Senescent macrophages hide tumors behind scar tissue
Senescent P-selectin+ macrophages, making up 3 to 5% of fibrotic tissue around liver and lung tumors, sustain scarring and block immune access; fucoidan nanoparticles selectively neutralized them in mice and in three human tumor samples, restoring sensitivity to immunotherapy.
These cells make up 3 to 5% of the fibrotic tissue surrounding tumors, but Scott Lowe's laboratory at Memorial Sloan Kettering showed in Science on September 24 that removing them sharply reduced scarring in mice. They are senescent macrophages, immune cells that stopped dividing but keep releasing inflammatory signals. They carry P-selectin, a marker of inflamed tissue, on their surface.
Macrophages normally engulf pathogens. This subset recruits collagen into scar tissue and suppresses neighboring immune cells. Liver and lung tumors often grow in organs scarred by chronic inflammation (hepatitis, cirrhosis). The scar wall keeps immune cells away from the tumor, and the few that infiltrate are suppressed, which is why immunotherapy (treatment that directs the immune system to attack the tumor) largely fails in these settings.
A genetic experiment in mice two years earlier had shown that removing this specific macrophage subset caused liver fibrosis to regress (unlike clearing p16-positive liver cells, which worsened it). But the marker used then, the p16 protein, sits inside the cell where a drug cannot reach it from outside. P-selectin, on the surface, solved that problem.
Bioengineer Daniel Heller had previously built a fucoidan nanoparticle (fucoidan binds P-selectin) to deliver drugs into the brain. The team repurposed it, loading the nanoparticles with navitoclax (which kills senescent cells) and dBET6 (which silences their signals). Both drugs had failed in clinical trials because in free form they depleted platelets throughout the body. In mice, the nanoparticles reduced fibrosis as effectively as the free drugs, without platelet depletion: blood counts and survival stayed normal.
Combined with immunotherapy, the nanoparticles produced durable tumor regression. When CD8+ T cells (the immune system's killer cells) were removed from the mice, the effect nearly vanished: the immune system does the killing; the nanoparticle clears the barrier.
The same cell subset appeared in tumors from patients with liver and lung cancer. The more of these cells present, the greater the fibrosis and the less likely a response to immunotherapy. Among 19 lung cancer patients assessed before surgery, non-responders had more of them. In tumor samples from three patients, the nanoparticles killed the target subset without affecting other cells. This is tissue-sample and mouse work. Sloan Kettering is seeking partners for clinical trials.
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Sources
[1] pmc.ncbi.nlm.nih.gov
[2] mskcc.org
[3] t.me
The study provides a cellular-level example of what the Eternal Search chronic inflammation page describes: sustained inflammatory signals maintaining tissue damage. The 3-5% figure, the mechanism (senescent macrophages recruiting collagen and suppressing immune cells), and the restoration of immunotherapy sensitivity in mice make the connection to the glossary entry concrete rather than generic.