A prodrug enzyme covalently photoconjugated to a live cell receptor survives endosomal proteolysis and retains its catalytic activity on the living cell membrane over multiple days. Antibody-directed enzyme prodrug therapy is a promising approach for selective treatment of solid tumors, but methods are needed to preserve enzyme activity on living cell membranes over multiple prodrug dosings. A fusion protein was designed with both an anti-epidermal growth factor receptor (EGFR) affibody and the prodrug enzyme cytosine deaminase, which can convert prodrug 5-fluorocytosine to the anticancer drug 5-fluorouracil. A benzophenone group was added at a site-specific mutation within the affibody portion, and the fusion protein was selectively and irreversibly photoconjugated to EGFR receptors expressed on membranes of live MDA-MB-468 breast cancer cells. Affinity-mediated covalent conjugation of the affibody-enzymes to cell receptors allows for prolonged expression on membranes and retained enzymatic activity without genetic engineering.