The immunosuppressive microenvironment in PDAC prevents tumor control but strategies to restore anti-cancer immunology, by increasing CD8 T cell activity, have not been successful. Here we demonstrate how inducing localized physical damage using ionizing radiation (IR) unmasks the benefit of immunotherapy by increasing tissue-resident NK (trNK) cells that support CD8 T activity. Our data confirms that targeting mouse orthotopic PDAC tumors with IR together with CCR5 inhibition and PD1 blockade reduces E-cadherin positive tumor cells by recruiting a hypofunctional NKG2C-ve NK population that supports CD8 T cell involvement. We show an equivalent population in human PDAC cohorts that represents an adaptive-like immunomodulatory trNK-cell that similarly supports CD8 T cell levels in a cDC1-dependent manner. Importantly, a trNK signature associates with survival in PDAC and solid malignancies revealing a potential beneficial role for trNK in improving adaptive anti-tumor responses and supporting CCR5i/αPD1 and IR-induced damage as a novel therapeutic approach.

Tissue-resident NK cells support survival in pancreatic cancer through promotion of cDC1-CD8T activity