Targeting VCP enhances colorectal cancer therapy through STING stabilization

作者：Hongdao Zhu, Fujing Ge, Jing Dai, Shuyu Yang, Tao Yuan, Churun Zheng, Xin Dong, Ronggui Hu, Tianhua Zhou, Qiaojun He, Bo Yang, Hong Zhu · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2025 · DOI：10.1136/jitc-2025-012652 · 被引用次数：3 · 研究领域：interferon and immune responses、Bacterial Infections and Vaccines、Ubiquitin and proteasome pathways

BACKGROUND: Immunotherapy resistance in microsatellite-stable colorectal cancer (CRC) remains a major therapeutic challenge. Recent strategies to overcome the immunosuppressive tumor microenvironment have focused on reactivating innate immune pathways, particularly the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) axis, which links cytosolic DNA sensing to proinflammatory cytokine production and T cell activation. Although STING agonists show promise, their clinical application is limited by poor drug stability and cytokine storms triggered by excessive STING activation. This study establishes valosin-containing protein (VCP/p97) as a druggable target to potentiate cGAS-STING-driven antitumor immunity, offering a promising therapeutic strategy to overcome immunotherapy resistance in CRC. METHODS: C57BL/6J mice with MC38 tumors and BALB/c mice with CT26 tumors were employed to evaluate the in vivo therapeutic effects of the VCP inhibitor and STING agonist/chemotherapy/immunotherapy combination. Flow cytometry, ELISA, immunofluorescence staining, and RNA-seq were performed to analyze the effectiveness of these interventions in remodeling the tumor microenvironment. RESULTS: In this study, we determined the importance of the cGAS-STING pathway activity in macrophages for antitumor immunity by bioinformatics analysis and identified VCP as a critical negative regulator of STING through analyzing genome-wide CRISPR screening data and performing pharmacological...