized STK25 global knockout (STK25-/-) and tumor-bearing knockout mice models.
- Analyzed PD-L1 protein levels, ubiquitination status, and T cell infiltration.
- Correlated STK25 expression with patient response to immune checkpoint blockade (ICB) therapy.
Main Results:
- STK25 deficiency enhanced anti-PD-1 immunotherapy effectiveness, leading to significant tumor suppression.
- STK25 knockout increased CD8+ T cell recruitment to tumors.
- STK25 deficiency stabilized PD-L1 protein by regulating K48-linked ubiquitination via NEDD4.
Conclusions:
- STK25 plays a critical role in regulating PD-L1 protein stability and tumor immune evasion in CRC.
- Targeting STK25 may represent a novel strategy to improve ICB therapy sensitivity in colorectal cancer patients.
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