Immunoediting is a mechanism by which tumors evade antitumor responses, but how tissue site of origin plays into the process is not yet clear. By testing different routes of tumor-cell administration, Diamond et al. show that tumors can undergo selective immune escape in some tissues, whereas tumors are eliminated in others. This process is independent of immunoediting and can occur even if tumors are highly immunogenic. Mechanistically, conventional dendritic cells (cDC1) in the tumor-permissive tissues have reduced CD8⁺ T-cell priming ability, thus, leading to insufficient induction of antitumor immunity, and can be rescued by enhancing cross-presentation via a CD40 agonist. The data highlight that although antigenicity is key for inducing antitumor responses, it alone is not sufficient, and tissue of origin needs to be considered. Read more in this issue on page 877. Original image from Supplementary Fig. S1E. Artwork by Lewis Long.