Cancer immunotherapy can confer durable benefit, but the percentage of patients who respond to this approach remains modest. The ability to concentrate immunostimulatory compounds at the site of disease can overcome local immune tolerance and reduce systemic toxicity. Surgical resection of tumors may improve the efficacy of immunotherapy by removing the concentrated immunosuppressive microenvironment; however, it also removes tumor-specific leukocytes as well as tumor antigens that may be important to establishing antitumor immunity. Moreover, surgery produces a transient immunosuppressive state associated with wound healing that has been correlated with increased metastasis. Using multiple models of spontaneous metastasis, we show that extended release of agonists of innate immunity-including agonists of Toll-like receptor 7/8 (TLR7/8) or stimulator of interferon genes (STING)-from a biodegradable hydrogel placed in the tumor resection site cured a much higher percentage of animals than systemic or local administration of the same therapy in solution. Depletion and neutralization experiments confirmed that the observed prevention of local tumor recurrence and eradication of existing metastases require both the innate and adaptive arms of the immune system. The localized therapy increased the numbers of activated natural killer (NK) cells, dendritic cells, and T cells and induced production of large amounts of type I interferons, thereby converting an immunosuppressive post-resection microenvironment into an immunostimulatory one. The results suggest that the perioperative setting may prove to be a useful context for immunotherapy, particularly when the release of the therapy is extended locally.