Immunotherapies have revolutionized cancer treatment; however, they do not work for all patients. Today’s immunotherapies, including checkpoint blockade and CAR-T cells, rely on knowing a patient’s specific tumor mutations to target treatments. Developing off-the-shelf tumor agnostic immunotherapies would overcome barriers to effective treatment including cost and development time. Salmonella locate to the tumor microenvironment with high specificity, are innately immunostimulatory, and can produce protein products – making them a promising treatment vehicle. In this dissertation, I engineered Salmonella using three approaches to develop tumor agnostic therapies. First, immune controlling Salmonella were engineered to controllably produce surface lipopolysaccharides through tuned expressed of the gene msbB to increase their immunogenicity. Production levels were controlled by distinct ribosomal binding sites and protein degradation tags to produce an effective dose below the toxicity threshold. Controlled lipopolysaccharide production activated monocytes in vitro and in vivo increasing TNFα production without inducing mouse illness. Immune controlling Salmonella reduced tumor growth and increased survival. Second, Salmonella were engineered to intracellularly deliver the COVID-19 spike protein to cancer cells to redirect vaccine immunity. In this work, I engineered a fusion protein of the most immunogenic regions of the spike protein. Delivery of this fusion protein activated spike-specific T cells from prior vaccination. In vivo, spike protein delivery by Salmonella reduced tumor growth and activated antigen presenting cells to generate further anti-tumor immunity. I developed a mathematical model of tumor immunotherapy using antigen delivering Salmonella to elucidate the interactions between Salmonella, cancer cells, and T cells. In this model, I observed that a balance between intracellular and extracellular Salmonella is critical for effective therapies. Thirdly, I developed a technique of bacterial pre-targeted radioimmunotherapy for the localization of the radiohapten DOTA to tumors. I engineered Salmonella to express DOTA binding antibody fragments on their surface. In this project, I tested three systems for surface display and determined that using an OmpA fusion protein strongly bound to DOTA in vitro with similar kinetics to the free antibody. Each of these antigen agnostic therapies targets treatments to tumors without knowledge of the tumor mutations, overcoming a major limitation of traditional immunotherapies.