Master regulator blocking immunotherapy, paving the way for a new lung cancer treatment

KAIST researchers have discovered that 'DEAD-box helicases 54 (DDX54)', a type ofRNA-binding protein, is the master regulator that hinders the effectiveness of immunotherapy -- opening a new path for lung cancer treatment. This breakthrough technology has been transferred to faculty startup BioRevert Inc., where it is currently being developed as a companion therapeutic and is expected to enter clinical trials by 2028.

KAIST (represented by President Kwang-Hyung Lee) announced on April 8 that a research team led by Professor Kwang-Hyun Cho from the Department of Bio and Brain Engineering had identified DDX54 as a critical factor that determines the immune evasion capacity of lung cancer cells. They demonstrated that suppressing DDX54 enhances immune cell infiltration into tumors and significantly improves the efficacy of immunotherapy.

Immunotherapy using anti-PD-1 or anti-PD-L1 antibodies is considered a powerful approach in cancer treatment. However, its low response rate limits the number of patients who actually benefit.

To identify likely responders, tumor mutational burden (TMB) has recently been approved by the FDA as a key biomarker for immunotherapy. Cancers with high mutation rates are thought to be more responsive to immune checkpoint inhibitors. However, even tumors with high TMB can display an "immune-desert" phenotype -- where immune cell infiltration is severely limited -- resulting in poor treatment responses.

This study is especially significant in that it successfully demonstrated that suppressing DDX54 in immune-desert lung tumors can overcome immunotherapy resistance and improve treatment outcomes.

The team used transcriptomic and genomic data from immune-evasive lung cancer patients and employed systems biology techniques to infer gene regulatory networks. Through this analysis, they identified DDX54 as a central regulator in the immune evasion of lung cancer cells.

In a syngeneic mouse model, the suppression of DDX54 led to significant increases in the infiltration of anti-cancer immune cells such as T cells and NK cells, and greatly improved the response to immunotherapy.

Single-cell transcriptomic and spatial transcriptomic analyses further showed that combination therapy targeting DDX54 promoted the differentiation of T cells and memory T cells that suppress tumors, while reducing the infiltration of regulatory T cells and exhausted T cells that support tumor growth.

The mechanism is believed to involve DDX54 suppression inactivating signaling pathways such as JAK-STAT, MYC, and NF-κB, thereby downregulating immune-evasive proteins CD38 and CD47. This also reduced the infiltration of circulating monocytes -- which promote tumor development -- and promoted the differentiation of M1 macrophages that play anti-tumor roles.

Professor Kwang-Hyun Cho stated, "We have, for the first time, identified a master regulatory factor that enables immune evasion in lung cancer cells. By targeting this factor, we developed a new therapeutic strategy that can induce responsiveness to immunotherapy in previously resistant cancers."

He added, "The discovery of DDX54 -- hidden within the complex molecular networks of cancer cells -- was made possible through the systematic integration of systems biology, combining IT and BT."

The study, led by Professor Kwang-Hyun Cho, was published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) on April 2, 2025, with Jeong-Ryeol Gong being the first author, Jungeun Lee, a co-first author, and Younghyun Han, a co-author of the article.

This work was supported by the Ministry of Science and ICT and the National Research Foundation of Korea through the Mid-Career Research Program and Basic Research Laboratory Program.