Targeting P2RY2 reprograms tumor immunity and inhibits tumor growth in non-small cell lung cancer
(2026) In Cancer Letters 647.- 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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2026-06-01
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Cytotoxic CD8 T cells, M2-like macrophages, Non-small cell lung cancer, P2RY2, Purinergic receptors
- in
- Cancer Letters
- volume
- 647
- article number
- 218448
- publisher
- Elsevier
- external identifiers
-
- pmid:41887391
- scopus:105033661835
- ISSN
- 0304-3835
- DOI
- 10.1016/j.canlet.2026.218448
- language
- English
- LU publication?
- yes
- id
- f3ce64c5-5bb0-4802-84be-958cb69b8f80
- date added to LUP
- 2026-06-08 16:19:29
- date last changed
- 2026-09-02 05:29:47
@article{f3ce64c5-5bb0-4802-84be-958cb69b8f80,
abstract = {{<p>The enrichment of immunosuppressive M2 macrophages, combined with diminished CD8<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> 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 <sup> −/− </sup> 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<sup>+</sup> T cells from the TME. Targeting P2RY2 may offer a novel immunotherapeutic intervention for NSCLC.</p>}},
author = {{El-Gazzar, Ahmed and Aschenbrenner, Bertram and Forsthuber, Agnes and Kramer, Markus and Kargarpour, Zahra and Metekol, Seda and John, Lisa and Papaporfyriou, Anastasia and Bereš, Maša and Trouvilliez, Sarah and Homolya, Monika and Döme, Balázs and Megyesfalvi, Zsolt and Horvath, Lilla and Lang, Christian and Hoda, Mir Alireza and Zeillinger, Robert and Obermayr, Eva and Geleff, Silvana and Frommlet, Florian and Lichtenberger, Beate M. and Gompelmann, Daniela and Casanova, Emilio and Moll, Herwig P. and Idzko, Marco}},
issn = {{0304-3835}},
keywords = {{Cytotoxic CD8 T cells; M2-like macrophages; Non-small cell lung cancer; P2RY2; Purinergic receptors}},
language = {{eng}},
month = {{06}},
publisher = {{Elsevier}},
series = {{Cancer Letters}},
title = {{Targeting P2RY2 reprograms tumor immunity and inhibits tumor growth in non-small cell lung cancer}},
url = {{http://dx.doi.org/10.1016/j.canlet.2026.218448}},
doi = {{10.1016/j.canlet.2026.218448}},
volume = {{647}},
year = {{2026}},
}