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Tumors Hijack Immune-Privileging Regulons via Distinct Cell Types to Confer T Cell Desertion and Immunotherapy Resistance Across Various Cancers

ABSTRACT: Immune checkpoint blockade (ICB) has transformed oncology, yet most patients fail to respond, suffer from hyper-progressive disease, or face severe immune-related toxicities, underscoring the urgent need for biomarkers identifying non-responders. Here we show that tumors co-opt an immune-privileging regulon signature (IMPREG) mirroring transcriptional programs of immune-privileged organs — to enforce T-cell desertion and ICB resistance across cancer types. Single-cell and spatial transcriptomic analyses reveal that tumors activate IMPREG through three distinct cellular routes — malignant cells adopting immature neuronal states, cancer-associated fibroblasts assuming myofibroblast identities, or endothelial cells — each creating localized niches of immune suppression and antigen-presentation collapse. Across 4 discovery and 36 validation clinical datasets, IMPREG consistently predicts immunotherapy resistance in 14 distinct cancer types, functioning as an orthogonal marker independent of established biomarkers. Crucially, IMPREG-expressing tumors show enhanced sensitivity to EGFR inhibitors or anti-angiogenic therapies in specific tumor entities. These findings suggest IMPREG as a dual-utility predictive biomarker for personalized treatment stratification.

ORGANISM(S): Homo sapiens

PROVIDER: GSE312235 | GEO | 2026/03/21

REPOSITORIES: GEO

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