Metastasis of primary breast cancer to distant sites and recurrence to incurable disease are the main causes of breast cancer fatalities. While migration of breast cancer cells out of a duct or lobule is a prerequisite for invasion and metastasis, the ability of these cells to migrate at all is due to intrinsic intratumoral and extrinsic microenvironment changes. Little is known of the factors that regulate these intrinsic and extrinsic functions. Previous work has shown that expression of the transcription factor interferon regulatory factor 5 (IRF5) is significantly decreased as a breast lesion progresses from a non-malignant stage to ductal carcinoma in situ and is eventually lost in ~80% of invasive ductal carcinomas examined. Human in vitro and murine in vivo models of invasive breast cancer cell growth confirm an important role for IRF5 in regulating breast cancer cell migration, invasion and metastasis. We recently identified the protein domain necessary for the intrinsic migratory function of IRF5 and found that this function is cytoplasmic and transcription-independent. Given that IRF5 is also a key transcriptional immune regulator, we examined cytokine/chemokine expression in IRF5(+) and (-) breast cancers grown in 3D culture and found that IRF5 positively regulates the expression of key cytokines/chemokines, such as CXCL13, that define a pro- or anti-tumor immune microenvironment. We found that anti-tumorigenic primary T cell subsets, including Th1, Treg and Tfh cells, were specifically recruited to IRF5(+) tumors as compared with IRF5(-) tumors. We also found that CD19+CXCR5+ B cells were specifically recruited to IRF5(+) tumors. This finding is intriguing since CXCR5+ B and T cells (Tfh) are essential for the formation of tertiary lymphoid structures (TLS). Together, these data support that IRF5 controls intrinsic mammary epithelial cell migration and directly regulates a network of genes that shapes a tumor immune response.