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Many immune mechanisms exist to prevent unchecked inflammation. Monjazeb and colleagues demonstrate that, after stimulatory immunotherapies such as radiotherapy + CpG, there is an onset of suppression orchestrated by indolamine-2,3-dioxygenase (IDO) that limits the antitumor effects of therapy. The addition of IDO blockade significantly improves efficacy by preventing this therapy-induced immune suppression in mouse and canine clinical trials. This study shows how a deeper understanding of the checks and balances of the immune system can further improve the efficacy of cancer immunotherapy and also demonstrates the potential of canines with spontaneous tumors as a highly relevant model of human malignancy.Hyperactive MYC signaling is an oncogenic driver for a large proportion of human tumors, but so far no MYC-directed therapeutic has been approved for clinical use. Polyamines are cationic chaperones that support MYC activities, and their homeostasis is critical to both initiating and maintaining the cancer phenotype. Evageliou and colleagues demonstrate therapeutics that deplete tumoral polyamines (such as DFMO, celecoxib, and SAM486), synergize to block tumor initiation, and regress established tumors in models of lethal childhood tumor neuroblastoma. These data strongly support the testing of such approaches in the clinic.EPI binds the N-terminal domain of an androgen receptor (AR) to block the transcriptional activities of full-length AR and constitutively active AR splice variants (AR-V). EPI is the first drug developed against AR NTD, and its prodrug is currently in clinical trials for prostate cancer patients failing abiraterone and/or enzalutamide, which have no effect on AR-V. Yang and colleagues show that EPI displays potent in vivo efficacy against enzalutamide-resistant tumors that are considered to be driven by AR-V and show that EPI blocks other known AR mechanisms of resistance. EPI may provide significant therapeutic benefit for patients with prostate cancer.Epithelial-to-mesenchymal transition is a complex process through which epithelial cancer cells acquire a reversible change in phenotype. Boufraqech and colleagues show that LOX transcriptionally regulates SNAI2 expression. SNAI2 knockdown recapitulates the phenotypic effects of LOX in vitro and in vivo, suggesting a LOX–SNAI2 axis in cancer progression. In addition, the effect of the LOX–SNAI2 axis in cancer progression is mediated by TIMP4 secretion SNAI2, and TIMP4 proteins are overexpressed in aggressive thyroid, breast, and colon cancer. These findings have important consequences for developing strategies to block this axis and control cancer progression.