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Elevated expression of the myeloid cell-specific Src-family kinase HCK occurs in a majority of solid malignancies and correlates with poor patient survival [Poh et al., Frontiers Oncol 2018]. We have recently shown that genetic ablation, or therapeutic inhibition, of HCK suppresses the growth of primary tumors arising in the colon, stomach, lung and other mutagenized epithelia of mice. Mechanistically, we have attributed this to the capacity of HCK activity to support and retain the polarization of a wound-healing, Tie2+ (i.e. alternative activated) endotype of tumor-associated macrophages and concomitant tumor vascularization [Poh et al., Cancer Cell2017]. Here we extend these observations to MC38 colon cancer, B6/F10 melanoma and EO771 breast cancer allograft model, where the growth of the primary lesion and its metastatic spread is suppressed in HCK knockout hosts. More importantly, HCK gene deletion or therapeutic HCK inhibition with a small kinase inhibitor in mouse models further enhances the anti-tumor effects conferred by either chemotherapy or single agent immunotherapies based on anti-PD-L1, anti-CTLA4 or agonistic-CD40 antibodies. These observations are underpinned by increased tumour cell apoptosis that coincides with enhanced expression of ifng, gzmb, prf1 and other effector proteins in NK and infiltrating CD8+ cells. Likewise, HCK inhibition confers increased expression of il12 and ifng in tumor-associated macrophages, which adopt a more conventional activated endotype. Because HCK-deficiency of the host also associated with increased abundance of tumor infiltrating effectors cells, we propose that therapeutic targeting of HCK not only “makes tumors hotter”, but also improves host anti-tumor immunity. We are therefore developing novel HCK-specific small molecule inhibitors. Citation Format: Matthias R. Ernst, Ashwini Chand, Nicholas Huntington, Robert O'Donoghue, Ashleigh Poh. Targeting the myeloid-cell specific SRC-kinase HCK improves anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-135.