FOXM1 protein identified as key driver in immunotherapy resistance, unlocking new therapeutic avenues
For years, scientists have found the overexpression of a specific protein called FOXM1 in a wide range of cancers, including ovarian, breast and pediatric cancers. A recent study by scientists at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) has now led to understanding its exact role in cancer development and is the first study to define the cascade of events that FOXM1 initiates to help cancer cells escape immune detection. The study, published April 2025 in Nature Communications, examines how this key protein allows several types of cancer to evade the immune system. The insight opens the door to more effective immunotherapies, personalized treatments and even therapies to prevent cancer recurrence.
“In many cancers, FOXM1 expression is high, but it was unclear how and whether it contributed to immune evasion,” said Manjeet Rao, PhD, professor in the Department of Cell Systems and Anatomy, deputy director of the Greehey Children’s Cancer Research Institute and Greehey Distinguished Chair in pediatric heme-malignancies at UT Health San Antonio. “We discovered that FOXM1 has an amazing ability to support cancer cell survival and progression by dampening the anti-tumor immune response.”
How cancer hides
As cancer cells develop, they mutate and divide uncontrollably, but also manipulate their environment to shield themselves from immune attack. Normally, immune cells such as T-cells detect and destroy abnormal cells, like cancer cells. However, tumors protect themselves by sending chemical signals that either exhaust immune cells or create an environment that prevents immune cells from functioning.
One way cancer evades immune attack is by suppressing cell-surface proteins called stress ligands, which alert the immune system to cancer cells. Rao’s team found that FOXM1 directly manipulates this process. When FOXM1 levels are high, the expression of stress ligands is blocked, effectively making cancer cells invisible to immune surveillance.
Eye-opening discovery
Using CRISPR-Cas9 gene editing technology, scientists removed FOXM1 in cancer cells and tested their ability to form tumors in mouse models with intact immune systems. The results were dramatic — cancer cells without FOXM1 developed few or no tumors. In cases where small tumors developed, they regressed rapidly in most cases.
“It was eye-opening to see that a protein long known to be important for cancer cell growth also plays a central role in educating immune cells to not attack cancer cells,” said Rao.
New path for immunotherapy
Current immunotherapies, such as immune checkpoint inhibitors, have revolutionized cancer treatment but remain ineffective for many patients. In breast and ovarian cancers, for instance, only a small number of patients respond to existing immunotherapy drugs. Rao believes that FOXM1 inhibition could dramatically improve these odds.
“FOXM1 is highly expressed not only in breast and ovarian cancers, but in many other types of cancer as well,” he said. “By blocking FOXM1, we may be able to turn so-called ‘cold tumors’ into ‘hot tumors’— tumors that attract immune cells and respond better to immunotherapy.”
Building immune memory
In another significant finding, Rao’s team discovered that depleting FOXM1 not only enabled the immune system to attack tumors but also facilitated the creation of long-term immune memory. In mouse models where tumors were eliminated after FOXM1 depletion, reintroduction of cancer cells failed to generate new tumors.
“This tells us that immune memory has developed,” said Rao. “If we can support that memory function, it could become a maintenance therapy to prevent cancer recurrence.”
Toward personalized medicine
FOXM1 also holds promise as a biomarker to help guide treatment decisions. Rao’s team found that patients whose tumors exhibit higher FOXM1 expression are less likely to respond to immunotherapy. Measuring FOXM1 levels could help physicians predict who might benefit from immunotherapy and who might require alternative therapies.
Promising early clinical results
While a specific FOXM1 inhibitor has yet to be developed, Rao and other UT Health San Antonio scientists have found early success in reducing the protein using imipramine, an antidepressant drug. In a small-scale clinical trial, breast cancer patients treated with an imipramine derivative showed promising response.
“Computer modeling revealed that this molecule may bind to FOXM1’s DNA-binding domain, destabilizing the protein and causing it to degrade,” said Rao. “The early clinical data are very encouraging.”
The road ahead
Rao’s team is also identifying peptides downstream of FOXM1 that may serve as targets for a multi-component preventative approach.
“The idea is to create a cocktail of these peptides and prime patients who have high FOXM1 expression, allowing the immune system to recognize and destroy cancer cells before they can establish new tumors,” Rao said.
This approach has the potential to not only improve outcomes for current patients but may one day serve to prevent cancer recurrence.
“By targeting FOXM1, we are not just attacking the tumor directly but may also be able to retrain the immune system to identify and eliminate several types of cancer,” Rao said.
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Timilsina, S., et al. “Epigenetic silencing of DNA sensing pathway by FOXM1 blocks stress ligand-dependent antitumor immunity and immune memory,” April 28, 2025, Nature Communications. https://www.nature.com/articles/s41467-025-59186-3