Described herein are compositions and methods that confine Cerenkov light to a localized area for targeted treatment and/or imaging of tumor cells. In certain embodiments, such compositions include a Cerenkov-activated tagging agent comprising a payload and a covalent binding unit such as an azide. The payload can be an imaging agent, a contrast agent, and/or a therapeutic. In certain embodiments, a radiolabelled biomarker (e.g., 18F-FDG (fluorodeoxyglucose), 18F-FLT (fluorothymidine)) or other radiolabelled tumor cell targeting agent that emits Cerenkov luminescence is also administered. Upon local illumination by the Cerenkov luminescence at or near the location of the tumor cells, the payload (the imaging agent, contrast agent, and/or therapeutic) is activated. In this way, activation of the imaging agent, contrast agent, and/or therapeutic agent is limited to the region at or near the location of the tumor cells.