GM-CSF switches MDSCs from STAT3 to STAT5 dependent programming, conferring sunitinib resistance. (A,B) Mouse MDSCs were prepared in Flt3L +SCF (STAT3 dependent pathway) and when exposed to sunitinib in vitro were increasingly ssuceptible to apoptosis. Exposure to STAT3 potentiating agents G-CSF and IL-6 was not protective, but exposure to GM-CSF was fully protective. (C) G-CSF or IL-6 cotreatment was associated with elevated pSTAT3, which was disrupted if sunitinib was also added. In contrast, GM-CSF itself preempted pSTAT3 activation with pSTAT5 activation, with no further modulations observed when sunitinib was also added. (D) Preparing MDSCs from STAT5 knockout mice eliminates GM-CSF’s conferral of resistance to MDSCs.