肝内胆管癌（iCCA）是一种侵袭性癌症，预后极差，需要新的治疗方案。最近，免疫疗法已成为对抗恶性肿瘤的有效治疗方法，但对 iCCA 效果较差。干扰素基因刺激物 (STING) 信号传导的激活可以重新引发免疫惰性肿瘤，但 STING 在 iCCA 中的表达和作用仍有待确定。在这里，我们显示 STING 在 iCCA 中表达，早期 iCCA 中 STING 高表达的患者比低表达的患者具有更长的总生存期。早期 iCCA 中免疫细胞浸润的增加对应于 STING 表达的升高。在小鼠 iCCA 模型中，STING 激动剂 MSA-2 治疗显示出对肿瘤的阶段特异性抑制作用，对早期肿瘤有有益作用，但对晚期癌症则不然。这种差异与晚期肿瘤中更高的程序性细胞死亡配体 1 (PD-L1) 表达有关。与任一单一疗法相比，针对 PD-L1 和 MSA-2 的联合疗法显着降低了此类肿瘤的肿瘤负荷。总的来说，这些数据表明 STING 激动单一疗法改善了早期 iCCA 肿瘤微环境的免疫状况，而联合疗法则改善了晚期 iCCA。版权所有 © 2024。由 Elsevier B.V 出版。

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive cancer with an extremely poor prognosis, and new treatment options are needed. Recently, immunotherapy has emerged as an efficient treatment against malignant tumors, but less effective in iCCA. Activation of stimulator of interferon genes (STING) signaling could reignite immunologically inert tumors, but the expression and role of STING in iCCA remains to be determined. Here, we show STING is expressed in iCCA, and patients with high expression of STING in early-stage iCCA have a longer overall survival than those have low expression. Increased immune cell infiltration in early-stage iCCA corresponds to elevated STING expression. In mice iCCA models, treatment with the STING agonist MSA-2 show stage-specific inhibitory effects on tumors, with beneficial effects in early-stage tumors but not with advanced-stage cancer. This discrepancy was associated with greater programmed cell death ligand 1 (PD-L1) expression in advanced-stage tumors. Combination therapy targeting PD-L1 and MSA-2 strikingly reduced tumor burden in such tumors compared to either monotherapy. Cumulatively, these data demonstrate that STING agonism monotherapy improves the immune landscape of the tumor microenvironment in early-stage iCCA, while combination therapy ameliorates advanced-stage iCCA.Copyright © 2024. Published by Elsevier B.V.