Pin1 mediates immune evasion in fibrotic breast cancers via suppression of Transposable Elements [mouse_py]

ABSTRACT: Therapy resistance in cancer is frequently driven by tumor heterogeneity and an immunosuppressive tumor microenvironment, particularly in fibrotic tumors with stiff extracellular matrices (ECM). However, the mechanisms linking ECM stiffness to immune evasion remain poorly understood. Here, we identify the prolyl isomerase Pin1 as a central mediator of immune suppression in fibrotic breast cancer. ECM stiffening stabilizes Pin1 and drives its nuclear accumulation, where it preserves nuclear envelope NE and heterochromatin (HC) integrity, thereby preventing activation of the cGAS/STING/IFN-I pathway. Pin1 inhibition disrupts NE and HC structure, reactivates transposable elements (TEs), and induces both innate and adaptive immune responses through TE-derived neoantigens. In preclinical models of primary BC and metastases, Pin1 loss triggers immune cell infiltration, converting immune-cold tumors into immune-checkpoint blockade-responsive ones. These findings uncover a mechanosensitive immune evasion mechanism and establish Pin1 as a promising therapeutic target to enhance immunotherapy efficacy in fibrotic cancers.

ORGANISM(S): Mus musculus

PROVIDER: GSE294973 | GEO | 2026/04/01

REPOSITORIES: GEO