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ResearchIn-Press PreviewCell biologyImmunology Open Access | 10.1172/JCI193354

PPP2R2A insufficiency enhances PD-L1 immune checkpoint blockade efficacy in lung cancer through cGAS-STING activation

Zhaojun Qiu,1 No-Joon Song,2 Anqi Li,2 Deepika Singh,1 Chandra B. Prasad,1 Chunhong Yan,3 David P. Carbone,4 Qi-en Wang,1 Xiaoli Zhang,5 Zihai Li,2 and Junran Zhang1

1Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center and College of Medicine, Columbus, United States of America

2The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncol, The Ohio State University, Columbus, United States of America

3Georgia Cancer Center, Augusta University, Augusta, United States of America

4The James Comprehensive Cancer Center, The Ohio State University, Columbus, United States of America

5USF Health, University of South Florida, Tampa, United States of America

6The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncol, The Ohio State University, Colombus, United States of America

Find articles by Qiu, Z. in: PubMed | Google Scholar

1Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center and College of Medicine, Columbus, United States of America

2The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncol, The Ohio State University, Columbus, United States of America

3Georgia Cancer Center, Augusta University, Augusta, United States of America

4The James Comprehensive Cancer Center, The Ohio State University, Columbus, United States of America

5USF Health, University of South Florida, Tampa, United States of America

6The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncol, The Ohio State University, Colombus, United States of America

Find articles by Song, N. in: PubMed | Google Scholar

1Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center and College of Medicine, Columbus, United States of America

2The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncol, The Ohio State University, Columbus, United States of America

3Georgia Cancer Center, Augusta University, Augusta, United States of America

4The James Comprehensive Cancer Center, The Ohio State University, Columbus, United States of America

5USF Health, University of South Florida, Tampa, United States of America

6The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncol, The Ohio State University, Colombus, United States of America

Find articles by Li, A. in: PubMed | Google Scholar

1Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center and College of Medicine, Columbus, United States of America

2The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncol, The Ohio State University, Columbus, United States of America

3Georgia Cancer Center, Augusta University, Augusta, United States of America

4The James Comprehensive Cancer Center, The Ohio State University, Columbus, United States of America

5USF Health, University of South Florida, Tampa, United States of America

6The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncol, The Ohio State University, Colombus, United States of America

Find articles by Singh, D. in: PubMed | Google Scholar

1Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center and College of Medicine, Columbus, United States of America

2The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncol, The Ohio State University, Columbus, United States of America

3Georgia Cancer Center, Augusta University, Augusta, United States of America

4The James Comprehensive Cancer Center, The Ohio State University, Columbus, United States of America

5USF Health, University of South Florida, Tampa, United States of America

6The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncol, The Ohio State University, Colombus, United States of America

Find articles by Prasad, C. in: PubMed | Google Scholar

1Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center and College of Medicine, Columbus, United States of America

2The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncol, The Ohio State University, Columbus, United States of America

3Georgia Cancer Center, Augusta University, Augusta, United States of America

4The James Comprehensive Cancer Center, The Ohio State University, Columbus, United States of America

5USF Health, University of South Florida, Tampa, United States of America

6The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncol, The Ohio State University, Colombus, United States of America

Find articles by Yan, C. in: PubMed | Google Scholar

1Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center and College of Medicine, Columbus, United States of America

2The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncol, The Ohio State University, Columbus, United States of America

3Georgia Cancer Center, Augusta University, Augusta, United States of America

4The James Comprehensive Cancer Center, The Ohio State University, Columbus, United States of America

5USF Health, University of South Florida, Tampa, United States of America

6The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncol, The Ohio State University, Colombus, United States of America

Find articles by Carbone, D. in: PubMed | Google Scholar

1Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center and College of Medicine, Columbus, United States of America

2The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncol, The Ohio State University, Columbus, United States of America

3Georgia Cancer Center, Augusta University, Augusta, United States of America

4The James Comprehensive Cancer Center, The Ohio State University, Columbus, United States of America

5USF Health, University of South Florida, Tampa, United States of America

6The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncol, The Ohio State University, Colombus, United States of America

Find articles by Wang, Q. in: PubMed | Google Scholar

1Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center and College of Medicine, Columbus, United States of America

2The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncol, The Ohio State University, Columbus, United States of America

3Georgia Cancer Center, Augusta University, Augusta, United States of America

4The James Comprehensive Cancer Center, The Ohio State University, Columbus, United States of America

5USF Health, University of South Florida, Tampa, United States of America

6The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncol, The Ohio State University, Colombus, United States of America

Find articles by Zhang, X. in: PubMed | Google Scholar

1Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center and College of Medicine, Columbus, United States of America

2The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncol, The Ohio State University, Columbus, United States of America

3Georgia Cancer Center, Augusta University, Augusta, United States of America

4The James Comprehensive Cancer Center, The Ohio State University, Columbus, United States of America

5USF Health, University of South Florida, Tampa, United States of America

6The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncol, The Ohio State University, Colombus, United States of America

Find articles by Li, Z. in: PubMed | Google Scholar |

1Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center and College of Medicine, Columbus, United States of America

2The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncol, The Ohio State University, Columbus, United States of America

3Georgia Cancer Center, Augusta University, Augusta, United States of America

4The James Comprehensive Cancer Center, The Ohio State University, Columbus, United States of America

5USF Health, University of South Florida, Tampa, United States of America

6The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncol, The Ohio State University, Colombus, United States of America

Find articles by Zhang, J. in: PubMed | Google Scholar

Published December 18, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI193354.
Copyright © 2025, Qiu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published December 18, 2025 - Version history
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Abstract

PP2A B55α, a regulatory subunit of protein phosphatase 2 (PP2A), is underexpressed in over 40% of non-small cell lung cancer (NSCLC) cases due to loss of heterozygosity of PPP2R2A, the gene encoding this protein. Given that low PPP2R2A expression correlates with poor prognosis, treating PPP2R2A-deficient NSCLC represents an unmet medical need. Here, we show that PPP2R2A knockdown or its heterozygosity (PPP2R2A+/–) increases cytosolic DNA, leading to cGAS-STING-type I interferon (IFN) pathway activation. PPP2R2A deficiency results in elevated expression of immune checkpoint protein PD-L1 via GSK-3β- and STING-dependent mechanisms. PPP2R2A+/– cancer cells have enhanced sensitivity to PD-L1 blockade in a mouse model of lung cancer due to modulation of the tumor immune microenvironment, resulting in increased NK cells and reduced infiltration and function of regulatory T cells (Tregs). Consequently, PD-L1 antibody treatment increases CD8+ T infiltration and activity, especially in tumors with PPP2R2A heterozygosity. Further, systemic or Treg-specific IFNAR1 blockade reduces the efficacy of PD-L1 blockade in PPP2R2A+/– tumors. Patients with NSCLC with a low PPP2R2A/PD-L1 ratio respond better to immune checkpoint blockade (ICB). These findings underscore the therapeutic potential of ICB in treating PPP2R2A-deficient NSCLC while suggesting that PPP2R2A deficiency could serve as a biomarker for guiding ICB-based therapies.

Supplemental material

View Unedited blot and gel images

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View Supplementary Table 1. Output of Cox Proportional Hazard regression testing the association between PPP2R2A and patient surival.

View Supplementary Table 2. shRNAs used in this study

View Supplementary Table 3. Primers for qRT-PCR

View Supplementary Table 4. Antibodies for immune blotting

View Supplementary Table 5. Immune profiling panel

View Supplementary Table 6. T cell exhaustion panel

View Materials and methods for supplementary data

Version history
  • Version 1 (December 18, 2025): In-Press Preview
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