During infection, inflammatory cytokines mobilize and activate dendritic cells (DCs), which are essential for efficacious T cell priming and immune responses that clear the infection. Here, macroporous poly(lactide-co-glycolide) (PLG) matrices are designed to release the inflammatory cytokines GM-CSF, Flt3L, and CCL20 in order to mimic infection-induced DC recruitment. The ability of these infection mimics to function as cancer vaccines is tested via induction of specific anti-tumor T cell responses. All vaccine systems tested are able to confer specific anti-tumor T cell responses and long-term survival in a therapeutic B16-F10 melanoma model. However, GM-CSF and Flt3L vaccines result in similar survival rates and outperformed CCL20-loaded scaffolds, even though they have differential effects on DC recruitment and generation. GM-CSF signaling is identified as the most potent chemotactic factor for conventional DCs and significantly enhanced surface expression of MHC(II) and CD86(+), which are utilized for priming T cell immunity. In contrast, the use of Flt3L vaccines leads to greater numbers of plasmacytoid DCs, correlating with increased levels of T cell-priming cytokines that amplify T cell responses. These results demonstrate that 3D polymer matrices modified to present inflammatory cytokines may be utilized to effectively mobilize and activate different DC subsets in vivo for immunotherapy.