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Patients with metastatic breast cancer (MBC) have limited opportunities for a cure, as they develop resistance to therapies and continually form new metastases. Clinical overt metastases emerge from metastasis-initiating cancer cells (MICs) that disseminate during breast cancer (BC) progression. Currently, there are no available therapies that inhibit MIC dissemination to prevent overt metastasis. We provide preclinical evidence that intratumoral (IT) delivery of type I polarized dendritic cells (DC1) limited the MIC dissemination mechanisms in tumor lesions of human epidermal growth factor receptor 2 (HER2)+ mammary carcinoma. Interferon gamma, a prominent cytokine secreted by T helper 1 and innate-like immune effector cells, inhibited dissemination of MICs from the tumor lesions via the modulation of HER2/progesterone receptor/Wnt family member 4/receptor activator of nuclear factor kappa beta ligand signaling. Importantly, we provide clinical evidence that in patients with stage I-III HER2+ BC, there was significant regression of the primary tumor treated with IT DC1, as well as inhibition of disseminating MIC phenotypes. We observed a reduced burden of MICs in the bone marrow (BM) of patients with stage I-III HER2+BC treated with IT DC1, compared with untreated patients and those treated with standard neoadjuvant HER2 therapies paclitaxel, with or without carboplatin, trastuzumab and pertuzumab (Taxol, Carboplatin, Herceptin and Perjeta or THP). We also treated a single patient with de novo stage IV HER2+ MBC with trastuzumab, pertuzumab and tamoxifen in combination with IT DC1. Remarkably, this treatment resulted in near-complete regression of primary tumor and metastatic disease, along with inhibition of MIC seeding in the BM. These findings suggest an intriguing strategy to inhibit the dissemination of MICs and prevent further overt metastasis in all patients with BC.