Work

Epigenetic repression of oncogenic signaling defines immune-permissive tumor states associated with response to immune checkpoint inhibitors in advanced NSCLC

Year: 2026

Type: article

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.

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-015745