Tumor-intrinsic Ist1 restricts IFNγ responsiveness to drive immune evasion in pancreatic cancer

<title>Abstract</title> <p> Tumour-cell-intrinsic mechanisms that determine whether immune encounter culminates in effective killing or immune escape remain incompletely understood, particularly in immune-refractory solid tumours such as pancreatic cancer. Here, through integrative analysis of CRISPR-based genetic screening datasets, we identify the endosomal sorting complex required for transport (ESCRT)-associated factor Ist1 as a key determinant of tumour-cell susceptibility to cytotoxic CD8 ⁺ T-cell attack. Loss of Ist1 enhanced CD8 ⁺ T-cell-mediated killing in vitro and increased tumour clearance in an <italic>in vivo</italic> zebrafish xenograft model. Ist1 deficiency also sensitized tumour cells to exogenous interferon-γ (IFNγ), amplified IFNγ-driven JAK-STAT1 signalling, and upregulated antigen-presentation programs, accompanied by increased surface major histocompatibility complex class I (MHC-I) expression. Mechanistically, Ist1 regulated the membrane stability of the IFNγ receptor, and its loss increased surface availability and persistence, thereby restoring tumour-cell responsiveness to IFNγ. Consistent with this model, IFNγ blockade rescued the increased killing phenotype caused by Ist1 inhibition, indicating that Ist1-dependent membrane regulation controls tumour-cell responsiveness to immune-derived signals. Pharmacological disruption of the Ist1- Charged multivesicular body protein 1 (Chmp1) interaction similarly sensitized tumour cells to cytotoxic CD8 ⁺ T-cell killing, highlighting a tractable vulnerability in cytokine-resistant tumours. Clinically, high Ist1 expression was associated with immune-evasive features and poorer outcomes, whereas low Ist1 expression in the context of high CD8 ⁺ T-cell infiltration correlated with improved prognosis. Together, these findings identify Ist1, for the first time, as a membrane-regulatory determinant of tumour immune susceptibility and suggest that ESCRT-linked control of IFNγ receptor availability may provide a targetable entry point for immune sensitization in pancreatic cancer. </p>