Nanoparticles That Clear Scar-Driving Immune Cells Open Tumors to Immunotherapy

Many of the deadliest cancers do not emerge from healthy tissue. Liver and lung tumors typically arise in organs already scarred by years of chronic disease—hepatitis, cirrhosis, or long-standing lung damage—and that scarring does more than set the stage for cancer. It builds a fortress. Fibrotic tissue physically walls tumors off from patrolling immune cells while actively suppressing the ones that do get through, which helps explain why immunotherapy, one of the most celebrated advances in modern oncology, fails for the majority of patients with these cancers. Now a team at Memorial Sloan Kettering Cancer Center (MSK) has devised a way to dismantle that fortress from within, using engineered nanoparticles to selectively eliminate a tiny population of immune cells that drives fibrosis and immune exclusion. The findings, published September 24 in Science, could reshape how researchers approach not only immunotherapy-resistant tumors but a broad spectrum of fibrotic and inflammatory diseases.

The strategy grew out of a long-standing interest in cellular senescence, a stress response that permanently halts cell division. Senescent cells are famously double-edged. When a cell accumulates dangerous damage, senescence shuts it down before it can become cancerous, and during wound healing, senescent cells coordinate repair by broadcasting signals that recruit other cells to the injury site. The trouble begins when these cells overstay their welcome. Instead of quietly disappearing once their job is done, lingering senescent cells keep emitting inflammatory and profibrotic signals that drive chronic inflammation and scarring. Scott Lowe, who chairs the Cancer Biology and Genetics Program at MSK’s Sloan Kettering Institute and is a Howard Hughes Medical Institute investigator, has spent years probing this duality. The therapeutic dream, he explains, is to clear the harmful senescent cells while sparing the helpful ones—a goal that has proven difficult because senescent cells in different contexts can look deceptively similar.

The breakthrough came when the researchers examined macrophages, the scavenger immune cells that patrol tissues, in fibrotic environments. Within these populations, they identified a small subset expressing a surface protein called P-selectin alongside multiple molecular hallmarks of senescence. The team dubbed these cells MΦP+sen+—macrophages that are both P-selectin positive and senescence positive. What struck the scientists was their consistency: the same distinctive population appeared in fibrotic tumor niches in liver and lung cancers and in heavily scarred liver and lung tissue, and its presence correlated with poorer responses to immunotherapy in patients. Clemens Hinterleitner, a postdoctoral researcher and co-first author of the study, notes that finding this specific macrophage population so reliably in fibrotic tissue was remarkable, and that its presence signaled a compromised local immune environment.

These cells are far more than innocent bystanders. According to the study, MΦP+sen+ macrophages contribute to the fibrosis that forms a physical barrier around tumors, and they simultaneously dampen the activity of neighboring immune cells by sending out profibrotic and immunosuppressive signals. Co-first author Valentin Barthet describes them as actively erecting a wall that prevents the immune system from doing its job. The cells make up only about 3 to 5 percent of fibrotic tissue, yet experiments in mouse models of liver and lung fibrosis and fibrotic liver and lung cancers showed that selectively killing them or silencing their signals had a profound effect on fibrosis. The team validated the key findings in tumor samples from lung cancer patients treated at MSK and in human lung and liver cancer datasets, lending clinical weight to the mouse data.

The consequences of eliminating or disabling these macrophages were dramatic. The scar tissue shielding the tumor began to dissolve, and the suppression of other immune cells eased. Freed from both the physical and chemical barriers, checkpoint inhibitor immunotherapy—the class of drugs that unleashes T cells against cancer—suddenly worked in mice, shrinking tumors that had previously been resistant to treatment. In other words, the intervention did not attack the cancer cells directly. It removed the ecosystem support that allowed the tumor to hide, converting a cold, immune-excluded tumor microenvironment into one that existing therapies could penetrate.

Delivering a lethal payload to such a small and specific cell population posed a formidable engineering challenge, and this is where the collaboration with Daniel Heller’s biomedical engineering lab proved decisive. Heller’s group had previously developed a nanoparticle platform that targets P-selectin, and the team adapted it with new drugs and a new mission. The particles are roughly a thousand times smaller than the width of a human hair and are coated with fucoidan, a naturally occurring sugar molecule found in brown seaweed and sold as an anti-inflammatory supplement. Fucoidan binds specifically to P-selectin, ensuring that the nanoparticles are taken up not by just any macrophage but by the precise P-selectin-positive subset driving the fibrosis. When the targeted macrophages ingest and digest a particle, the drug inside is released—an effect Heller likens to soldiers springing from a Trojan Horse to launch a precision attack from within.

The researchers loaded the nanoparticles with two drugs that are potent against senescent cells but have been hampered by toxicity in clinical use. The first, Navitoclax, exploits a vulnerability in senescent cells’ survival machinery: these stressed cells block their own natural self-destruct program, and Navitoclax removes that block, causing them to die. The second, a BET inhibitor called dBET6, takes a different tack—it silences the inflammatory signals that senescent cells broadcast into surrounding tissue. With the alarm switched off, the cells stop producing the signals that drive fibrosis and immune suppression, even though the cells themselves survive. Both drugs had shown promise against cellular senescence in the laboratory but failed clinically because, when administered conventionally, they damage healthy cells and tissues throughout the body. In the mouse experiments, the nanoparticle-packaged versions appeared safe and did not produce the same toxicity, raising the possibility that targeted delivery could give both drugs a second chance in the clinic.

The implications may extend well beyond liver and lung cancer. Searching a large database of immune cell profiles, the researchers found the same harmful macrophage population associated with breast and colon cancers as well as chronic inflammatory diseases including osteoarthritis and rheumatoid arthritis. Aveline Filliol, a senior scientist in the Lowe Lab and co-corresponding author, points out that these macrophages also share important features with lipid-associated macrophages, a cell type found in the atherosclerotic plaques that cause heart disease—suggesting the platform could one day be adapted to deliver drugs to those cells as well. If MΦP+sen+ cells prove to be a common culprit across many diseases, a single nanoparticle platform, retargeted with different drug cargoes, could address an unusually wide range of conditions united by a shared cellular mechanism.

Beyond the specific findings, the work exemplifies an increasingly influential strategy in oncology: targeting the cancer ecosystem rather than the tumor cells alone. Cancer cells, Lowe argues, do not act in isolation; building a tumor-supportive environment requires coordinated interactions between malignant cells and the surrounding tissue, and disrupting those interactions represents a significant new frontier. The study also showcases the kind of interdisciplinary collaboration—between biologists and engineers, and between bench scientists and clinicians—that allowed the team to move from a biological observation to an engineering solution to validation in human tissue within a single institution. MSK is now seeking commercialization partners to advance the research into clinical trials, first in cancer and potentially in other fibrotic and inflammatory diseases. A patent application covering the use of fucoidan nanoparticles to treat senescence-associated pathologies has been published, and related intellectual property has been granted, signaling that the road from laboratory insight to patient benefit is already under construction. If the approach survives the rigors of human testing, it could offer a way to make immunotherapy work for the many patients it currently fails—and to treat the scarred, inflamed tissue that underlies diseases far beyond cancer.

Subject of Research: Senescence-directed nanoparticle targeting of fibrosis-driving macrophages to overcome immune exclusion in cancer

Article Title: Using nanoparticles to target fibrosis in cancer and other diseases

Article References: Using nanoparticles to target fibrosis in cancer and other diseases. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: nanoparticles, fibrosis, cellular senescence, macrophages, immunotherapy, cancer, P-selectin, fucoidan, Navitoclax, BET inhibitor, tumor microenvironment, checkpoint inhibitors