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Summary: CDH1 and PIK3CA are the two most frequently mutated genes in invasive lobular carcinoma (ILC) of the breast. Transcription profiling has identified molecular subtypes for ILC, one of which, immune-related (IR), is associated with gene expression linked to lymphocyte and macrophage infiltration. Here, we report that deletion of Cdh1, together with activation of Pik3ca in mammary epithelium of genetically modified mice, leads to formation of IR-ILC-like tumors with immune cell infiltration, as well as gene expression linked to T-regulatory (Treg) cell signaling and activation of targetable immune checkpoint pathways. Interestingly, these tumors show enhanced Rac1- and Yap-dependent transcription and signaling, as well as sensitivity to PI3K, Rac1, and Yap inhibitors in culture. Finally, high-dimensional immunophenotyping in control mouse mammary gland and IR-ILC tumors by mass cytometry shows dramatic alterations in myeloid and lymphoid populations associated with immune suppression and exhaustion, highlighting the potential for therapeutic intervention via immune checkpoint regulators. : An et al. describe the development and characterization of a mouse model for invasive lobular carcinoma (ILC) of the breast based on the two most mutated genes in human ILC. This model is analogous to immune-related ILC, shows myeloid and T cell alterations consistent with immune suppression and exhaustion, and represents a platform for therapeutics. Keywords: lobular breast cancer, Cdh1, Pik3ca, immune infiltration, immune checkpoint, Rac1, Yap, Hif1a, tumor-associated macrophages, tumor-infiltrative lymphocytes