Interleukin-4 modulates type I interferon to augment antitumor immunity
- Hannah V. Newnes
- Jesse D. Armitage
- Anthony C. Buzzai
- Emma de Jong
- Katherine M. Audsley
- Samantha A. Barnes
- Shamini Srinivasan
- Michael Serralha
- Vanessa S. Fear
- Belinda B. Guo
- Matt E. Jones
- Alistair R. R. Forrest
- Bree Foley
- Phil K. Darcy
- Paul A. Beavis
- Anthony Bosco
- Jason Waithman
2025-05-14
Despite advances in immunotherapy, metastatic melanoma remains a considerable therapeutic challenge due to the complexity of the tumor microenvironment. Intratumoral type I interferon (IFN-I) has long been associated with improved clinical outcomes. However, several IFN-I subtypes can also paradoxically promote tumor growth in some contexts. We investigated this further by engineering murine B16 melanoma cells to overexpress various IFN-I subtypes, where a spectrum of outcomes was observed. Characterization of these tumors by RNA sequencing revealed a tumor immune phenotype, where potent IFN-I signaling concomitant with diminished type 2 inflammation failed to confer durable tumor control. T cell–mediated rejection of these tumors was restored by introducing interleukin-4 (IL-4) into the tumor microenvironment, either through ectopic expression or in a preclinical adoptive T cell therapy model. Collectively, our findings highlight the IFN-I/IL-4 axis in promoting antitumor immunity, which could be harnessed to target and stratify solid tumors that are nonresponsive to frontline therapies.