Here we show that by shiUing the tautomeriza=on driving force from the Tz to the TCO, we are able to rewrite the equa=ons of reac=on performance (Fig. ). In this work, we introduce iTCO, a click-cleavable trans-cyclooctene linker equipped with an intramolecular tautomeriza=on-direc=ng group, enabling excep=onally efficient release with a full array of Tz types, independent of click orienta=on and without compromising the click reac=vity or stability of the Tz. By systema=c mapping of click-to-release performance and the underlying mechanisms, we iden=fied that even the most reac=ve tetrazines trigger complete (>95%) release with iTCO, opening new routes to drive fast click and near-instantaneous release in seconds even at low micromolar concentra=ons. Exploi=ng the unparalleled chemical performance of iTCO and its excellent stability in biological media, we demonstrate bioorthogonal ac=va=on of caged prodrugs in cellular environments and even inside Tz-pretargeted cells with unmatched efficiency. Transla=ng these findings from in vitro to in vivo, we achieved complete intravital cleavage of an iTCO-linked an=body-dye conjugate in less than 5 minutes at remarkably low Tz concentra=ons.