Respirable Particulate Matter Induces Natural Killer Cell Dysfunction via Oxidative Stress-Mediated Lysosomal and Mitochondrial Injury: Implications for Mineral-Rich Mining Dust Exposure

Abstract Epidemiological and occupational studies increasingly link respirable particulate matter (PM), including mineral dust, exposure with elevated lung cancer risk, yet the immunological mechanisms underlying these associations remain poorly defined. In this study, we investigated how compositionally distinct respirable PMs affect natural killer (NK) cells, a key component of immune surveillance. Using in vitro exposure and K562 target-cell challenge models, we show that respirable mineral-containing PMs induce dose- and composition-dependent NK-cell injury, including increased apoptosis/necrosis, altered cytokine profiles, changes in perforin/granzyme B-associated functions, and impaired effector responses under tumor-cell challenge conditions. Silica- and silicate-rich particles caused the most pronounced dysfunction, whereas iron-bearing and carbonaceous dusts produced distinct patterns of oxidative injury and cell loss. Mechanistic analyses identified mitochondrial depolarization, reduced mitochondrial mass, and lysosomal deacidification as convergent organelle stress pathways associated with altered NK-cell function. Ascorbic acid-associated improvements in organelle function and IFN-γ production further support a contribution of ROS-associated organelle dysfunction to impaired NK-cell responses. Collectively, these findings provide the first integrated adverse outcome pathways linking respirable PM exposure to NK-cell dysfunction, highlighting oxidative stress-driven lysosomal and mitochondrial injury as central pathways that may compromise NK-cell-mediated immune surveillance under tumor-cell challenge conditions.