Obesity and adverse SDoH impact NK cell function

African American (AA) women are disproportionally affected by obesity, particularly in the setting of adverse social determinants of health (aSDoH), which contribute to cardiovascular disease (CVD) and cancer disparities. Obesity and aSDoH appear to impair Natural Killer cells (NKs), which are critical in the innate immune response; however, the underlying mechanisms are largely unknown. We sought to investigate signaling pathways involved in NK dysfunction related to obesity in AA women from under-resourced neighborhoods disproportionately exposed to aSDoH. We determined in freshly isolated NK cells that obesity and higher social isolation, as well as higher depression and lower socioeconomic status, are associated with a shift in NK cell subsets away from CD56dim/CD16+ cytotoxic NK cells. Using ex vivo data, we identified LDL as a serum marker related to NK cell function in an AA population from under-resourced neighborhoods. Additionally, NK cells from AA women with obesity and LDL-treated NK cells displayed a loss in NK cell function. Comparative unbiased RNA sequencing analysis revealed DUSP1-dependent signaling as a common factor. Subsequent experiments involving chemical inhibition of DUSP1 signaling and DUSP1 overexpression in NK cells highlighted the significance of DUSP1 in lysosome biogenesis and, ultimately, NK cell function. Our data demonstrate a pathway by which obesity in the setting of aSDoH may relate to NK dysfunction, making DUSP1 an important target for further investigation of CVD and cancer disparities.