Abstract B018: Integrated Stress Response (ISR) activation coupled to epigenetic reprogramming enables CNS tumor survival

Abstract Central nervous system (CNS) tumors originate from neuroectodermal cells, display biological behaviors ranging from indolent lesions to highly aggressive malignancies. To understand how CNS tumors gain a survival benefits, we performed pathway-level analyses with primary omics datasets and found ISR as a most frequently activated program. ISR is a conserved, stress-adaptation pathway suppresses global protein synthesis while selectively promoting ATF4 translation in tumor cells, makes ISR a potentially targetable vulnerability. However, its relevance in CNS tumors remain understudied. Here, we interrogate multi-omics datasets in CNS tumors to define regulatory programs linked to ISR activation. We evaluated ISR activation using primary single-cell transcriptomes (scRNA-seq) and single-cell chromatin accessibility (scATAC-seq) data from multiple patient-derived pituitary adenomas (PA), schwannomas (SCH), and hemangioblastomas (HB). We used curated ATF4 target genes signature (∼200) to computed ISR activity, parallelly with differential expression analysis and single-cell transcription factor activity inference (SCENIC). Our analysis was expended utilizing publicly available scRNA-seq datasets spanning multiple CNS tumor types, including medulloblastomas (MB), meningiomas (MG), and ependymomas (EPN), alongside normal human spinal cord datasets. Chromatin accessibility of ISR related gene was evaluated using scATAC-seq, and DNA methylation profiling of ISR downstream genes was performed in PA and MG samples to explore epigenetic modulation. Across PA, EPN, MG, SCH, and HB, tumor cells showed significantly (p < 0.05) higher ISR activity compared to normal counterparts . Differential expression and functional enrichment analysis revealed upregulation of genes in tumor-cells related to protein translation, protein folding, ER stress, and proteostasis. ISR associated transcriptional program were activated, including ATF4 and related TFs such as DDIT3, ATF3, ATF5, ATF6, XBP1 and CEBPB. However, elements of the ATF4-DDIT axis linked apoptotic signaling were induced in selected tumor types (MG), tumor cells preferentially engaged with chronic ISR programs that survival, reflected by upregulation of ER stress-resolution and chaperone genes together with HSPA5, HERPUD1, PDIA3, PDIA6, DNAJB9, DNAJC3, SEC61A, CANX, and CALR. scATAC-seq analysis pinpoints increased promoter accessibility across multiple ISR-linked genes and DNA methylation analysis showd heterogeneous promoter methylation patterns, with both hypo and hypermethylation of ISR downstream genes in PA and MG, strongly supporting epigenetic reprogramming of ISR pathways. Overall, our findings demonstrate that ISR activation in CNS tumors (PA, EPN, MG, SCH, HB) contributes to tumor adaptation by enhancing protein homeostasis and stress resilience. Our study highlights adaptive ISR signaling as a key tumor adaptation mechanism and identifying the ISR axis as a potential therapeutic vulnerability in these CNS tumor entities. Only for language editing and grammatical correction AI tools were used. Citation Format: Santosh Kumar, Debjani Mandal, Kory R Johnson, Prashant Chittiboina. Integrated Stress Response (ISR) activation coupled to epigenetic reprogramming enables CNS tumor survival [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr B018.