Targeting P2RY2 reprograms tumor immunity and inhibits tumor growth in non-small cell lung cancer
Year: 2026
Type: article
Abstract: The enrichment of immunosuppressive M2 macrophages, combined with diminished CD8 + T cell infiltration, represents a key mechanism driving tumor progression and limiting immunotherapy efficacy in non-small cell lung cancer (NSCLC). Here, we provide evidence that the purinergic P2Y2 receptor (P2RY2) is a key regulator of M2 macrophage enrichment and contributes to the exclusion of CD8 + T cells from the tumor microenvironment (TME). P2RY2 expression is significantly elevated in human NSCLC compared to non-malignant tissues and M2-like macrophages expressing P2RY2 are more prevalent in tumors with an advanced TNM (Tumor, Node, Metastasis) stage. Elevated P2RY2 mRNA levels are significantly associated with poorer overall survival in a NSCLC patients. Furthermore, we selectively inhibited P2RY2 in syngeneic or autochthonous mouse models of NSCLC driven by Kras or Egfr mutations. This resulted in a significant reduction of M2-like macrophages, enhanced CD8 + T cell migration and tumor infiltration and a marked decrease in tumor burden. Similar results were evident following the genetic deletion of P2ry2 , validating the impact on the TME. Importantly, macrophages are the predominant P2RY2-expressing cells within the TME. Moreover, tumor-educated macrophages (TEMs) isolated from P2ry2 −/− tumor-bearing mice exhibited reduced proliferation compared with wild-type macrophages when co-cultured with LLC1 cells, revealing a potential mechanism underlying P2RY2-mediated pro-tumorigenic activity. Our study underscores the clinical significance of P2RY2 in NSCLC and provides evidence of its pivotal role in the regulation of M2 macrophage enrichment and the exclusion of CD8 + T cells from the TME. Targeting P2RY2 may offer a novel immunotherapeutic intervention for NSCLC.
Source: Cancer Letters
Authors: Ahmed El-Gazzar, Bertram Aschenbrenner, Agnes Forsthuber, Markus Kramer, Zahra Kargarpour, Seda Metekol, Lisa John, Anastasia Papaporfyriou, Maša Bereš, Sarah Trouvilliez, Monika Homolya, Balázs Döme, Zsolt Megyesfalvi, Lilla Horvath, Christian Lang, Mir Alireza Hoda, Robert Zeillinger, Eva Obermayr, Silvana Geleff, Florian Frommlet, Beate M. Lichtenberger, Daniela Gompelmann, Emilio Casanova, Herwig P. Moll, Marco Idzko
Language: English
Subfield: Physiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,960
Funders: International Association for the Study of Lung Cancer, Österreichischen Akademie der Wissenschaften, Austrian Science Fund, Magyar Tudományos Akadémia, Medizinische Universität Wien, Magistrat der Stadt Wien, Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, Innovációs és Technológiai Minisztérium
OpenAlex ID: W7140174659