Scientists have identified a new weakness in harmful “zombie-like” cells, which could open the door to better cancer treatments and treatments for age-related diseases. These cells, known as senescent cells, survive in vulnerable conditions by producing large amounts of protective proteins that prevent cell death. Researchers from the MRC Institute of Medical Sciences (LMS) and Imperial College London have discovered that removing this protection can force cells to self-destruct, offering a promising new treatment strategy.
The findings suggest that this approach could be used in combination with chemotherapy and other existing cancer treatments to improve patient outcomes.
Why aging “zombie cells” are dangerous
Cancer occurs when cells divide uncontrollably. However, many tumors also contain senescent cells, which no longer divide but remain highly active in harmful ways. Chemotherapy is designed to stop rapid tumor growth, so it often increases the number of these cells.
Although senescent cells do not directly increase the size of a tumor, they release molecules that can damage nearby tissues, accelerate the spread of cancer, and trigger harmful immune system activity. These cells are also associated with aging-related conditions such as fibrosis. Because of the role of senescent cells in disease, scientists are increasingly interested in developing drugs that specifically eliminate senescent cells.
Mariantonietta D’Ambrosio, a postdoctoral researcher at LMS and lead author of the study published in Nature Cell Biology, explained the reasoning behind the study.
“Aging has long been thought to be a positive thing because senescent cells, a core feature of cancer, do not proliferate. Regular chemotherapy induces senescence and blocks cancer cell proliferation, so tumors do not grow. This is because senescent cells secrete many factors that affect neighboring cells, inducing further proliferation, metastasis, and recruitment of the bad parts of the immune system.”We therefore set out to find some drugs that could kill senescent cells. ”
Screened 10,000 drug candidates
To search for possible treatments, researchers tested 10,000 different compounds on both aging and healthy cells. Working with collaborators in Imperial’s medicinal chemistry department, they focused on a group of molecules known as ‘covalent compounds’.
These compounds can permanently bind to target proteins, allowing scientists to block proteins that were previously thought impossible to target with drugs. The research team searched for compounds that selectively kill senescent cells while leaving normal cells relatively intact. Drugs that have this effect are called “senolytic” therapies.
After narrowing down the list to four promising candidates, the researchers discovered that three of the compounds targeted the same protein, called GPX4.
Targeting GPX4 and ferroptosis
GPX4 helps protect cells from ferroptosis, a form of cell death associated with high iron levels and damaging “reactive oxygen species.” Recent studies suggest that senescent cells are particularly vulnerable to ferroptosis, making them attractive targets for new therapeutics.
Professor Mariantonietta said: “Recent papers have shown this predisposition of senescent cells to ferroptosis, which is a new vulnerability of aging. This creates an opportunity for us to exploit this. Research is now being carried out to find senolytic drugs to kill cells through ferroptosis.”
Senescent cells appear to survive by producing abnormally high levels of GPX4 to combat dangerous conditions within the cell. The researchers likened this to taking painkillers while continuing to run with an injured ankle. The underlying damage remains, but the symptoms are temporarily suppressed.
By blocking GPX4, the experimental drug removes the cell’s protective shield. Without this protection, ferroptosis becomes inevitable and senescent cells die.
Promising results in cancer models
The researchers tested the drug in three different mouse models of cancer and observed improved outcomes in all models. Killing senescent cells reduced tumor size and improved survival.
Professor Jesús Gil, senior author of the study and head of the aging group at LMS, said the next step was to understand how the treatment affected the immune system.
“In mouse models, we found that these drugs reduced tumor size and improved survival. Next, we need to see the effect on the immune system. Does this improvement also awaken the ‘good side’ of the immune system (T cells, natural killer cells) that help kill tumors?” Professor Jesus Gill, senior author and head of the Aging Group at LMS, said: “Once we know more, the next step is to understand which cancer cell types or specific patients respond better to this treatment. For example, if a patient undergoing chemotherapy overexpresses GPX4, this approach could be used in combination with existing drugs to improve efficacy.”
Researchers believe this strategy could be an important addition to chemotherapy and immunotherapy by targeting parts of cancer biology that have so far been largely overlooked.
Mariantonietta said the possibilities go beyond single therapeutic approaches: “Targeting aging is a huge opportunity for cancer treatment and could ultimately play an adjunctive role in addition to chemotherapy and immunotherapy.”
Scientists from several other institutions also contributed to the study, including the Institute of Oncology (IOR) in Bellinzona, Switzerland, and the M3 Research Center at the University of Tübingen, Germany.
