Researchers reveal how chronic stress drives immune dysfunction in cold tumors

A stress-sensing pathway that helps natural killer cells mature and attack cancer may become a liability when activated continuously, according to a study led by researchers at Pusan National University. The work identifies a molecular chain involving Growth Differentiation Factor 15 (GDF15), indoleamine 2,3-dioxygenase 1 (IDO1), kynurenine, and the aryl hydrocarbon receptor (AhR) as a driver of immune dysfunction in so-called “cold” tumors. These tumors contain relatively few effectively activated immune cells and often respond poorly to immune checkpoint inhibitors and other immunotherapies. The findings suggest that chronic metabolic and environmental stress can gradually reprogram the immune response, leaving natural killer cells present inside tumors but unable to perform their cancer-killing role.

Natural killer, or NK, cells are lymphocytes that can recognize and destroy abnormal cells without requiring the same antigen-specific priming used by conventional T cells. They release cytotoxic molecules, including perforin and granzymes, and produce signaling proteins that help coordinate broader antitumor immunity. Their activity is controlled by a balance of activating and inhibitory receptors, as well as signals from the surrounding tissue. In ovarian, breast, and prostate cancers, however, the tumor microenvironment can become metabolically hostile, nutrient-depleted, and rich in suppressive factors. Under these conditions, NK cells may accumulate inside tumors while progressively losing their ability to kill malignant cells. This state resembles exhaustion, but the researchers describe it more broadly as maladaptation because the cells are not simply inactive; they have been functionally reshaped by persistent environmental signals.

The study focused on AhR, a transcription factor that acts as a sensor for a wide range of chemical signals. AhR can be activated by compounds originating from pollutants, dietary components, drugs, and endogenous metabolism. Once activated, it moves into the cell nucleus and alters the expression of genes involved in immune development, metabolism, barrier function, and inflammatory responses. The researchers found that AhR activity has a context-dependent effect on NK cells. Brief or controlled activation can support NK-cell maturation and enhance antitumor functions. By contrast, prolonged stimulation appears to push the cells toward a dysfunctional state. The distinction is important because it shows that the same signaling system can be beneficial during an acute response but damaging when a tumor or chronic exposure keeps it switched on.

Using epithelial ovarian cancer as a model of an immunologically cold tumor, the investigators combined several experimental approaches to reconstruct this process. Their analyses included bulk gene-expression profiling, single-cell RNA sequencing, functional studies of isolated NK cells, mouse tumor models, clinical cohort data, and samples from patients with epithelial ovarian cancer. These methods allowed the team to examine both the molecular programs operating in individual immune cells and the clinical features associated with those programs. The single-cell analyses were particularly important because tumor-infiltrating NK cells are not a uniform population. Some retain cytotoxic activity, while others display gene-expression patterns associated with altered metabolism, persistent receptor signaling, and reduced effector function.

The proposed mechanism begins with GDF15, a stress-associated protein produced at elevated levels by chemoresistant tumor cells. GDF15 is known to participate in responses to cellular injury, metabolic imbalance, and inflammation, but in the tumor microenvironment it can also act as an immunomodulatory signal. According to the study, increased GDF15 is linked to enhanced IDO1 activity. IDO1 is an enzyme that converts tryptophan into kynurenine-pathway metabolites. This reaction can deprive local immune cells of tryptophan while generating molecules that influence immune-cell behavior. Kynurenine and related metabolites can enter NK cells and activate AhR, establishing a biochemical connection between tumor stress, altered amino-acid metabolism, and immune-cell reprogramming.

The resulting GDF15–IDO1–kynurenine–AhR axis appears to maintain NK cells in a state of chronic stimulation. At first, AhR signaling may help the cells adapt to the tumor environment and support their maturation. Over time, however, continual exposure to tumor-derived metabolites and stress signals changes the transcriptional and functional state of the cells. The NK cells become less effective at releasing cytotoxic molecules and killing cancer cells, even though they remain inside the tumor. This combination of retention and functional decline may be particularly advantageous to malignant tissue: immune cells are drawn into the tumor, but their capacity for surveillance and elimination is progressively weakened. The tumor can therefore appear immune-infiltrated without being genuinely immune-responsive.

The researchers also examined the possibility that environmental factors may reinforce this process. Because AhR responds to xenobiotics and other externally derived compounds, long-term exposure to AhR-activating chemicals could theoretically intensify signaling already initiated by tumor metabolism. The study places this possibility within a broader framework that links environmental toxicology to cancer immunology, including the potential influence of endocrine-disrupting compounds and dietary metabolites. The findings do not mean that any single environmental exposure directly causes ovarian cancer or NK-cell exhaustion. Rather, they raise the possibility that chronic exposure to chemical signals may interact with tumor-derived pathways and influence how immune cells behave after cancer has developed. This interaction could help explain why immune responses vary substantially among patients with apparently similar tumors.

A key experimental observation was that blocking AhR signaling restored aspects of NK-cell function. In the researchers’ models, inhibiting the pathway reduced the maladaptive program and improved the cells’ ability to respond against tumor targets. These results identify AhR as a possible therapeutic entry point, although the approach remains investigational. An AhR inhibitor would need to suppress harmful, persistent signaling without disrupting the receptor’s normal roles in immune development and tissue biology. The same caution applies to the upstream components of the pathway. GDF15 and IDO1 have functions in normal physiology, and broad inhibition could produce unintended effects. Future studies will need to determine which patients have pathway activity high enough to justify targeted treatment and whether blocking AhR can work safely alongside established immunotherapies.

The findings may also offer a strategy for predicting treatment response. The researchers propose that circulating GDF15 levels, combined with measurements of AhR activity in NK cells, could help identify patients whose immune systems are less likely to respond to checkpoint blockade. Such biomarkers would not replace clinical evaluation, but they could eventually help distinguish tumors that are merely infiltrated by dysfunctional immune cells from those with active antitumor immunity. The study further suggests that combining an AhR-targeting treatment with immune checkpoint inhibitors might help convert an immune-cold tumor into a more responsive one. For now, these implications require validation in larger patient groups and prospective clinical trials. Nevertheless, the work provides a mechanistic explanation for how chronic stress signals can transform a frontline immune defense into a source of persistent but ineffective tumor infiltration, and it places the GDF15–AhR pathway at the center of efforts to restore immune function in resistant cancers.

News Publication Date: 5 June 2026

Web References: https://doi.org/10.1038/s41392-026-02690-9; https://www.pusan.ac.kr/eng/Main.do

References: Signal Transduction and Targeted Therapy, DOI: 10.1038/s41392-026-02690-9