Characterization of the tumor microenvironment (TME) can enhance understanding of the processes that occur in cancer, especially rare, aggressive cancers known to have poor responses to therapy such as intrahepatic cholangiocarcinoma (ICC). A comprehensive multi-omics analysis of ICC reported by Bao, Li, Chen, Chen, and Ye et al. reveals three distinct ICC molecular subtypes and identifies a specific tumor-associated macrophage (TAM) subset, APOE⁺C1QB⁺ TAMs, that can reshape the TME by inducing T cells with an inflammatory profile. This, in turn, can alter the ICC molecular subtype. The data provide novel insight into the TME of ICC and highlight a TAM population that could serve as a therapeutic target. Read more in this issue on page 811. Original image from Fig. 5C. Artwork by Lewis Long.