Research team led by Pusan National University professor Moon Yu-seok identifies how environmental hormone receptors trigger immune cell deterioration

A diagram illustrating the mechanism by which exposure to environmental toxins and tumor-derived factors causes natural killer cells to become dysfunctional and accelerate tumor progression. [Pusan National University]
A diagram illustrating the mechanism by which exposure to environmental toxins and tumor-derived factors causes natural killer cells to become dysfunctional and accelerate tumor progression. [Pusan National University]

Why does cancer immunotherapy work differently from patient to patient?

Scientists have now found a molecular answer, linking chronic environmental stress and modern lifestyle habits to impaired cancer treatment outcomes.

The National Research Foundation of Korea announced Monday that a research team led by Moon Yu-seok, a professor at Pusan National University, has identified the molecular process by which natural killer cells — exhausted and rendered dysfunctional by chronic stimulation of environmental stress receptors, including endocrine-disrupting chemicals — accumulate within tumor tissue and ultimately fail to eliminate cancer cells.

Breast, prostate and ovarian cancers rank among the most common cancers in Korean men and women and belong to a category known as "cold tumors" — solid tumors with extremely low immune responsiveness. Cold tumors are so named because immune cells fail to gather around or infiltrate the tumor, leaving them largely unresponsive to anticancer immunotherapy drugs. Lifestyle and environmental factors have long been suspected as key contributors to this poor immune response, but the specific biological mechanisms had remained unclear.

Tens of thousands of endocrine-disrupting chemicals enter the body through air, water and food and are known to pose health risks. How they directly interact with immune cells inside tumors to drive disease progression, however, had not been established.

The research team found that Gdf15, a factor derived from cancer cells, promotes signaling through the aryl hydrocarbon receptor (AhR) — an environmental stress receptor — and restructures the tumor immune microenvironment.

When NK cells that have entered a tumor are subjected to sustained AhR stimulation, they initially display anticancer activity but over time undergo a process of "maladaptive deterioration," marked by rising energy depletion and accumulating genetic damage, the team confirmed.

Moon Yu-seok, professor at Pusan National University. [Pusan National University]
Moon Yu-seok, professor at Pusan National University. [Pusan National University]

The team demonstrated through clinical data and animal models that these deteriorated "dysfunctional NK cells" accumulate within tumor tissue, fail to destroy cancer cells, and serve as a predictive marker for tumor recurrence and progression.

Moon said the research "lays the groundwork for developing next-generation anticancer immunotherapies that go beyond simply increasing the number of NK cells — approaches that instead prevent or reverse the deterioration of NK cells caused by environmental stress."

The study, supported by the Ministry of Science and ICT and the National Research Foundation of Korea, was published in Signal Transduction and Targeted Therapy, a top-ranked international journal in biochemistry and molecular biology.


nbgkoo@heraldcorp.com