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Scientists have identified a new weakness in harmful “zombie-like” cells that could open the door to better cancer treatments and therapies for age-related diseases. These cells, known as senescent cells, survive in a fragile state by producing large amounts of a protective protein that keeps them from dying. Researchers at the MRC Laboratory of Medical Sciences (LMS) and Imperial College London discovered that removing this protection can force the cells into self-destruction, offering a promising new treatment strategy.
The findings suggest the approach could work alongside chemotherapy and other existing cancer therapies to improve patient outcomes.
Why Senescent “Zombie Cells” Are Dangerous
Cancer develops when cells divide uncontrollably. However, many tumors also contain senescent cells, which no longer divide but remain highly active in harmful ways. Chemotherapy often increases the number of these cells because it is designed to stop rapid tumor growth.
Although senescent cells do not directly make tumors larger, they release molecules that can damage nearby tissue, encourage cancer spread, and trigger harmful immune system activity. These cells are also linked to aging-related conditions such as fibrosis. Because of their role in disease, scientists have become increasingly interested in developing drugs that specifically eliminate senescent cells.
Mariantonietta D’Ambrosio, a postdoctoral researcher at the LMS and lead author of the study published in Nature Cell Biology, explained the reasoning behind the research.
“Senescence was considered for a long time to be positive, because senescent cells don’t proliferate, which is the core feature of cancer. Normal chemotherapy induces senescence blocking the proliferation of cancer cells, so the tumour doesn’t get bigger. But with time you also see the negative side of the senescent cells, because they secrete a lot of factors that influence neighboring cells and induce even more proliferation, metastasis, and recruitment of bad parts of the immune system that will provoke even more aggressiveness in the tumor. For this reason, we tried to find some drugs that were able to kill the senescent cells.”
Screening 10,000 Drug Candidates
To search for possible treatments, the researchers tested 10,000 different compounds on both senescent and healthy cells. Working with collaborators from Imperial’s Department of Medicinal Chemistry, they focused on a group of molecules known as ‘covalent compounds’.
These compounds can permanently attach to target proteins, allowing scientists to block proteins that were once thought impossible to target with drugs. The team searched for compounds that selectively killed senescent cells while leaving normal cells relatively unharmed. Drugs with this effect are called ‘senolytic’ therapies.
After narrowing the list down 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 linked to high iron levels and damaging ‘reactive oxygen species’. Recent research has suggested that senescent cells are especially vulnerable to ferroptosis, making it an attractive target for new therapies.
Mariantonietta says, “recent papers have shown this predisposition of senescent cells to ferroptosis, but it’s a new senescence vulnerability. That creates an opportunity for us to exploit. So now there is research to find senolytic drugs to kill cells through ferroptosis.”
Senescent cells appear to survive by producing unusually high levels of GPX4 to counteract the dangerous conditions inside the cell. Researchers compared it to taking painkillers while continuing to run on an injured ankle. The underlying damage remains, but the symptoms are temporarily suppressed.
By blocking GPX4, the experimental drugs remove the cells’ protective shield. Without that defense, ferroptosis becomes unavoidable, leading the senescent cells to die.
Promising Results in Cancer Models
The researchers tested the drugs in three different mouse models of cancer and observed improved outcomes in all of them. Killing senescent cells reduced tumor size and increased survival.
Professor Jesus Gil, senior author of the study and Head of the Senescence group at the LMS, said the next step is understanding how the treatment affects the immune system.
“In mouse models we saw that these drugs reduced tumour size, and improved survival. Now we need to see the effect on the immune system. Is the improvement also awakening the ‘good side’ of the immune system (T cells, natural killer cells) that helps to kill the tumor?” says Professor Jesus Gil, senior author and Head of the Senescence group at the LMS, “Once we know more, the next step is to understand which cancer cell types or specific patients might better respond to this treatment. For example, if a patient undergoing chemotherapy overexpressed GPX4 then you could use this approach in combination with existing drugs to improve efficacy.”
Researchers believe the strategy could become an important addition to chemotherapy and immunotherapy by targeting a part of cancer biology that has largely been overlooked.
Mariantonietta says the potential goes beyond a single treatment approach: “Targeting senescence is a huge opportunity for cancer treatments, and ultimately it can play a supporting role in addition to chemotherapy and immunotherapy.”
Scientists from several other institutions also contributed to the study, including the Institute of Oncology Research (IOR) in Bellinzona, Switzerland and the M3 Research Centre at the University of Tübingen in Germany.
