As anionic biopolymers, oligonucleotides can have biological functions independent from their roles as the medium for the storage and flow of genetic information. In this paper, we investigated the interaction between DNA and the pro-inflammatory cytokine tumor necrosis factor-? (TNF?). Although various forms of DNA bind to TNF? with low ?m dissociation constants, the interaction stabilizes the trimeric form of TNF? and enhances its cytotoxic effect. Based on this mechanism, a photoswitchable TNF? (TNF?-2-nitroveratryloxycarbonyl) has been designed whose sensitivity to DNA-mediated up-regulation of TNF? activity can be tuned by light irradiation. The mechanism described in this study represents a general model to understand the involvement of nonspecific interactions among biomolecules in regulating their biological functions. Because the interaction is not DNA sequence-specific, the resulting effect should be considered for oligonucleotide-based therapeutics in general.