The cooperative role of the Wnt/β-catenin and PI3K/Akt pathway in resistance to anti-cancer therapies, including immune escape, made the Pten:β-catAct double mutant mice served as an ideal model to study cancer therapy resistance. We found that cooperative Akt:β-catenin signaling is particularly critical for therapy-resistant LSCs. a, Investigating the mechanism underlying this resistance, we unexpectedly found that Akt-activated β-catenin binds to multiple IC genes, which are expressed on LSCs. b, In identifying DXR as an inhibitor of Akt:β-catenin interaction at low doses, we found that DXR could be repurposed as a targeted therapy for resistant LSCs, in part by inhibiting multiple ICs, particularly PD-1/PD-L1. Notably, LSCs but not blast cells exhibit unique properties of immune resistance, which can be reduced with low-dose DXR.