Metastatic breast cancer is a leading cause of cancer-related mortality worldwide. While existing interventions are effective at treating localized tumors, disseminated malignancies remain incurable. Vaccine-induced anti-tumor immunity is a promising approach for treating disseminated tumors, as immune responses are systemic, have antigen-restricted cytotoxicity, and generate protective immune “memory” populations. Our group has developed a novel heterologous prime/boost vaccine protocol that treats established 4T1 murine mammary tumors. Briefly, this approach entails a vaccine prime consisting of tumor lysate antigens encapsulated within poly(lactic-co-glycolic) acid (PLGA) microparticles (MPs). The vaccine prime was followed by a vaccine boost consisting of tumor lysates plus adjuvants. Spontaneous 4T1 lung metastasis was evaluated at a pre-determined endpoint in vaccinated versus untreated mice. Vaccinated mice demonstrated significant, but incomplete, reductions in metastatic tumor burdens relative to untreated control mice. Encouraged by these results, we evaluated additional vaccine variations with the goal of improving therapeutic responses. The addition of immunomodulatory chemotherapy or checkpoint blockade immunotherapy failed to significantly improve the initial vaccine’s efficacy. Conjugation of streptavidin/biotin complexes to the PLGA MP significantly improved vaccine efficacy, with vaccinated mice demonstrating 88% less metastatic tumor burdens than their untreated counterparts. These findings illustrate that vaccines based upon PLGA MP-mediated delivery of tumor lysates can form the basis of an effective treatment for metastatic breast cancer and suggest that similar approaches may be both efficacious and well-tolerated in the clinic.