Feng Fangyoumin, He Tian, Lin Ping, Hu Jinwu, Shen Bihan, Tang Zhixuan, Zhou Jian, Fan Jia, Hu Bo, Li Hong
Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 20032, China.
Cell Rep Med. 2025 Aug 19;6(8):102276. doi: 10.1016/j.xcrm.2025.102276. Epub 2025 Aug 5.
Combination therapy has emerged as an effective approach to overcome resistance to immunotherapy. However, only a small number of drugs have been identified with synergistic effects with immunotherapy. Here, we develop a computational framework (IGeS-BS) to recommend compounds that potentially overcome resistance to immunotherapy. A meta-analysis of approximately 1,000 transcriptomes from immunotherapy patients revealed 33 tumor microenvironment (TME) signatures that can robustly and accurately estimate immunotherapy responses. An immuno-boosting landscape for more than 10,000 compounds and 13 cancer types was subsequently generated on The Cancer Genome Atlas (TCGA) and The Library of Integrated Network-Based Cellular Signatures (LINCS) datasets. Furthermore, the immuno-boosting effects of several high-scoring compounds were evaluated by in vitro and in vivo experiments in hepatocellular carcinoma and other cancer types. The results showed that the two best compounds (SB-366791 and CGP-60474) significantly alleviate the resistance of hepatocellular carcinoma to anti-PD1 therapy by activating immune cells. Collectively, our research provides an efficient framework for discovering compounds that enhance immunotherapy responses.
联合疗法已成为克服免疫治疗耐药性的有效方法。然而，仅有少数药物被确定与免疫治疗具有协同作用。在此，我们开发了一个计算框架（IGeS-BS）来推荐可能克服免疫治疗耐药性的化合物。对来自免疫治疗患者的约1000个转录组进行的荟萃分析揭示了33种肿瘤微环境（TME）特征，这些特征能够可靠且准确地估计免疫治疗反应。随后，基于癌症基因组图谱（TCGA）和基于综合网络的细胞特征库（LINCS）数据集，生成了针对10000多种化合物和13种癌症类型的免疫增强图谱。此外，通过对肝癌和其他癌症类型进行体外和体内实验，评估了几种高分化合物的免疫增强作用。结果表明，两种最佳化合物（SB-366791和CGP-60474）通过激活免疫细胞显著减轻了肝癌对抗PD1治疗的耐药性。总体而言，我们的研究为发现增强免疫治疗反应的化合物提供了一个有效的框架。
