Epigenetic repression of oncogenic signaling defines immune-permissive tumor states associated with response to immune checkpoint inhibitors in advanced NSCLC
5 affiliations
- 1Translational Oncology Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur). SERGAS-UVIGO, Vigo, Spain
- 2Epigenomics Unit, Cancer Epigenomics, Translational Medical Oncology Group (ONCOMET), Health Research Institute of Santiago, Santiago de Compostela, Spain
- 3Centro de Investigación Biomédica en Red Cáncer (CIBERONC), ISCIII, Madrid, Spain
- 4Department of Clinical Analysis, University Hospital Complex of Santiago de Compostela (CHUS), Santiago de Compostela, Spain
- 5Rheumatology & Immuno-mediated Diseases Research Group (IRIDIS), Galicia Sur Health Research Institute (IIS Galicia Sur). SERGAS-UVIGO, Vigo, Spain
Abstract
Background: Immune checkpoint inhibitors (ICI) have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC), yet response rates remain below 40% and currently used biomarkers such as programmed cell death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB) show limited predictive accuracy. We investigated whether tumor epigenetic programs define biological states associated with response to immunotherapy.
Methods: We performed comprehensive multiomic profiling of pretreatment tumor biopsies from 32 patients with advanced NSCLC receiving anti-programmed cell death protein 1/PD-L1 therapy. Genome-wide DNA methylation, RNA sequencing, locus-specific transposable element (TE) quantification, and whole genome/exome sequencing were integrated to identify molecular determinants of ICI response. Predictive models were evaluated using nested leave-one-out cross-validation. Baseline peripheral blood mononuclear cells (PBMC) immune profiling and functional studies using PI3K inhibition and DNA demethylation in NSCLC cell models provided orthogonal validation.
Results: Responders exhibited coordinated promoter hypermethylation and transcriptional repression of PI3K-Akt, Ras, MAPK, Wnt and NF-κB signaling pathways, independently of downstream genomic alterations. These changes were accompanied by enhanced antigen presentation, T cell receptor-major histocompatibility complex signaling, CD8+ T cell activation and other immune-related pathways, consistent with an immune-permissive tumor state. Independent baseline PBMC profiling provided orthogonal validation of these immune-related findings. Responders also displayed TE expression patterns linked to antiviral signaling and viral mimicry, while high TE load was associated with prolonged overall survival. Finally, we identified a 12-CpG hypermethylation signature associated with longer progression-free survival and developed an integrated multiomic random forest classifier with robust predictive performance under nested cross-validation (area under the curve=0.833), outperforming PD-L1 expression and TMB.
Conclusions: Our findings define an epigenetically orchestrated immune-permissive tumor state associated with clinical benefit from immune checkpoint blockade in advanced NSCLC. Coordinated repression of oncogenic signaling together with enhanced antigen presentation, antiviral signaling and adaptive immune activation provides a biological framework linking tumor epigenetic states with immunotherapy efficacy. These results support integrated epigenetic biomarkers for precision immunotherapy and provide a rationale for exploring epigenetic and PI3K-targeted combination strategies.
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BibTeX
@article{gallardogomez2026epigenetic,
title = {{Epigenetic repression of oncogenic signaling defines immune-permissive tumor states associated with response to immune checkpoint inhibitors in advanced NSCLC}},
author = {María Gallardo-Gómez and Uxía Termenón-Rivas and Irene Alonso-Álvarez and Martín Lázaro-Quintela and Caterina Aversa and Alejandro Francisco-Fernández and Maria Rodríguez-Rodríguez and Jenifer Brea and Sámer Abdulkader-Sande and Aitor Rodríguez-Casanova and Angel Díaz-Lagares and Samuel García and Mónica Martínez-Fernández},
journal = {Journal for Immunotherapy of Cancer},
year = {2026},
month = oct,
doi = {10.1136/jitc-2026-015745},
url = {https://doi.org/10.1136/jitc-2026-015745},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Epigenetic repression of oncogenic signaling defines immune-permissive tumor states associated with response to immune checkpoint inhibitors in advanced NSCLC
AU - María Gallardo-Gómez
AU - Uxía Termenón-Rivas
AU - Irene Alonso-Álvarez
AU - Martín Lázaro-Quintela
AU - Caterina Aversa
AU - Alejandro Francisco-Fernández
AU - Maria Rodríguez-Rodríguez
AU - Jenifer Brea
AU - Sámer Abdulkader-Sande
AU - Aitor Rodríguez-Casanova
AU - Angel Díaz-Lagares
AU - Samuel García
AU - Mónica Martínez-Fernández
PY - 2026
DA - 2026/10/28
JO - Journal for Immunotherapy of Cancer
DO - 10.1136/jitc-2026-015745
UR - https://doi.org/10.1136/jitc-2026-015745
AB - Background: Immune checkpoint inhibitors (ICI) have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC), yet response rates remain below 40% and currently used biomarkers such as programmed cell death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB) show limited predictive accuracy. We investigated whether tumor epigenetic programs define biological states associated with response to immunotherapy. Methods: We performed comprehensive multiomic profiling of pretreatment tumor biopsies from 32 patients with advanced NSCLC receiving anti-programmed cell death protein 1/PD-L1 therapy. Genome-wide DNA methylation, RNA sequencing, locus-specific transposable element (TE) quantification, and whole genome/exome sequencing were integrated to identify molecular determinants of ICI response. Predictive models were evaluated using nested leave-one-out cross-validation. Baseline peripheral blood mononuclear cells (PBMC) immune profiling and functional studies using PI3K inhibition and DNA demethylation in NSCLC cell models provided orthogonal validation. Results: Responders exhibited coordinated promoter hypermethylation and transcriptional repression of PI3K-Akt, Ras, MAPK, Wnt and NF-κB signaling pathways, independently of downstream genomic alterations. These changes were accompanied by enhanced antigen presentation, T cell receptor-major histocompatibility complex signaling, CD8+ T cell activation and other immune-related pathways, consistent with an immune-permissive tumor state. Independent baseline PBMC profiling provided orthogonal validation of these immune-related findings. Responders also displayed TE expression patterns linked to antiviral signaling and viral mimicry, while high TE load was associated with prolonged overall survival. Finally, we identified a 12-CpG hypermethylation signature associated with longer progression-free survival and developed an integrated multiomic random forest classifier with robust predictive performance under nested cross-validation (area under the curve=0.833), outperforming PD-L1 expression and TMB. Conclusions: Our findings define an epigenetically orchestrated immune-permissive tumor state associated with clinical benefit from immune checkpoint blockade in advanced NSCLC. Coordinated repression of oncogenic signaling together with enhanced antigen presentation, antiviral signaling and adaptive immune activation provides a biological framework linking tumor epigenetic states with immunotherapy efficacy. These results support integrated epigenetic biomarkers for precision immunotherapy and provide a rationale for exploring epigenetic and PI3K-targeted combination strategies.
SN - 2051-1426
ER -