Chronic Stress Drives NK-Cell Exhaustion in Cold Tumors via GDF15–AhR Axis
核心洞察
Researchers at Pusan National University identified the GDF15 (搜索)–IDO1 (搜索)–kynurenine–AhR signaling axis as a key driver of natural killer (NK) cell exhaustion in immunologically "cold" tumors such as ovarian, breast, and prostate cancers.
Persistent AhR activation under chronic environmental and metabolic stress reprograms NK cells from an active tumor-killing state into a dysfunctional, exhausted state that enables immune escape.
Blocking AhR signaling restored NK-cell function, positioning the GDF15 (搜索)–AhR axis as a promising therapeutic target for converting cold tumors into immunotherapy-responsive tumors.
Researchers led by Professor Yuseok Moon at Pusan National University have uncovered the molecular mechanism by which chronic environmental and metabolic stress exhausts natural killer (NK) cells—the body's frontline defenders against cancer—in immunologically "cold" tumors. The findings, published in Signal Transduction and Targeted Therapy on June 5, 2026, identify the GDF15 (搜索)–AhR signaling axis as a key driver of NK-cell maladaptation and point toward new therapeutic strategies for cancers that respond poorly to existing immunotherapies.
Cold tumors, including ovarian, breast, and prostate cancers, evade immune attack and respond poorly to immunotherapy because immune cells cannot effectively infiltrate deep into the tumor. Although chronic environmental and metabolic stress is known to impair immune function, how long-term environmental and dietary stress reprograms NK cells has remained poorly understood.
Using epithelial ovarian cancer (搜索) as a representative model of an immunologically cold tumor, the team examined how persistent activation of the Aryl Hydrocarbon Receptor (AhR) (搜索)—a cellular sensor that responds to environmental chemicals, dietary compounds, and endogenous metabolites—reshapes NK-cell function. The researchers combined bulk transcriptomic analyses, single-cell RNA sequencing, clinical patient cohort analyses, NK-cell functional assays, mouse tumor models, and clinical patient samples. They also investigated the roles of Growth Differentiation Factor 15 (GDF15 (搜索)), indoleamine 2,3-dioxygenase 1 (IDO1 (搜索)), kynurenine, and AhR signaling in regulating NK-cell activity.
The study revealed that chronic environmental and metabolic stress sustains activation of the GDF15 (搜索)–IDO1 (搜索)–kynurenine–AhR signaling axis, gradually reprogramming NK cells from an active tumor-killing state into an exhausted, maladaptive state. While transient AhR activation supports NK-cell maturation and antitumor activity, persistent activation under chronic stress impairs immune surveillance. Chemoresistant tumor cells produce high levels of GDF15, driving sustained AhR activation 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.
The team further showed that as cancer progresses and GDF15 (搜索) overexpression and AhR stimulation by environmental toxicants persist, expression of GATA2 (搜索)—a key regulatory factor that maintains normal NK-cell function—becomes suppressed, while markers of stress and DNA damage rise sharply. As energy is depleted and function is lost, dysfunctional NK cells accumulate within the tumor, leading to failure of tumor clearance and ultimately promoting cancer recurrence and progression. Blocking AhR signaling restored NK-cell function, highlighting the GDF15–AhR axis as a promising therapeutic target.
"We found that a cancer-secreted factor, GDF15 (搜索), activates a stress-sensing receptor (AhR) in natural killer (NK) cells—the body's frontline defense against cancer," explained Prof. Moon. "While this initially helps NK cells attack tumor cells, persistent activation by tumor-derived metabolites together with environmental chemical stressors, such as endocrine-disrupting compounds, gradually exhausts these cells, causing them to accumulate within tumors, compromising their anticancer actions despite their sustained retention within tumors."
The findings carry important clinical implications. Prof. Moon noted, "Measuring circulating GDF15 (搜索) levels together with AhR activity in NK cells could help identify patients who are less likely to respond to immunotherapy, enabling earlier and more personalized treatment decisions." He added, "Targeting the GDF15–AhR axis, particularly through AhR inhibitors, may restore NK-cell function and help convert immune-cold tumors into immunotherapy-responsive tumors when combined with existing immune checkpoint inhibitors."
The findings also suggest that long-term exposure to environmental AhR-activating chemicals may contribute to immune dysfunction, reinforcing the importance of environmental factors in shaping cancer immunity. Prof. Moon concluded, "We have laid the groundwork for developing next-generation cancer immunotherapies that prevent or reverse NK cell dysfunction caused by environmental stress, going beyond approaches that simply increase NK cell numbers."
Overall, the study identifies the GDF15 (搜索)–AhR axis as a key driver of NK-cell maladaptation in cold tumors, providing a foundation for therapies that restore NK-cell function and improve the response of immune-resistant cold tumors to immunotherapy.