By Elodie Vaz | Published on May 4, 2026 |
4 min read
In most cancers, not all
tumor cells actively proliferate. A fraction enters senescence, a state of
durable arrest of cell division. Often referred to as “zombie” cells, these
cells remain metabolically active without multiplying. Long considered beneficial,
senescence is indeed one of the mechanisms through which chemotherapy slows
tumor growth.
However, this protective
status has a downside. Senescent cells secrete a range of pro-inflammatory and
pro-tumoral molecules capable of reshaping their microenvironment. They thereby
promote the proliferation of neighboring cells, metastasis, and the recruitment
of harmful immune cells. They are also involved in age-related conditions such
as fibrosis.
“Senescence has long been
viewed as a positive phenomenon because senescent cells do not proliferate,
unlike the main hallmark of cancer,” recalls Mariantonietta D’Ambrosio,
postdoctoral researcher at the MRC Laboratory of Medical Sciences (LMS) and
first author of the study published on April 24 in Nature Cell Biology,
in a press release. “However, over time, senescent cells also display negative
aspects.”
Identifying a new
therapeutic vulnerability
In light of this,
researchers from LMS and Imperial College London are seeking to identify
molecules capable of selectively eliminating these senescent cells, known as
senolytics.
Their strategy is based
on a recently described weakness: the increased sensitivity of senescent cells
to ferroptosis, a form of cell death triggered by the accumulation of iron and
reactive oxygen species.
“Recent studies have
highlighted this predisposition of senescent cells to ferroptosis, but this
represents a new vulnerability linked to senescence. This gives us an
opportunity to exploit,” emphasizes Mariantonietta D’Ambrosio.
Glutathione peroxidase
4: a key target
To exploit this weakness,
the researchers conducted a large-scale pharmacological screening. In
collaboration with the Department of Medicinal Chemistry at Imperial College
London, they focused on a class of molecules known as “covalent compounds,”
which can bind durably to their protein targets and inhibit proteins previously
considered difficult to drug.
A total of 10,000
covalent compounds were tested on senescent cells and normal cells, with the
aim of identifying molecules that preferentially destroy the former.
Four promising candidates
emerged. Three of them targeted the same protein: glutathione peroxidase 4
(GPX4).
This enzyme protects
cells against ferroptosis. Senescent cells, exposed to high levels of iron and
oxidative stress, overexpress GPX4 to survive. By inhibiting this protection,
the identified compounds make ferroptosis inevitable.
The researchers compare
this mechanism to taking painkillers preventively to keep running with a
sprain. The danger remains, but the symptoms are masked. Removing the analgesic
abruptly reveals the underlying fragility.
The team then evaluated
these molecules in three distinct mouse models of cancer. In each case,
eliminating senescent cells resulted in reduced tumor size and improved
survival.
“In mouse models, we
observed that these drugs reduced tumor size and improved survival,” explains
Professor Jesus Gil, senior author of the study and head of the Senescence
group at LMS.
Researchers are now
seeking to better understand the immunological impact of this strategy. “Does
this improvement also stimulate beneficial immune cells (T lymphocytes, NK
cells) that contribute to tumor destruction?” he asks.
A complementary
approach to chemotherapy and immunotherapy
Beyond proof of concept,
this study paves the way for more personalized medicine. Patients whose tumors
overexpress GPX4, particularly after chemotherapy, could be good candidates for
combination therapies.
“Targeting senescence
represents a tremendous opportunity for cancer treatment and could ultimately
serve as a supportive approach alongside chemotherapy and immunotherapy,”
concludes Mariantonietta D’Ambrosio.
The next step will be to
confirm these findings in humans and to identify the tumors most likely to
benefit from this approach, at the intersection of oncology and aging biology.
Read next: Dietary
nitrogen compounds: what the evidence shows about GI cancer risk
About the Author – Elodie Vaz
Health journalist, CFPJ graduate (2023).
Élodie explores the marks diseases leave on bodies and, more broadly, on
human life. A registered nurse since 2010, she spent twelve years at patients’
bedsides before exchanging her stethoscope for a notebook. She now investigates
the links between environment and health, convinced that the vitality of life
cannot be reduced to that of humans
