Fes-deficient macrophages enhance CD8 ⁺ T cell priming and tumour control through increased proinflammatory cytokine production and presentation

Activating the immune system is crucial for successful cancer immunotherapies, various proteins, such as the Fes non-receptor tyrosine kinase exist to limit activation and maintain homeostasis. However, in cancer settings, this serves as a barrier to the desired effects of immune activation following immunomodulatory treatment. Here, we demonstrate the role of Fes, a protein abundantly expressed in macrophages, as a novel innate intracellular immune checkpoint. Fes inactivity is associated with delayed tumour onset in a dose-dependent manner, and its deletion delays tumour growth, improves survival, enhances response to doxorubicin treatment, and sensitizes resistant tumours to PD-1 immune checkpoint inhibition. These effects are associated with an increase in Toll-like receptor signaling in antigen presenting cells, leading to an increase in proinflammatory cytokine production and cytotoxic T cell effector functions. Furthermore, we demonstrate a novel role for Fes in regulating the presentation of IL-12 on macrophage cell surfaces to enhance T-cell activation. Our results highlight Fes as a novel innate immune checkpoint with potential to serve as predictive biomarker to effective immune checkpoint blockade, and a potential novel therapeutic target for improved response to immunotherapy.