Sex determines the natural killer cell-mediated immunity against pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) ranks among the most aggressive malignancies and exhibits a higher prevalence and poorer prognosis in male patients. While both the importance of natural killer (NK) cells in anti-tumor immunity and sex differences in NK cell function are well established, the interplay between biological sex and NK cell-mediated responses in PDAC has not been systematically addressed. Here, we provide novel insights revealing that both the intrinsic cytotoxic capacity of NK cells and the tumor microenvironment differ between sexes and jointly modulate anti-tumor immunity in PDAC. Using <i>in vitro</i> assays with primary NK cells from male and female mice, we found that female-derived NK cells exhibit consistently superior cytotoxic activity and immune activation. Importantly, these findings were reflected and even amplified <i>in vivo</i>. In a syngeneic allograft PDAC model, female mice displayed enhanced NK cell function, and female tumors exhibited distinct structural characteristics supporting stronger NK cell activity. Notably, this occurred despite the use of the same cell line in both sexes, indicating that host sex significantly shapes the composition and architecture of the tumor microenvironment. Our results provide new evidence that sex differences in NK cell-mediated immunity, within the broader immune and stromal landscape, may differentially impact tumor control in male and female PDAC hosts. This study therefore underscores the importance of considering sex as a biological variable in the preclinical evaluation of pancreatic cancer therapies.