Intratumoral immune status influences tumor therapeutic response, but it remains largely unclear how the status determines therapies for patients with intrahepatic cholangiocarcinoma. Here, we examine the single-cell transcriptional and TCR profiles of 18 tumor tissues pre- and post- therapy of gemcitabine plus oxaliplatin, in combination with lenvatinib and anti-PD1 antibody for intrahepatic cholangiocarcinoma. We find that high CD8 GZMB⁺ and CD8 proliferating proportions and a low Macro CD5L⁺ proportion predict good response to the therapy. In patients with a poor response, the CD8 GZMB⁺ and CD8 proliferating proportions are increased, but the CD8 GZMK⁺ proportion is decreased after the therapy. Transition of CD8 proliferating and CD8 GZMB⁺ to CD8 GZMK⁺ facilitates good response to the therapy, while Macro CD5L⁺–CD8 GZMB⁺ crosstalk impairs the response by increasing CTLA4 in CD8 GZMB⁺. Anti-CTLA4 antibody reverses resistance of the therapy in intrahepatic cholangiocarcinoma. Our data provide a resource for predicting response of the combination therapy and highlight the importance of CD8⁺T-cell status conversion and exhaustion induced by Macro CD5L⁺ in influencing the response, suggesting future avenues for cancer treatment optimization.

瘤内免疫状态影响肿瘤治疗反应，但目前尚不清楚该状态如何决定肝内胆管癌患者的治疗。在这里，我们检查了吉西他滨加奥沙利铂联合乐伐替尼和抗 PD1 抗体治疗肝内胆管癌前后 18 个肿瘤组织的单细胞转录和 TCR 谱。我们发现高 CD8 GZMB ⁺和 CD8 增殖比例以及低 Macro CD5L ⁺比例预示着对治疗的良好反应。反应差的患者治疗后CD8 GZMB ⁺和CD8增殖比例升高，但CD8 GZMK ⁺比例下降。 CD8 增殖和 CD8 GZMB ⁺向 CD8 GZMK ⁺的转变促进了对治疗的良好反应，而宏 CD5L ⁺ –CD8 GZMB ⁺串扰通过增加 CD8 GZMB ⁺中的 CTLA4 来损害反应。抗 CTLA4 抗体可逆转肝内胆管癌治疗的耐药性。我们的数据为预测联合疗法的反应提供了资源，并强调了 CD8 ⁺ T 细胞状态转换和 Macro CD5L ⁺诱导的耗竭在影响反应中的重要性，为癌症治疗优化的未来途径提出了建议。