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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., (© 2024. The Author(s).)