Abstract
The absence of cytotoxic effector cells, such as CD8⁺ T cells or Natural Killer (NK) cells, within tumors establishes an immune-cold tumor microenvironment (TME), contributing to poor immunotherapy responses, as observed in ovarian cancer. Although prior studies implicate NK cell exhaustion within the TME related to ferroptosis, the underlying mechanisms remain undefined. This study demonstrates that upon infiltrating the ovarian cancer TME, NK cells activate an integrated stress response (ISR) centered on ATF3. This ATF3-mediated ISR suppresses NRF2 expression, compromising their ability to counteract oxidative stress and ultimately triggering ferroptosis. Critically, we show that co-treatment with the ISR inhibitor ISRIB and NK cells not only prevents NK cell ferroptosis but also synergizes to enhance tumor cell killing. These findings provide novel insights into the mechanisms driving NK cell exhaustion within the TME and identify ISR inhibition as a promising therapeutic target and intervention strategy for developing NK cell-based therapies against ovarian cancer.