The study investigates the functional impairment of natural killer (NK) cells within the tumor microenvironment (TME) and its impact on anti-tumor immunity. Using photo-labeling and longitudinal transcriptomic and cellular analyses, the researchers found that intratumoral NK cells rapidly lose their effector functions and adopt a distinct phenotypic state associated with tissue residency. Depletion of NK cells from established tumors did not affect tumor growth, indicating that these cells cease to contribute to anti-tumor responses. Administration of IL-15 prevented the loss of function and improved tumor control by generating intratumoral NK cells with both tissue-residency characteristics and enhanced effector function. The findings reveal the fate of NK cells after recruitment into tumors and provide insights into how their function can be revived.The study investigates the functional impairment of natural killer (NK) cells within the tumor microenvironment (TME) and its impact on anti-tumor immunity. Using photo-labeling and longitudinal transcriptomic and cellular analyses, the researchers found that intratumoral NK cells rapidly lose their effector functions and adopt a distinct phenotypic state associated with tissue residency. Depletion of NK cells from established tumors did not affect tumor growth, indicating that these cells cease to contribute to anti-tumor responses. Administration of IL-15 prevented the loss of function and improved tumor control by generating intratumoral NK cells with both tissue-residency characteristics and enhanced effector function. The findings reveal the fate of NK cells after recruitment into tumors and provide insights into how their function can be revived.