BEIJING, June 25 (Xinhua) -- Chinese researchers have uncovered a previously unreported immune-activating function of methotrexate, a classic immunosuppressive drug, providing a theoretical foundation for its combined use with tumor immunotherapy and radiotherapy in clinical practice.

The findings have been published online in Science Translational Medicine.

While significant progress has been made in tumor immunotherapy in recent years, challenges of primary and acquired drug resistance persist.

In this study, the research team revealed methotrexate's previously unrecognized immune-activating role within the tumor microenvironment, said Zheng Mingyue, corresponding author of the paper and researcher at Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences.

The team developed a novel algorithm predicting that methotrexate exerts its anti-tumor immune effect by inhibiting ENPP1, an enzyme widely distributed across various human tissues and cells.

The research demonstrated that low-dose methotrexate treatment not only significantly enhanced the anti-tumor efficacy of immunotherapy and radiotherapy in mouse models but also played a similar synergistic role in preliminary clinical trials.

According to the results, methotrexate treatment can enhance the efficacy of radiotherapy and help overcome the drug resistance of tumors to immune checkpoint blockade therapy.

This discovery provides a theoretical basis for combining methotrexate with radiotherapy or immunotherapy, Zheng said, adding that it also paves the way for novel anti-tumor drug development strategies and holds significant clinical translation value.