RT Journal Article SR Electronic T1 Inhibition of Vps34 reprograms cold into hot inflamed tumors and improves anti–PD-1/PD-L1 immunotherapy JF Science Advances JO Sci Adv FD American Association for the Advancement of Science SP eaax7881 DO 10.1126/sciadv.aax7881 VO 6 IS 18 A1 Noman, Muhammad Zaeem A1 Parpal, Santiago A1 Van Moer, Kris A1 Xiao, Malina A1 Yu, Yasmin A1 Arakelian, Tsolere A1 Viklund, Jenny A1 De Milito, Angelo A1 Hasmim, Meriem A1 Andersson, Martin A1 Amaravadi, Ravi K. A1 Martinsson, Jessica A1 Berchem, Guy A1 Janji, Bassam YR 2020 UL http://advances.sciencemag.org/content/6/18/eaax7881.abstract AB One of the major challenges limiting the efficacy of anti–PD-1/PD-L1 therapy in nonresponding patients is the failure of T cells to penetrate the tumor microenvironment. We showed that genetic or pharmacological inhibition of Vps34 kinase activity using SB02024 or SAR405 (Vps34i) decreased the tumor growth and improved mice survival in multiple tumor models by inducing an infiltration of NK, CD8+, and CD4+ T effector cells in melanoma and CRC tumors. Such infiltration resulted in the establishment of a T cell−inflamed tumor microenvironment, characterized by the up-regulation of pro-inflammatory chemokines and cytokines, CCL5, CXCL10, and IFNγ. Vps34i treatment induced STAT1 and IRF7, involved in the up-regulation of CCL5 and CXCL10. Combining Vps34i improved the therapeutic benefit of anti–PD-L1/PD-1 in melanoma and CRC and prolonged mice survival. Our study revealed that targeting Vps34 turns cold into hot inflamed tumors, thus enhancing the efficacy of anti–PD-L1/PD-1 blockade.