Combined type 2 cytokine blockade enhances PD-1-mediated antitumor immunity.

Abstract

Immune checkpoint inhibitors improve outcomes for many patients with cancer, but resistance remains a major clinical challenge. Type 2 cytokines, including IL-4, IL-13, and thymic stromal lymphopoietin (TSLP), have been implicated in suppressing anti-tumor immunity. Here, we investigated whether combined blockade of IL-4, IL-13, and TSLP enhances anti-tumor responses alone and in combination with PD-1 inhibition. IL-4 impaired T cell-mediated tumor control and reduced expression of immune-stimulatory molecules by monocyte-derived dendritic cells in vitro. In CT26 and KP787 tumor models, combined blockade of IL-4, IL-13, TSLP, and PD-1 improved tumor growth inhibition and was associated with reprogramming of T cells, monocytes, and dendritic cells toward anti-tumor phenotypes. Across multiple human cancer datasets, transcriptional signatures associated with IL-4/IL-13 and TSLP activity correlated with poorer survival. These findings identify type 2 cytokine signaling as a suppressive pathway in anti-tumor immunity and support its therapeutic targeting to enhance checkpoint inhibitor efficacy.