Many liver and lung cancers arise in tissue that’s already been scarred by chronic disease — such as hepatitis, cirrhosis, or long-term lung damage. That scarring creates an environment that suppresses nearby immune cells, so by the time a tumor takes hold, it’s often already shielded from the immune system and immunotherapy.
Now, scientists at Memorial Sloan Kettering Cancer Center (MSK) have developed a new approach to breaking down this barrier. They engineered nanoparticles — tiny particles about 1,000 times smaller than the width of a human hair — that can be loaded with drugs and directed at specific cells in the body. By selectively eliminating a small population of immune cells found to drive fibrosis, the approach could make immunotherapy work for more patients with minimal toxicity to healthy cells.
The laboratory findings, published September 24 in Science , potentially pave the way for new approaches against immunotherapy-resistant tumors, as well as for a host of other fibrotic and inflammatory diseases.
“Immunotherapy can elicit amazing therapy responses — but right now it doesn’t work for the vast majority of patients,” says Scott Lowe, PhD , a co-corresponding author of the study. “So anything we can do to make it work better and for more people is worth pursuing.”
The study was led by co-first authors Clemens Hinterleitner, MD , and Valentin Barthet, PhD , both postdoctoral researchers in the Lowe Lab, and doctoral student Hailey Goldberg, MS , also of the Lowe Lab. It was additionally overseen by co-corresponding authors Aveline Filliol, PhD , and Daniel Heller, PhD .
For years, Dr. Lowe’s lab has been interested in a biological process called cellular senescence — a response to stress that causes cells to permanently stop dividing.
“Senescence is a double-edged sword,” says Dr. Lowe, who chairs the Cancer Biology and Genetics Program at MSK’s Sloan Kettering Institute .
On one hand, senescence is beneficial: When cells are damaged, it can shut them down before they turn cancerous. It also plays an important role in wound healing, where senescent cells help coordinate the repair process by sending out signals that recruit other cells to the injury.
But those same signals can present a problem when senescent cells stick around too long. Rather than disappearing after doing their job, lingering cells continue broadcasting signals that drive chronic inflammation and fibrosis.
This makes them an attractive therapeutic target, says Dr. Lowe, who is also a Howard Hughes Medical Institute investigator and holds the Geoffrey Beene Chair at MSK.
“If we could find a way to clear out the harmful cells while leaving the helpful ones intact, we might be able to treat a wide range of conditions driven by chronic inflammation and fibrosis — including cancer,” he says. “The challenge has been how to target just the harmful cells while preserving the helpful ones.”
In this research, the team observed that within a group of immune cells called macrophages, a small number express the protein P-selectin as well as multiple features of senescence.
“What was striking was how consistently we found this specific population of macrophages in fibrotic tissue,” Dr. Hinterleitner says. “They had all the hallmarks of senescence, and their presence was a strong signal that the local immune environment had been compromised.”
These cells — dubbed MΦP + sen + (meaning a macrophage that is P-selectin positive and senescence positive) — are prevalent in the fibrotic tumor niches found in liver and lung cancers, as well as in other heavily scarred liver and lung tissue. And their presence is linked to poorer immunotherapy responses in patients.
Along with contributing to the fibrosis that creates a physical barrier, these macrophages also actively dampen the response of other immune cells, creating an immunosuppressive environment around the tumor.
“These cells aren’t just bystanders in the tumor environment,” Dr. Barthet says. “By sending out profibrotic and immunosuppressive signals, they essentially put up a wall that keeps the immune system from being able to do its job.”
The study was conducted in mouse models of liver and lung fibrosis, and fibrotic liver and lung cancers. The team validated key findings in tumor samples from lung cancer patients treated at MSK, and using human lung and liver cancer datasets.
“These key macrophages make up just 3% to 5% of fibrotic tissue, but our experiments showed that selectively killing them or silencing their signals had a profound effect on fibrosis,” says Goldberg, who successfully defended her doctoral thesis this month.
The research is a great example of team science and collaboration that MSK seeks to foster, Dr. Lowe notes, and these three young scientists were the driving force behind this work — conceiving the study, designing and performing the experiments, and analyzing the data behind these discoveries.
Eliminating or disabling the MΦP + sen + cells had two effects:
This allowed checkpoint inhibitor immunotherapy to work in the mice, shrinking tumors that had previously been resistant to treatment.
Precisely targeting this small-but-critical subpopulation of macrophages, however, wasn’t an easy task.
To accomplish it, the Lowe Lab teamed up with Dr. Heller, a biomedical engineer whose lab has previously developed a nanoparticle platform that targets P-selectin. Now they were using that platform with new drugs and a new goal.
“When they identified this important population of P-selectin-positive senescent macrophages, we thought they’d be good candidates to target with our nanoparticles,” Dr. Heller says.
The two drugs tested in the study — Navitoclax and a BET inhibitor called dBET6 — have powerful effects against senescent cells, but their use in the clinic has been held back because they cause side effects in patients when the therapies are given conventionally.
The nanoparticles attempt to solve this issue by delivering a small dose of the drug directly and selectively to the problem cells driving the fibrosis.
The drugs are packaged using a naturally occurring sugar molecule called fucoidan, which is found in brown seaweed and commonly sold as an anti-inflammatory supplement. Fucoidan naturally binds to P-selectin.
“Macrophages are specialized immune cells that track down, swallow, and destroy germs and debris,” Dr. Heller says. “The key is that our nanoparticles are coated with fucoidan, which specifically binds to P-selectin — so it’s not just any macrophage that takes up the drug, but the precise subset driving the fibrosis.”
When the macrophages ingest and break down a nanoparticle, the drug is released — like soldiers springing from the inside of the Trojan Horse to launch a precision attack on the MΦP + sen + cells in the tumors.
The two tested drug cargoes in the nanoparticles work in different ways:
Both drugs have shown promise against cellular senescence in the lab but failed in clinical trials because they also cause a lot of damage to healthy cells and tissues when administered broadly. Here, the nanoparticle appeared safe compared to the unpackaged drugs and did not produce the same toxicity in mice. Therefore, the nanoparticle delivery method could potentially give both drugs a second chance, the researchers say.
The research could have implications beyond just lung and liver cancer, says Dr. Filliol, a senior scientist in the Lowe Lab.
In a large database of immune cell profiles, the researchers found the same harmful macrophages associated with breast and colon cancer, as well as chronic inflammatory diseases like osteoarthritis and rheumatoid arthritis.
If MΦP + sen + cells turn out to be a common culprit across a range of diseases, the nanoparticle platform might be adapted to treat them, she says.
“This subset of macrophages also shares important features with a type of cell called lipid-associated macrophages — which are found, for example, in the atherosclerotic plaques that cause heart disease,” Dr. Filliol adds. “This approach might help to selectively deliver drugs to them.”
The work also exemplifies a broader strategy of undermining cancer by targeting key cells that directly support and protect tumors — what scientists call the cancer ecosystem.
“The simple truth is that cancer cells don’t act alone,” says Dr. Lowe, who also serves as scientific director of the Marie-Josée and Henry R. Kravis Cancer Ecosystems Project at MSK. “It requires coordinated interactions between cancer cells and nearby tissues to develop a tumor-supportive environment. Targeting these interactions — beyond just targeting cancer cells themselves — represents a significant new frontier against cancer.”
The research is also an example of the type of collaboration — between scientists specializing in different disciplines, and between bench scientists and clinicians — that MSK has long cultivated.
“Being able to efficiently move from a biological observation to an engineering solution to human tissue validation within one institution is one of the things that sets MSK apart,” Dr. Lowe says.
MSK is seeking commercialization partners to advance the research into clinical trials — first in cancer and potentially in other diseases down the road.
Additional authors, all from MSK, include Kristen C. Vogt, Ana Marie Perea, Logan R. Hillger, Stephen Ruiz, Domhnall McHugh, Yu-Jui Ho, Almudena Chaves-Perez, Maria Skamagki, Sara Flowers, Hannah C. Styers, Natasha Rekhtman, Xueqian Zhuang, Gabriel Dessotti Barretto, Xiang Li, Jadae T. Watson, Wei Luan, Janelle Simon, Tuomas Tammela, Rui Gardner, Charles M. Rudin, Paul B. Romesser, and Matthew J. Bott.
The work was supported by the Mark Foundation Endeavor Award; the National Institute of Aging (U01AG077921); the Marie Josée and Henry Kravis Cancer Ecosystems Project; Cycle for Survival; the National Cancer Institute (R01CA215719); the National Institute of Neurological Disorders and Stroke (R01NS116353, R01NS122987); the American Cancer Society Research Scholar Grant (GC230452); the U.S.-Israel Binational Science Foundation (2023077); the Expect Miracles Foundation – Financial Services Against Cancer; the Louis and Rachel Rudin Foundation; the Geoffrey Beene Cancer Research Center; the MSK Cycle for Survival Equinox Innovation Award in Rare Cancers; Mr. William H. Goodwin and Mrs. Alice Goodwin; the Commonwealth Foundation for Cancer Research; the Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center; MSK’s National Cancer Institute Cancer Center Support grant (P30 CA08748); the Ludwig Center Postdoctoral Fellowship; the Francois Wallace Monahan Fellowship; the Cancer Research Irvington Postdoctoral Fellowship (CRI5088, CRI5693); the National Science Foundation Graduate Research Fellowship (1746886); the National Institutes of Health T32 grants (GM115327, GM136640); the MSK MERIT Graduate Fellowship; the EMBO Long-Term Postdoctoral Fellowship; the Helen Hey Whitney Foundation Fellowship; the Kravis WiSE Fellowship; the National Cancer Institute (R37CA304010, K08CA255574, K08CA245206); an anonymous U.K. donor; and the American Association for Thoracic Surgery Surgical Investigator Award.
A patent application covering methods for treating senescence-associated pathologies using fucoidan nanoparticles (PCT/US2024/027510) has been published as WO2024229271A1; Drs. Barthet, Hinterleitner, Heller, and Lowe are listed as inventors. Patent US9737614B2 has been granted and covers the formulation of fucoidan nanoparticles; Dr. Heller is an inventor. Dr. Lowe is a founder and member of the scientific advisory board of Blueprint Medicines, ORIC Pharmaceuticals, and Faeth Therapeutics, and is on the scientific advisory board of PMV Pharmaceuticals and Selectin. Dr. Heller is a cofounder, officer, and board member with equity interest of Nine Diagnostics Inc., cofounder with equity interest in Lime Therapeutics Inc., cofounder with equity and intellectual property interests in Selectin Therapeutics Inc., an advisor with equity and intellectual property interests in Block Code Protected Ltd., an advisor with equity interest in Celine Therapeutics Inc., Nano-robotics Inc., Mediphage Bioceuticals Inc., and Concarlo Therapeutics Inc., and a consultant for Metis Therapeutics, Inc. Additional authors report equity interests, advisory roles, and other financial relationships with biotechnology and pharmaceutical companies, for a full list please refer to the study.
Read the paper: “ Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer ,” Science . DOI: 10.1126/science.aeg4791
Science
Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer
24-Sep-2026