Rational design of chemically responsive cytokines for cancer immunotherapy

Cytokines are key signal mediators of the immune system, playing essential roles in regulating central immunological processes. Despite their unique ability to modulate the immune system, the translation of cytokine-based therapies to the clinic has been significantly hindered by severe toxicities resulting from the pleiotropy and off-target effects of many cytokines. Here, we present a general strategy for the design of switchable cytokines that enables precise control over cytokine activity using the clinically approved drug, Venetoclax. We rationally designed self-inhibited Switchable InterLeukins (SwILs) by embedding the chemically controlled interface (Bcl-2: BIM-BH3) into the cytokine’s structure, resulting in conditional cytokines activated by Venetoclax. We showed the broad applicability of this strategy across various cytokines, including IL-2, IL-15, and IL-10. In vivo studies with IL-15 demonstrated that the SwILs achieved Venetoclax-dependent tumor control comparable to that of the native cytokine. Additionally, we showed that this strategy can be expanded to respond to other tumor-intrinsic stimuli, such as tumor-specific proteases. Overall, SwILs offer control of cytokine activity, enhancing the safety and clinical applicability of cytokine-based therapeutics.