Purpose: Cancer stem-like cells (CSC) contribute to the progression and androgen 
deprivation therapy (ADT) resistance of prostate cancer. As CSCs depend on their 
specific niche, including tumor-associated macrophages (TAM), elucidating the 
network between CSCs and TAMs may help to effectively inhibit the progression 
and ADT resistance of prostate cancer.Experimental Design: The underlying 
intracellular mechanism that sustains the stem-like characteristics of CSCs in 
prostate cancer was assessed via RNA sequencing, co-immunoprecipitation, 
chromatin immunoprecipitation, and other assays. A coculture system and cytokine 
antibody arrays were used to examine the interaction network between CSCs and 
TAMs. In addition, an orthotopic prostate cancer model was established to 
evaluate the in vivo effects of the combined targeting of CSCs and their 
interaction with TAMs on ADT resistance.Results: Autophagy-related gene 7 (ATG7) 
facilitated the transcription of OCT4 via β-catenin, which binds to the OCT4 
promoter, promoting CSC characteristics in prostate cancer, including 
self-renewal, tumor initiation, and drug resistance. In addition, CSCs remodeled 
their specific niche by educating monocytes/macrophages toward TAMs, and the 
CSC-educated TAMs reciprocally promoted the stem-like properties of CSCs, 
progression and ADT resistance of prostate cancer via IL6/STAT3. Furthermore, 
the combined targeting of CSCs and their interaction with TAMs by inhibiting 
ATG7/OCT4 and IL6 receptor effectively ameliorated ADT resistance in an 
orthotopic prostate cancer model.Conclusions: Targeting CSCs and their niche may 
prove to be a more powerful strategy than targeting CSCs alone, providing a 
rational approach to ameliorating ADT resistance in prostate cancer. Clin Cancer 
Res; 24(18); 4612-26. ©2018 AACR.