Fes-deficient macrophages enhance CD8 ⁺ T cell priming and tumour control through increased pro-inflammatory cytokine production and localization

Homeostatic immunoregulatory mechanisms that prevent adverse effects of immune overaction can serve as barriers to successful anti-cancer immunity, representing attractive targets to improve cancer immunotherapy. Here, we demonstrate a novel role of the Fes tyrosine kinase, abundantly expressed in immune cells, as an innate intracellular immune checkpoint. Host Fes-deficiency delays tumour onset in a gene dose-dependent manner and improves murine triple negative breast cancer and melanoma tumour control, survival, doxorubicin efficacy, and anti-PD-1 therapy sensitization. These effects were associated with a shift to an anti-tumourigenic tumour immune microenvironment. In vitro , we observed increased Toll-like receptor signaling, and proinflammatory cytokine production and presentation from antigen presenting cells, leading to increased T cell activation, cancer cell killing and tumour control. This study highlights Fes as a novel innate immune checkpoint with potential as a predictive biomarker for effective immune checkpoint blockade treatment, and a potential therapeutic target to improve anti-cancer immunotherapy.