Fes-Deficient Macrophages Prime CD8+ T Cells to Stimulate Antitumor Immunity and Improve Immunotherapy Efficacy

Abstract Homeostatic immunoregulatory mechanisms that prevent adverse effects of immune overaction can serve as barriers to successful anticancer immunity, representing attractive targets to improve cancer immunotherapy. Here, we demonstrated the role of the nonreceptor tyrosine kinase Fes, abundantly expressed in immune cells, as an innate intracellular immune checkpoint. Host Fes deficiency delayed tumor onset in a gene dose-dependent manner and improved tumor control, survival, doxorubicin efficacy, and sensitized tumors to anti–PD-1 therapy in murine triple-negative breast cancer and melanoma models. These effects were associated with a shift to an antitumorigenic immune microenvironment. Fes-deficient macrophages displayed increased Toll-like receptor signaling, proinflammatory cytokine production, and antigen presentation to and activation of T cells, leading to increased cancer cell killing in vitro and tumor control in vivo. This study highlights Fes as an innate immune checkpoint with potential as a therapeutic target and a predictive biomarker to guide immune checkpoint inhibitor treatment. Significance: Fes activity modulates the inflammatory cytokine presentation and T-cell priming capabilities of macrophages, supporting the potential of Fes as a target for developing therapeutic and biomarker strategies to improve cancer immunotherapy.