Rapamycin, an mTORC1 inhibitor, reversed resistance to immune checkpoint therapy in the RAC1 A159V context, highlighting potential for combination treatment.

A RAC1 A159V mutation appears in a subset of immune ‘cold’ tumors, and the combined approach could help stratify these patients and guide treatment if findings translate to humans.

The RAC1 A159V mutation activates mTORC1 signaling, increases tumor glucose consumption, and suppresses chemokine production and IFNGR1 expression, dampening immune communication and attack.

Clinical validation is needed through human trials, which could take years, and there are considerations about rapamycin’s immunosuppressive effects and the search for more targeted RAC1 inhibitors.

The findings suggest that patients with RAC1 A159V may benefit from adding rapamycin to immune checkpoint inhibitors, pending validation in human trials.

The research team led by Mingjun Cai and Yi Zheng at Cincinnati Children’s published the work in Science Advances on October 29, 2025, with funding from NIH and other foundations.

In mouse models, combining the FDA-approved rapamycin with an immune checkpoint inhibitor restored tumor sensitivity, including in RAC1 A159V mutant tumors.

Future translation will require safer, more targeted RAC1 signaling inhibitors to minimize immune suppression while improving efficacy.

RAC1 A159V drives faster tumor growth and creates an immunosuppressive microenvironment, reducing response to immune checkpoint inhibitors across several cancers.

The mutation fosters an immunosuppressive environment in colon, lung, head and neck cancers, and melanoma, hindering immune cell activity and therapy response.

The Cincinnati team emphasizes a potential for a more effective, lower-dose combination therapy to boost efficacy while reducing side effects, pending further validation.