This Funding Opportunity Announcement (FOA) solicits grant applications proposing to utilize bacteria, archaebacteria, bacteriophages, or other non-oncolytic viruses and their natural products to study the underlying mechanisms of the complex interactions between microorganisms, tumors, and the immune system, and to explore their clinical potential for cancer imaging, therapeutics or diagnostics. Projects can focus on using microorganisms as anti-tumor agents, as activators of anti-tumor immunity, or as delivery vehicles for treatment, diagnosis, or imaging, complementing or synergizing with existing tools and approaches. This FOA will support basic mechanistic and preclinical studies in cell culture and animal models. Applicants are encouraged to address both the microbial and tumor aspects of microbial tumor interactions relevant to microbial-based cancer therapy (including therapies for oral cancer), tumor imaging, tumor detection, or diagnosis. The R21 FOA is intended to encourage exploratory projects that are at an early conceptual stage feasibility study (inception through preliminary development) to demonstrate the core functional capabilities of the proposed approach. The proposed projects may involve considerable risk and should be aimed at producing breakthroughs in microbial-based cancer therapy, imaging, or diagnosis. This funding opportunity is part of broader NCI-sponsored research on microbial-based cancer therapy.