DRAM1-defined autophagy-JAK-STAT-Tregs axis drives immunosuppression and predicts immunotherapy response in pan-cancer

Abstract

Background: DNA damage-regulated autophagy modulator 1 (DRAM1) is a lysosomal protein involved in autophagy regulation, yet its comprehensive role across human cancers, particularly within the TIME, remains systematically uncharacterized.

Methods: We performed an integrated pan-cancer analysis of DRAM1 across 33 malignancies using multi-omics data from TCGA, GTEx, and other platforms. Our approach included expression profiling, survival analysis, genomic and epigenetic characterization, functional enrichment, immune infiltration assessment, and therapy response prediction. The DRAM1-JAK-STAT axis was experimentally validated by DRAM1 knockdown in A549 cells, and STAT3 phosphorylation was assessed by Western blot.

Results: DRAM1 demonstrated pervasive dysregulation across cancers with strong context-dependent prognostic significance, serving as a favourable factor in UCEC (HR = 0.34) but unfavourable in PDAC (HR = 1.90). We confirmed DRAM1’s central positioning within autophagy networks and discovered its significant association with an immunosuppressive axis connecting IFN-γ signalling, JAK-STAT activation, and Tregs recruitment, supported by strong correlations with IFNG (ρ = 0.742 in DLBC), JAK1, STAT3, and Tregs markers (FOXP3 and CTLA4). These correlations were experimentally supported by demonstrating that DRAM1 knockdown in A549 cells attenuated STAT3 phosphorylation. DRAM1 expression correlated with multiple immune checkpoint molecules and predicted resistance to several chemotherapeutic agents. Importantly, DRAM1 showed significant predictive value for immunotherapy response across multiple cohorts, with an AUC of 0.742 in gastric cancer.

Conclusion: Our study suggests DRAM1 as a context-dependent regulator of the tumour immune microenvironment, with associations involving an IFN-γ/JAK-STAT/Tregs immunosuppressive axis. These findings nominate DRAM1 as a promising biomarker for immunotherapy response prediction and suggest its potential as a target for combination immunotherapy strategies.

Keywords

autophagy / DRAM1 / immunotherapy response / JAK-STAT pathway / pan-cancer / Tregs / tumour immune microenvironment

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2026 The Author(s). Clinical and Translational Discovery published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.