Targeting ABL kinases overcomes melanoma immune evasion following resistance to MAPK inhibition

MAPK inhibitors (MAPKi) are important treatment options for some patients with metastatic melanoma; however, resistance inevitably develops in the vast majority of cases (>70%). Here, using immune-proficient mouse models, single-cell RNA sequencing, flow cytometry, and datasets from patients treated with MAPKi, we demonstrate that ABL kinases (ABL1/2) promote MAPKi resistance not only by impacting intracellular signaling but also by driving secretion of chemokines that suppress the immune microenvironment. Targeting ABL1/2 reduces chemokine secretion by melanoma cells, prevents immunosuppressive myeloid-derived suppressor cell (MDSC) infiltration, and promotes accumulation of cytotoxic CD8⁺ T cells. Depletion of MDSCs prevents resistance, and depletion of CD8⁺ T cells or re-expression of chemokines blocks ABL inhibitors from preventing resistance. Importantly, CXCR2 receptor ligand expression and ABL1/2 activity are reduced in patients who respond to treatment but increased during resistance. Thus, the dual role of ABL1/2 in proliferation/survival and immune suppression makes them attractive targets for potential treatments.