The Gdf15-xenobiotic receptor axis shapes NK cell maladaptation predicting cold tumors under environmental stress

Cold tumors, including epithelial ovarian cancer (EOC), mostly arise from sporadic factors, particularly hormonal and environmental influences, and are characterized by limited immune cell infiltration. Growth differentiation factor 15 (Gdf15) is increasingly recognized as a prognostic marker for EOC, but its role in harsh tumor environments, including immune surveillance and xenobiotic stress, remains underexplored. Analysis via clinical and cellular analyses revealed that EOC cell-derived Gdf15 facilitates the biological actions of aryl hydrocarbon receptor (AhR) signaling in the tumor immune niche. Notably, AhR signaling is enriched in natural killer (NK) cells following chemotherapy and during relapse, which is correlated with poor patient prognosis. Moreover, elevated Gdf15 levels are associated with reduced postprogression survival, indicating the involvement of the Gdf15-AhR axis in chemoresistance and tumor progression. While Gdf15-high EOC cells exhibit resistance to NK actions, EOC cell-derived Gdf15 enhances NK cell surveillance against Gdf15-low EOC cells, a predominant population in primary tumors. Despite the initial anticancer activity of NK cells, the AhR signaling-high NK cell population eventually displays stress-associated features of cellular exhaustion with diminished immunological surveillance markers during malignancy. This AhR-associated exhaustive stress process in NK cells was further validated in allograft and xenobiotic exposure models, closely mirroring clinical observations. Although Gdf15-modulated AhR signaling initially mediates anticancer effects, the prolonged interplay between Gdf15 and AhR is linked to impaired NK cell surveillance. The prediction of adverse outcomes via the Gdf15-AhR axis provides new insights into the malignant evolution of the tumor-NK cell niche and the environmental susceptibility of EOC progression.