Boosting therapeutically relevant immunity against lethal epithelial tumors may require targeting tumor-induced immunosuppression on an individualized basis. Here, we show that, in the ovarian carcinoma microenvironment, CD11c⁺MHC-II⁺ dendritic cells spontaneously engulf tumor materials but, rather than enhancing antitumor immunity, suppress T-cell function. In situ costimulation of CD40 and Toll-like receptor (TLR) 3 on tumor-infiltrating dendritic cells decreased their l-arginase activity, enhanced their production of type I IFN and interleukin-12 (p70), augmented their capacity to process antigens, and up-regulated costimulatory molecules in vivo in mice and in vitro in human dissociated tumors. Synergistic CD40/TLR activation also induced the migration of activated dendritic cells to lymphatic locations and promoted their capacity to present antigens. Correspondingly, without exogenous antigen, combined CD40/TLR agonists boosted measurable T-cell–mediated antitumor immunity and induced the rejection of otherwise lethal i.p. ovarian carcinomas. Our results highlight the potential of transforming tumor-infiltrating dendritic cells (the most abundant leukocyte subset in the solid ovarian carcinoma microenvironment) from an immunosuppressive to an immunostimulatory cell type. Combined administration of synergistic CD40 and TLR3 agonists could enhance their individual therapeutic effects against ovarian and other lethal epithelial cancers. [Cancer Res 2009;69(18):7329–37]