Abstract
Despite the increasing recognition of pyroptosis, particularly that involving GSDME, its precise impact on tumor prognosis and the immune microenvironment remains elusive, necessitating a comprehensive investigation in the context of lung adenocarcinoma (LUAD). We aimed to construct a pyroptosis-related prognostic model and to elucidate the intricate dynamics of GSDME-mediated pyroptosis in shaping tumor immunity in LUAD. We developed a pyroptosis-related prognostic model using machine learning. GSDME-mediated pyroptosis in LUAD cells was induced using CHX and TNF-α. HMGB1 content in the cell supernatant after cell pyroptosis and in serum from patients before treatment with PD-1/PD-L1 antibodies was determined by Enzyme-Linked Immunosorbent Assay. In vivo, Lewis lung carcinoma (LLC)-bearing C57 mice were treated with cisplatin and/or caspase-3 inhibitors, anti-PD-1, and IL-8 inhibitors, with tumor growth monitored. Our prognostic prediction model (PYR_score), built upon pyroptosis-related genes, demonstrated high efficacy in predicting LUAD prognosis across diverse datasets. Machine learning analyses revealed that higher PYR_score values correlated with shorter progression-free and overall survival. CHX and TNF-α induced GSDME-mediated pyroptosis with elevated HMGB1. Increased HMGB1 was associated with worse therapeutic efficacy of immune checkpoint inhibitors in LUAD patients. HMGB1 increased the proliferative ability and IL-8 secretion of Treg cells in vitro. Caspase-3 and IL-8 inhibitors slowed tumor growth, and IL-8 inhibitors possibly enhanced the effectiveness of anti-PD-1 immunotherapy in LLC-bearing mice. In summary, our novel PYR_score is a robust prognostic marker, offering predictive power across different datasets. GSDME-mediated pyroptosis modulated the immunosuppressive microenvironment via elevations in HMGB1, Treg cells, and MDSCs. IL-8 inhibitors may inhibit Tregs and MDSCs and enhance the effectiveness of anti-PD-1 immunotherapy. Further clinical validation and exploration of therapeutic interventions targeting these pathways are essential for translating these findings into clinical practice.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to the full article PDF.
USD 39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Peltzer N, Walczak H. Cell death and inflammation - a vital but dangerous liaison. Trends Immunol. 2019;40:387–402.
Christgen S, Tweedell RE, Kanneganti TD. Programming inflammatory cell death for therapy. Pharmacol Ther. 2022;232:108010.
Hou J, Hsu JM, Hung MC. Molecular mechanisms and functions of pyroptosis in inflammation and antitumor immunity. Mol Cell. 2021;81:4579–90.
Tang R, Xu J, Zhang B, Liu J, Liang C, Hua J, et al. Ferroptosis, necroptosis, and pyroptosis in anticancer immunity. J Hematol Oncol. 2020;13:110.
Song W, Ren J, Xiang R, Kong C, Fu T. Identification of pyroptosis-related subtypes, the development of a prognosis model, and characterization of tumor microenvironment infiltration in colorectal cancer. Oncoimmunology. 2021;10:1987636.
Wang Q, Wang Y, Ding J, Wang C, Zhou X, Gao W, et al. A bioorthogonal system reveals antitumour immune function of pyroptosis. Nature. 2020;579:421–6.
Miao R, Jiang C, Chang WY, Zhang H, An J, Ho F, et al. Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis. Immunity. 2023;56:2523–41.e8.
Liu X, Lieberman J. Inflammasome-independent pyroptosis. Curr Opin Immunol. 2024;88:102432.
Zdanov S, Mandapathil M, Abu Eid R, Adamson-Fadeyi S, Wilson W, Qian J, et al. Mutant KRAS conversion of conventional T cells into regulatory T cells. Cancer Immunol Res. 2016;4:354–65.
Yang Z, Gao Y, He K, Sui X, Chen J, Wang T, et al. Voluntarily wheel running inhibits the growth of CRPC xenograft by inhibiting HMGB1 in mice. Exp Gerontol. 2023;174:112118.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.
Friedlaender A, Addeo A, Russo A, Gregorc V, Cortinovis D, Rolfo CD. Targeted therapies in early stage NSCLC: hype or hope? Int J Mol Sci. 2020;21:6329.
Meza R, Meernik C, Jeon J, Cote ML. Lung cancer incidence trends by gender, race and histology in the United States, 1973-2010. PLoS One. 2015;10:e0121323.
Thai AA, Solomon BJ, Sequist LV, Gainor JF, Heist RS. Lung cancer. Lancet. 2021;398:535–54.
Dong ZY, Zhang C, Li YF, Su J, Xie Z, Liu SY, et al. Genetic and immune profiles of solid predominant lung adenocarcinoma reveal potential immunotherapeutic strategies. J Thorac Oncol. 2018;13:85–96.
Borghaei H, Gettinger S, Vokes EE, Chow LQM, Burgio MA, de Castro Carpeno J, et al. Five-year outcomes from the randomized, phase III trials CheckMate 017 and 057: nivolumab versus docetaxel in previously treated non-small-cell lung cancer. J Clin Oncol. 2021;39:723–33.
Han G, Yang G, Hao D, Lu Y, Thein K, Simpson BS, et al. 9p21 loss confers a cold tumor immune microenvironment and primary resistance to immune checkpoint therapy. Nat Commun. 2021;12:5606.
Pan D, Hu AY, Antonia SJ, Li CY. A gene mutation signature predicting immunotherapy benefits in patients with NSCLC. J Thorac Oncol. 2021;16:419–27.
Tartour E, Zitvogel L. Lung cancer: potential targets for immunotherapy. Lancet Respir Med. 2013;1:551–63.
Luo G, He Y, Yang F, Zhai Z, Han J, Xu W, et al. Blocking GSDME-mediated pyroptosis in renal tubular epithelial cells alleviates disease activity in lupus mice. Cell Death Discov. 2022;8:113.
Kovács SA, Fekete JT, Győrffy B. Predictive biomarkers of immunotherapy response with pharmacological applications in solid tumors. Acta Pharmacol Sin. 2023;44:1879–89.
García-Mulero S, Alonso MH, Pardo J, Santos C, Sanjuan X, Salazar R, et al. Lung metastases share common immune features regardless of primary tumor origin. J Immunother Cancer. 2020;8:e000491.
Hänzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics. 2013;14:7.
Geeleher P, Cox N, Huang RS. pRRophetic: an R package for prediction of clinical chemotherapeutic response from tumor gene expression levels. PLoS One. 2014;9:e107468.
Gebhardt C, Sevko A, Jiang H, Lichtenberger R, Reith M, Tarnanidis K, et al. Myeloid cells and related chronic inflammatory factors as novel predictive markers in melanoma treatment with lpilimumab. Clin Cancer Res. 2015;21:5453–9.
Demoulin S, Herfs M, Somja J, Roncarati P, Delvenne P, Hubert P. HMGB1 secretion during cervical carcinogenesis promotes the acquisition of a tolerogenic functionality by plasmacytoid dendritic cells. Int J Cancer. 2015;137:345–58.
Fousek K, Horn LA, Palena C. Interleukin-8: a chemokine at the intersection of cancer plasticity, angiogenesis, and immune suppression. Pharmacol Ther. 2021;219:107692.
Sanmamed MF, Perez-Gracia JL, Schalper KA, Fusco JP, Gonzalez A, Rodriguez-Ruiz ME, et al. Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small-cell lung cancer patients. Ann Oncol. 2017;28:1988–95.
Schalper KA, Carleton M, Zhou M, Chen T, Feng Y, Huang SP, et al. Elevated serum interleukin-8 is associated with enhanced intratumor neutrophils and reduced clinical benefit of immune-checkpoint inhibitors. Nat Med. 2020;26:688–92.
Liu Q, Chen Z, Wang B, Pan B, Zhang Z, Shen M, et al. Leveraging network target theory for efficient prediction of drug-disease interactions: a transfer learning approach. Adv Sci (Weinh). 2025;12:e2409130.
Huang C, Lei C, Pan B, Fang S, Chen Y, Cao W, et al. Potential prospective biomarkers for non-small cell lung cancer: mini-chromosome maintenance proteins. Front Genet. 2021;12:587017.
Acknowledgements
This work was supported by National Natural Science Foundation of China (82072595, 81773207), Natural Science Foundation of Tianjin (23JCZDJC00710), Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-061B), Tianjin Health Science and Technology Project (TJWJ2022XK005), and Beijing Science and Technology Innovation Medical Development Fund grant (KC2023-JX-0288-PZ78).
Author information
Authors and Affiliations
Contributions
GSZ, XGL, PJC and HYL analyzed and interpreted the public data. ZHZ, YNW and YJW conducted the cell experiments. BSL and PJC conducted experiments based on tumor tissue. YWL, CC and HBZ collected tumor tissue and performed transcriptome sequencing. GSZ, HYL and JC were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Zhu, Gs., Li, Xg., Cao, Pj. et al. GSDME-mediated pyroptosis modulates the immunosuppressive microenvironment in lung adenocarcinoma. Acta Pharmacol Sin (2026). https://doi.org/10.1038/s41401-026-01771-3
Received:
Accepted:
Published:
Version of record:
DOI: https://doi.org/10.1038/s41401-026-01771-3
