Immunotherapy has transformed cancer treatment, yet many\u00a0tumors\u00a0remain\u00a0stubbornly resistant to its effects. Among the most challenging are “cold\u00a0tumors,” including ovarian, breast, and prostate cancers, which evade immune attack and respond poorly to existing immunotherapies.\u00a0Although chronic environmental and metabolic stress is known to impair immune function, how long-term environmental and dietary stress reprograms natural killer (NK) cells-the body’s frontline defenders against cancer-has\u00a0remained\u00a0poorly understood.\u00a0<\/p>\n
To address this challenge, researchers led by Professor Yuseok Moon at Pusan National University investigated how chronic environmental stress drives\u00a0NK-cell maladaptation in cold\u00a0tumors. Using epithelial ovarian cancer as a representative model of an immunologically “cold”\u00a0tumor, the team examined how persistent activation of the Aryl Hydrocarbon Receptor (AhR),\u00a0a cellular sensor that responds to environmental chemicals, dietary compounds, and endogenous metabolites,\u00a0reshapes NK-cell function. Their findings were published in\u00a0Signal Transduction and Targeted Therapy\u00a0on June 5, 2026.\u00a0<\/p>\n
To uncover this mechanism, the researchers combined bulk transcriptomic analyses, single-cell RNA sequencing, clinical patient cohort analyses, NK-cell functional assays, mouse\u00a0tumor\u00a0models, and clinical patient samples. They also investigated the roles of Growth Differentiation Factor 15 (GDF15), indoleamine 2,3-dioxygenase 1 (IDO1), kynurenine, and\u00a0AhR\u00a0signaling\u00a0in regulating NK-cell activity.\u00a0<\/p>\n
The study revealed that chronic environmental and metabolic stress sustains activation of the GDF15\u2013IDO1\u2013kynurenine\u2013AhR\u00a0signaling axis, gradually reprogramming NK cells from an active tumor-killing state into an exhausted, maladaptive state. While transient\u00a0AhR\u00a0activation supports NK-cell maturation and antitumor activity, persistent activation under chronic stress impairs immune surveillance. Using epithelial ovarian cancer as a representative model, the team showed that\u00a0chemoresistant\u00a0tumor cells produce\u00a0high levels\u00a0of GDF15, driving sustained\u00a0AhR\u00a0activation through increased IDO1 activity and kynurenine production. As NK cells become exhausted, their cancer-killing ability declines, enabling immune escape and reducing responsiveness to immunotherapy<\/a>. Blocking\u00a0AhR\u00a0signaling restored NK-cell function, highlighting the GDF15\u2013AhR\u00a0axis as a promising therapeutic target.\u00a0<\/p>\n
<\/p>\n We found that a cancer-secreted factor, GDF15, activates a stress-sensing receptor (AhR) in natural killer (NK) cells-the body’s frontline\u00a0defense\u00a0against cancer. While this initially helps NK cells attack\u00a0tumor\u00a0cells, persistent activation by\u00a0tumor-derived metabolites together with environmental chemical stressors, such as endocrine-disrupting compounds, gradually exhausts these cells, causing them to accumulate within\u00a0tumors, compromising their anticancer actions despite their sustained retention within\u00a0tumors.”\u00a0<\/p>\n
Professor Yuseok Moon, Pusan National University<\/p>\n
\n<\/p><\/blockquote>\n The findings also have important clinical implications.\u00a0Prof. Moon notes, “Measuring circulating GDF15 levels together with\u00a0AhR\u00a0activity in NK cells could help identify patients who are less likely to respond to immunotherapy, enabling earlier and more personalized treatment decisions.” He further adds, “Targeting\u00a0the GDF15\u2013AhR\u00a0axis, particularly through\u00a0AhR\u00a0inhibitors, may restore NK-cell function and help convert immune-cold\u00a0tumors\u00a0into immunotherapy-responsive\u00a0tumors\u00a0when combined with existing immune checkpoint\u00a0inhibitors.”\u00a0The findings also suggest that long-term exposure to environmental\u00a0AhR-activating chemicals may contribute to immune dysfunction, reinforcing the importance of environmental factors in shaping cancer immunity.\u00a0<\/p>\n Overall, the study\u00a0identifies\u00a0the GDF15\u2013AhR\u00a0axis as a key driver of NK-cell maladaptation in cold\u00a0tumors. The findings provide a foundation for therapies that restore NK-cell function and improve the response of immune-resistant cold\u00a0tumors\u00a0to immunotherapy.\u00a0<\/p>\n Source:<\/p>\n Pusan National University<\/a><\/p>\n Journal reference:<\/p>\n
\n
<\/p>\n