Harnessing Prophylactic Vaccines for Targeted Cancer Immunotherapy by Phage-Guided Delivery of Cognate Antigens to Tumors.

Immunotherapies hold great promise for cancer treatment, yet only a small fraction of patients respond to current approaches. We introduce a strategy that redirects pre-existing, vaccine-induced immunity to recognize and eliminate tumors. This method employs newly engineered phage-derived nanoparticles that achieve multilayered tumor specificity through ligand-mediated cell entry, transcriptional targeting, and the delivery of non-mammalian antigens absent from healthy tissues. By leveraging established immune memory, this platform enables highly specific and potent antitumor responses. We validated this concept using a malaria vaccine prototype for redirecting pathogen-specific immunity toward cancer. Specifically, we exploited the malaria epitope Pb9 (SYIPSAEKI), delivered by phage selectively to tumors in mice previously immunized with the Ad.ME-TRAP vaccine. In vitro , Pb9-expressing tumor cells were selectively recognized and destroyed by immune cells from immunized mice, accompanied by robust interferon-γ and tumor necrosis factor-α production. In vivo , systemic administration of the phage nanocarrier achieved highly selective Pb9 expression in tumors while sparing healthy organs. This tumor-restricted expression induced infiltration of antigen-specific cytotoxic T cells and natural killer cells, activation of pro-inflammatory pathways, and apoptosis within tumors. Interestingly, the combination of Ad.ME-TRAP immunization and phage-mediated Pb9 gene delivery led to complete tumor regression in a substantial proportion of animals, with durable long-term cures in over 40% of treated mice. These findings demonstrate a versatile immunotherapeutic strategy that redirects pre-existing vaccine-induced immune responses toward tumors using phage-derived, tumor-selective vectors. Beyond the malaria model, this platform offers a broadly applicable approach for repurposing preventive vaccines into safe and effective cancer immunotherapies.