Peng Yuchong, Qi Xuli, Ding Liuyang, Huang Jingjing, Liu Youhong, Zheng Rirong, Fu Yongming, Yin Linglong, Deng Tanggang, Ye Yubing, Chen Size, Li Xiong
Key Laboratory of Clinical Precision Pharmacy of Guangdong Higher Education Institutes, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China.
Key Specialty of Clinical Pharmacy, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China.
Br J Cancer. 2025 Jan;132(1):81-92. doi: 10.1038/s41416-024-02909-y. Epub 2024 Nov 24.
S-phase kinase-associated protein 2 (SKP2) is a typical oncogene aberrantly overexpressing in a variety of cancer types, but it remains elusive whether SKP2 regulates the antitumor immunity of triple-negative breast cancer.
The efficacy of anti-PD-1 was evaluated in the orthotopic xenografts of immunocompetent mice models. The infiltration of cytotoxic T cells in tumor microenvironment(TME) were assessed by immunofluorescence staining. The levels of pro-inflammatory chemokines were analyzed by ELISA. The protein interaction was analyzed by co-immunoprecipitation and GST pull-down. The genomic instability was analyzed by fluorescent microscopy.
SKP2 inhibition significantly improved the antitumor efficacy of immune checkpoint blockade (ICB). Furthermore, SKP2 inhibition activated the cGAS/STING signal pathway and induced the secretion of pro-inflammatory chemokines, thereby promoting cytotoxic T cell infiltration. Additionally, we identified CDC6, a DNA replication licensing factor as a novel substrate of SKP2 in addition to CDT1. SKP2 induced protein degradation of CDC6 and CDT1 through the ubiquitin-proteasome pathway. Conversely, SKP2 inhibition elevated CDC6 and CDT1 protein levels, which caused DNA aberrant replication, DNA damage and genomic instability, thereby resulting in the accumulation of cytosolic DNA, activating cGAS/STING signaling pathway and improving antitumor immunity.
SKP2 may be used as an effective therapeutic target to enable ICB antitumor immunotherapy.
Peng et al. found that SKP2 inhibition improved the antitumor immunotherapy by activating tumor cell-intrinsic immunity, thereby providing evidences that SKP2 may be used as an effective therapeutic target to enable ICB antitumor immunotherapy.
S期激酶相关蛋白2（SKP2）是一种典型的癌基因，在多种癌症类型中异常过表达，但SKP2是否调节三阴性乳腺癌的抗肿瘤免疫仍不清楚。
在免疫活性小鼠模型的原位异种移植中评估抗PD-1的疗效。通过免疫荧光染色评估肿瘤微环境（TME）中细胞毒性T细胞的浸润情况。通过酶联免疫吸附测定法分析促炎趋化因子的水平。通过免疫共沉淀和谷胱甘肽-S-转移酶沉降法分析蛋白质相互作用。通过荧光显微镜分析基因组不稳定性。
SKP2抑制显著提高了免疫检查点阻断（ICB）的抗肿瘤疗效。此外，SKP2抑制激活了cGAS/STING信号通路并诱导促炎趋化因子的分泌，从而促进细胞毒性T细胞浸润。此外，我们确定细胞分裂周期蛋白6（CDC6），一种DNA复制许可因子，是SKP2除CDT1之外的一种新底物。SKP2通过泛素-蛋白酶体途径诱导CDC6和CDT1的蛋白质降解。相反，SKP2抑制提高了CDC6和CDT1的蛋白质水平，这导致DNA异常复制、DNA损伤和基因组不稳定性，从而导致胞质DNA积累，激活cGAS/STING信号通路并改善抗肿瘤免疫。
SKP2可作为一种有效的治疗靶点，以实现ICB抗肿瘤免疫治疗。
彭等人发现SKP2抑制通过激活肿瘤细胞内在免疫改善了抗肿瘤免疫治疗，从而提供了证据表明SKP2可作为一种有效的治疗靶点，以实现ICB抗肿瘤免疫治疗。
