Rapamycin shows promise in treating cold tumors with specific gene mutation

Immune checkpoint inhibitors (ICIs) emerged in the US about 15 years ago as an exciting class of cancer treatments that have achieved complete and durable remissions for thousands of people with end-stage metastatic cancers. However, many other patients have tumors that remain "cold" and unresponsive to these treatments.

Now, scientists at Cincinnati Children's have discovered a specific gene mutation lurking behind this lack of response-and they reveal in mouse models that the well-known drug rapamycin makes such "cold" tumors responsive again.

The research, published Oct. 29, 2025, in Science Advances, was led by first author Mingjun Cai, a graduate student with the Division of Developmental Biology, corresponding author Yi Zheng, PhD, and a team of scientists in Division of Experimental Hematology and Cancer Biology.

If further research confirms this effect in humans, these findings may facilitate stratifying patients carrying this gene mutation who may benefit from a combination form of treatment. We look forward to continuing this work."

Yi Zheng, PhD, corresponding author 

The research team found that a specific mutation of the gene RAC1 (labeled A159V) leads to faster growth of several kinds of cancer tumors, including colon, lung, head and neck cancers, and melanoma. This mutation creates an immunosuppressive tumor microenvironment (dubbed TIME) that blocks the effectiveness of ICIs.

The team demonstrated that the mutated tumors show reduced immune cell infiltration and impaired communication between tumor and immune cells. Notably, the mutation activates mTORC1 signaling, which increases the tumor's glucose consumption while also depriving immune cells of the energy they need to fight the tumors. The mutation also suppresses chemokine production and downregulates IFNGR1 expression, further shielding tumors from immune attack.

The powerful news in this study is that researchers already know that an FDA-approved drug-rapamycin-inhibits mTORC1 signaling. Indeed, when rapamycin was provided in addition to an ICI, the mutant tumors in most cases became as sensitive to the treatments as non-mutant tumors.

A potential boost for a class of cancer treatments

The concept behind ICIs flows from the ability of cancer tumor cells to evade attack from the body's natural defenses. Tumors do this by using immune "checkpoints" to deactivate immune system responses. Reversing this process, when successful, makes tumors vulnerable.

The first immune checkpoint inhibitor approved for use in the United States was ipilimumab (brand name Yervoy) in 2011. This CTLA-4 blocker was initially approved for treating metastatic melanoma. Since then, several other checkpoint inhibitors have been approved for a variety of cancer types.

Researchers say the A159V gene mutation they found likely occurs only in a small portion of the people with immune "cold" tumors; it is not yet clear how many.

"Importantly, while this mutation in cancer may be under-appreciated, we found that rapamycin can reverse these resistant effects at low doses," Zheng says. "This approach could allow clinicians to more effectively treat patients with A159V-mutated cancers while also reducing the risk of side effects."

Next steps

Further clinical studies are needed to validate these mouse-based findings in human cancers. Such trials may take several years to complete. Also, rapamycin is an immune suppressant tool more commonly used to help prevent organ transplant rejection. Zheng predicts that other compounds may be developed that can more precisely inhibit RAC1 signaling to boost the cancer fighting abilities of ICIs with fewer overall impacts on the immune system.

About the study

Cincinnati Children's co-authors on this study also included Mike Adam, Xin Duan, and Fukun Guo, all with the Division of Experimental Hematology and Cancer Biology. The Research Flow Cytometry Facility, Single Cell Genomics Facility, and Genomics Sequencing Facility at Cincinnati Children's also supported this research.

Funding sources for this study include grants from the National Institutes of Health grants (R01 CA278756, U54 DK126108, P01 HL158688); the Louis Myer Foundation and CancerFreeKids.