To promote the clinical translation of “armed” oncolytic viruses (OVs), there is a pressing need for new methods enabling the external control of therapeutic transgene expression to optimize manufacturing, safety and therapeutic outcomes. RNA-switches, consisting of a ligand binding RNA-domain (aptamer) connected to a regulatory RNA-sequence (expression platform), represent promising tools for gene regulation in size-limited DNA- and RNA-based vectors, without relying on the expression of potentially antigenic regulatory proteins. So far, mostly ON-switches with rather moderate induction folds were described and medically relevant inducible systems are still rare. In this work, distinct Tetracycline (Tet)-responsive RNA-ON-switches were assessed for their gene regulatory potential. Transient transfections of RNA-switch systems relying on various expression platforms identified lead RNA-switches for constructing oncolytic adenoviruses (oAds) that express a firefly luciferase in a Tet-dependent manner. Engineered oAds comprising a ribozyme- or a splicing-based RNA-switch showed significant induction upon Tet-addition with up to a 24-fold increase when combined. Importantly, these viruses retained oncolytic activity. Furthermore, the functionality of the designed regulated oAds was validated across various cell lines and distinct temporal schedules. Finally, therapeutic payloads (IL-2, IL-12 and IFN-β) were placed under the control of the most effective RNA-switch system, allowing us to show Tet-inducible cytokine expression from a plasmid (40-fold). In ongoing work, we explore regulated cytokine delivery by oAds and its therapeutic potential to predominantly activate anti-tumor immunity and as safety switch in case of emerging toxicities. The data highlight the transgene-independent functionality of the system, emphasising its broad applicability in gene- and virotherapy.