Hu Xiao, Tang Xiaomei, Tian Xiaoman, Lv Xing, Zhang Yuanyuan, Pang Yingyue, Deng Weilong, Wang Yali, Shan Changliang, Shang Luqing
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300353, People's Republic of China.
Asymchem Pharmaceuticals (Tianjin) Co., Ltd., Tianjin 300457, People's Republic of China.
Theranostics. 2025 Jan 1;15(4):1285-1303. doi: 10.7150/thno.102228. eCollection 2025.
Hepatic carcinoma, one of the most malignant cancers in the world, has limited success with immunotherapy and a poor prognosis in patients. While pyroptosis is considered as a promising immunotherapy strategy for tumors, it still suffers from a lack of effective inducers. We designed, synthesized and screened an indole analogue, , featuring a 2, 4-thiazolidinedione substituted indole scaffold. Western blotting, qPCR and immunofluorescence were employed to detect the levels of pyroptosis pathway induced by . RNA sequencing was used to identify the mechanisms of in hepatic carcinoma. To validate anti-tumor effect of , we used CDXs and PDXs mouse models . Then, the syngeneic effects of with cisplatin and anti-PD-1 antibody were verified via western blotting, immunofluorescence, flow cytometry and ELISA. Treatment with notably inhibited the growth of hepatic carcinoma both and . Mechanistically, inhibited the function of PRDX1 and up-regulated excessive ROS. Then, induced gasderminE-mediated pyroptosis by activating the endoplasmic reticulum stress. Tumor cells with high expression of GSDME achieved better responses to -therapy. also improved the efficacy of cisplatin against hepatic carcinoma. Additionally, superior synergistic treatment was observed when was combined with anti-PD-1 antibody. Notably, activated the tumor immune microenvironment (TIME) and enhanced CD8 T cell infiltration in hepatic carcinoma. Collectively, we identified as a promising and effective compound for treating hepatic carcinoma and established its synergistic therapeutic strategy as a pyroptosis inducer.
肝癌是世界上最恶性的癌症之一，免疫治疗效果有限，患者预后较差。虽然细胞焦亡被认为是一种有前景的肿瘤免疫治疗策略，但仍缺乏有效的诱导剂。我们设计、合成并筛选了一种吲哚类似物，其具有2,4-噻唑烷二酮取代的吲哚骨架。采用蛋白质免疫印迹法、定量聚合酶链反应和免疫荧光法检测该类似物诱导的细胞焦亡途径水平。利用RNA测序确定其在肝癌中的作用机制。为了验证该类似物的抗肿瘤作用，我们使用了人源肿瘤细胞系移植瘤（CDXs）和人源肿瘤组织异种移植瘤（PDXs）小鼠模型。然后，通过蛋白质免疫印迹法、免疫荧光法、流式细胞术和酶联免疫吸附测定法验证了该类似物与顺铂和抗程序性死亡蛋白1（PD-1）抗体的协同作用。该类似物治疗显著抑制了体内外肝癌的生长。机制上，该类似物抑制了过氧化物还原酶1（PRDX1）的功能并上调了过量的活性氧（ROS）。然后，该类似物通过激活内质网应激诱导gasderminE介导的细胞焦亡。高表达gasderminE（GSDME）的肿瘤细胞对该类似物治疗反应更好。该类似物还提高了顺铂对肝癌的疗效。此外，当该类似物与抗PD-1抗体联合使用时，观察到了更好的协同治疗效果。值得注意的是，该类似物激活了肿瘤免疫微环境（TIME）并增强了肝癌中CD8 + T细胞浸润。总体而言，我们确定该类似物是一种有前景且有效的治疗肝癌的化合物，并确立了其作为细胞焦亡诱导剂的协同治疗策略。
