Systemic toxicity prevents full clinical application of cytokines such as type I interferons or Tumor Necrosis Factor, including their use in cancer. We will evaluate a novel strategy to selectively target cytokine activity in vivo, aiming at an up to 1000-fold enhanced activity on cells expressing a specific surface marker. We will develop so-called AcTakines (Activity-on-Target cytokines), which resemble immunocytokines but employ mutant cytokines with reduced binding affinity for their receptor complex.