Immunotherapy has transformed cancer treatment, yet many tumours remain stubbornly resistant to its effects.

Among the most challenging are "cold tumours," including ovarian, breast, and prostate cancers, which evade immune attack and respond poorly to existing immunotherapies.

Although 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 remained poorly understood.

To address this challenge, researchers led by Professor Yuseok Moon at Pusan National University investigated how chronic environmental stress drives NK-cell maladaptation in cold tumours.

Using epithelial ovarian cancer as a representative model of an immunologically "cold" tumour, the team examined how persistent activation of the Aryl Hydrocarbon Receptor (AhR), a cellular sensor that responds to environmental chemicals, dietary compounds, and endogenous metabolites, reshapes NK-cell function.

Their findings were published in Signal Transduction and Targeted Therapy on June 5, 2026.

To uncover this mechanism, the researchers combined bulk transcriptomic analyses, single-cell RNA sequencing, clinical patient cohort analyses, NK-cell functional assays, mouse tumour models, and clinical patient samples.

They also investigated the roles of Growth Differentiation Factor 15 (GDF15), indoleamine 2,3-dioxygenase 1 (IDO1), kynurenine, and AhR signalling in regulating NK-cell activity.

The study revealed that chronic environmental and metabolic stress sustains activation of the GDF15–IDO1–kynurenine–AhR signalling axis, gradually reprogramming NK cells from an active tumour-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.

Using epithelial ovarian cancer as a representative model, the team showed that chemoresistant tumour 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.

Blocking AhR signalling restored NK-cell function, highlighting the GDF15–AhR axis as a promising therapeutic target.

"We found that a cancer-secreted factor, GDF15, activates a stress-sensing receptor (AhR) in natural killer (NK) cells—the body's frontline defence against cancer," explains Prof. Moon.

"While this initially helps NK cells attack tumour cells, persistent activation by tumour-derived metabolites together with environmental chemical stressors, such as endocrine-disrupting compounds, gradually exhausts these cells, causing them to accumulate within tumours, compromising their anticancer actions despite their sustained retention within tumours."

The findings also have important clinical implications.

Prof. Moon notes, "Measuring circulating GDF15 levels together with AhR activity in NK cells could help identify patients who are less likely to respond to immunotherapy, enabling earlier and more personalised treatment decisions." He further adds, "Targeting the GDF15–AhR axis, particularly through AhR inhibitors, may restore NK-cell function and help convert immune-cold tumours into immunotherapy-responsive tumours 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.

Overall, the study identifies the GDF15–AhR axis as a key driver of NK-cell maladaptation in cold tumours.

The findings provide a foundation for therapies that restore NK-cell function and improve the response of immune-resistant cold tumours to immunotherapy.

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

Source: Pusan National University