Updated project metadata. Interleukin-12 (IL12) is a pro-inflammatory cytokine with potent anti-cancer activity. Attempts to develop recombinant IL12 as a biopharmaceutical have been hampered by severe toxicity, observed already at daily dose of 500 ng/kg. The antibody-based delivery of IL12 significantly increases the therapeutic index of the cytokine but does not completely prevent side effects associated with peak concentrations of the product in blood upon intravenous administration. Here we describe an innovative technology, named “Intra-CORK”, engineered to mask systemic IL12 activity without impacting anti-tumor efficacy. Our strategy relies on the transient inhibition of the intracellular signaling of IL12 by a kinetically-matched pre-administration of Ruxolitinib, a commercially available JAK2 inhibitor. When treating tumor-bearing mice with the L19-IL12 fusion protein, targeting alternatively-spliced fibronectin, we achieved a long residence time of the cytokine within the tumor with rapid clearance from circulation. The short half-life of Ruxolitinib substantially increased the tolerability profile of L19-IL12 while preserving anti-tumor activity. Our technology relies on judiciously-chosen inhibitors matching circulatory half-lives of biopharmaceuticals and may be broadly applied to other antibody-cytokine fusion products in clinical trials