@misc{10481/108582,
year = {2025},
month = {10},
url = {https://hdl.handle.net/10481/108582},
abstract = {Extracellular ATP (eATP) accumulates substantially in the tumor microenvironment (TME) and rises further during immunotherapy. While canonically an immune-activating “danger” signal, eATP also promotes immunosuppression in tumors, thus far largely attributed to its metabolite, adenosine. Here, we identify direct eATP signaling through P2RY2 as a dominant, adenosine-
independent mechanism of immune resistance. Specifically, eATP–P2RY2 signaling serves as the primary upstream driver of COX-1/2 upregulation and consequent accumulation of immunosuppressive PGE₂ in the TME, uncovering the long-sought TME-specific trigger of pathological COX–PGE₂ hyperactivation in solid tumors. Genetic deletion or pharmacologic inhibition of P2RY2 eliminates both baseline and therapy-induced intratumoral PGE₂, restores antitumor T cell responses, and reverses resistance to CAR-T, TCR-T, checkpoint blockade, and TIL therapies. Given that persistently elevated eATP is a hallmark of solid tumors, our work
reveals a fundamental mechanism by which tumors hijack innate “danger” signaling to establish immune suppression and develop adaptive resistance to immunotherapy. These findings establish P2RY2 as a purinergic immune checkpoint with translational potential for combinatorial cancer immunotherapies.},
organization = {European Research Council, 101078722},
organization = {DKFZ/Bayer Innovation Alliance, P2RY2},
organization = {Israel Ministry of Science and Technology, Ca 208},
publisher = {bioRxiv},
keywords = {P2RY2},
keywords = {Immunotherapy},
keywords = {ATP},
title = {P2RY2 is a purinergic immune checkpoint linking extracellular ATP to immune evasion and adaptive resistance to immunotherapy},
doi = {10.1101/2025.10.09.681049},
author = {Hu, Zhaoqing and Matsuo, Hitoshi and Du, Shangce and Berzain Battion, Cecilia and Jassowicz, Lena and Carretero, Rafael and Sator-Schmit, Melanie and Zhao, Xiyue and Miao, Beiping and Eris, Cansu and Engel, Helena and Mahmoud, Mohamed A.A. and Lapor, Elke and Xiao, Yanling and Hofmann, Ilse and Herold-Mende, Christel and Sun, Chong},
}