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Myeloid cell receptor tyrosine kinases TYRO3, AXL, and MERTK and their ligands, GAS6 and PROTEIN S, physiologically suppress innate immune responses, including in the tumor microenvironment. Here, we showed that myeloid-derived suppressor cells (MDSC) dramatically upregulated TYRO3, AXL, and MERTK and their ligands [monocytic MDSCs (M-MDSC)&gt;20-fold, polymorphonuclear MDSCs (PMN-MDSC)&gt;15-fold] in tumor-bearing mice. MDSCs from tumor-bearing Mertk -/- , Axl -/-  , and Tyro3 -/-  mice exhibited diminished suppressive enzymatic capabilities, displayed deficits in T-cell suppression, and migrated poorly to tumor-draining lymph nodes. In coimplantation experiments using TYRO3 -/- , AXL -/- , and MERTK -/- MDSCs, we showed the absence of these RTKs reversed the protumorigenic properties of MDSCs in vivo Consistent with these findings, in vivo pharmacologic TYRO3, AXL, and MERTK inhibition diminished MDSC suppressive capability, slowed tumor growth, increased CD8 + T-cell infiltration, and augmented anti-PD-1 checkpoint inhibitor immunotherapy. Mechanistically, MERTK regulated MDSC suppression and differentiation in part through regulation of STAT3 serine phosphorylation and nuclear localization. Analysis of metastatic melanoma patients demonstrated an enrichment of circulating MERTK + and TYRO3 + M-MDSCs, PMN-MDSCs, and early-stage MDSCs (e-MDSC) relative to these MDSC populations in healthy controls. These studies demonstrated that TYRO3, AXL, and MERTK control MDSC functionality and serve as promising pharmacologic targets for regulating MDSC-mediated immune suppression in cancer patients.

TAM Family Receptor Kinase Inhibition Reverses MDSC-Mediated Suppression and Augments Anti–PD-1 Therapy in Melanoma