BACKGROUND: Macrophages have been classically associated with their innate immune functions of responding to acute injury or pathogenic insult, but they have been largely overlooked as primary initiators of adaptive immune responses. Here, we demonstrate that adoptively transferred macrophages, with optimal activation prior to administration, act as a potent cellular cancer therapeutic platform against a murine melanoma model. METHOD: The macrophage therapy was prepared from bone marrow-derived macrophages, pretreated ex vivo with an activation cocktail containing interferon-γ, tumor necrosis factor-α, polyinosinic:polycytidylic acid, and anti-CD40 antibody. The therapy was administered to tumor-bearing mice via the tail vein. Tumor growth and survival of the treated mice were monitored to evaluate therapeutic efficacy. Tumors and spleens were processed to examine immune responses and underlying mechanisms. RESULTS: This immunotherapy platform elicits systemic immune responses while infiltrating the tumor to exert direct antitumor effects in support of the systemic adaptive response. The macrophage-based immunotherapy produced a strong CD8+T cell response along with robust natural killer and CD4+T cell activation, inducing a "hot" tumor transition and achieving effective tumor suppression. CONCLUSIONS: Owing to their inherent ability to home to and infiltrate inflamed tissues, macrophage-based cancer immunotherapies exhibited a unique in vivo trafficking behavior, efficiently reaching and persisting within tumors. Macrophages orchestrated a multiarmed immune attack led by CD8+T cells, with the potential for local, intratumoral activation of effector cells, demonstrating a novel cancer immunotherapy platform with meaningfully different characteristics than clinically evaluated alternatives.