Androgen receptor pathway inhibition (ARPI) therapy in prostate cancer induces metabolic stress in tumour cells, which generates acute stress response mechanisms that enable cells to survive. In a study published in Oncogene, the authors explore chaperone-mediated autophagy (CMA) — a selective protein degradation pathway — as a potential mechanism underlying this stress response. CMA was upregulated under ARPI treatment in cell and xenograft models of prostate cancer and promoted cell growth. Notably, CMA inhibition reduced cancer cell growth and re-sensitized enzalutamide-resistant prostate cancer cells. Proteomic analyses conducted in cells in which CMA was upregulated showed a metabolic shift towards amino acid metabolism and biosynthesis, which reversed the effect of ARPI, in turn favouring prostate cancer cell growth. Conversely, CMA inhibition induced a reduction in cancer cell proliferation, which was mediated by the downregulation of EF2 target genes. These results show that CMA is a cytoprotective stress response mechanism in prostate cancer cells, which selectively induces a shift in cell metabolism to support resistance to ARPI. CMI inhibition can counteract this resistance pathway and, therefore, is an important mechanism to investigate for future therapeutic strategies aimed at improving patient response to treatment.