Transient adenovirus-Cre infection causes long-lasting remodeling of the mammary gland immune landscape.

Understanding how immune cells respond to early oncogenic events is essential for designing immune-based strategies to intercept breast cancer. Mouse models that induce mammary tumorigenesis through Cre-mediated genetic manipulations can be used to study these early events. However, the immune effects of different induction methods remain unclear. Here, we compare adenovirus-delivered Cre with tamoxifen-inducible CreER systems in models targeting luminal mammary epithelial cells for p53-loss. We find that transient intraductal adenoviral infection produces not only an acute immune response but also long-lasting reshaping of the mammary gland immune microenvironment. Adenovirus exposure induces robust and persistent CD8+ T-cell infiltration dominated by CD103+ tissue-resident T cells displaying heightened activation. This sustained antiviral T-cell signature obscures the p53-loss-driven CD8+ T-cell activation detectable in the CreER/tamoxifen model. Adenoviral infection also transiently skews CD4+ T cells toward IFN-γ-producing antiviral states and affects the myeloid compartment, whereas tamoxifen-induced p53-loss increases macrophage abundance and activates CD8+ T-cells during premalignancy. Despite similar tumor latencies across induction strategies, our findings demonstrate that adenoviral infection exerts long-term immunological effects that can confound interpretation of immune dynamics during early mammary tumorigenesis. These results emphasize the importance of induction-method selection when using genetically engineered mouse models to study cancer-immune interactions.