Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer
Fibrotic remodeling of tissues and tumors establishes immunosuppressive microenvironments that drive organ dysfunction and, in cancer, limit response to immunotherapy. Senescent-like cells are conserved drivers of fibrosis and therapeutic targets, yet their functional heterogeneity complicates therapeutic intervention. Here, we show that P-selectin is expressed by a subset of senescent-like cells in fibrotic tissues and tumors. Leveraging fucoidan-based nanoparticles that bind P-selectin, we developed senescence-modulating nanoparticles (SMNPs) to selectively target these disease-associated states. SMNPs exerted potent antifibrotic and immunomodulatory effects while improving the therapeutic index. Mechanistically, we identified a pathogenic, immunosuppressive macrophage population as a functional target in vivo. In fibrotic tumors, niche remodeling restored immune infiltration and sensitized tumors to immune checkpoint–based therapies. These findings establish SMNPs as a generalizable strategy to target pathogenic senescent cell subsets across fibrosis and cancer.
Authors
- Kristen C. Vogt (ORCID: https://orcid.org/0000-0001-5404-3442)
- Hailey V. Goldberg (ORCID: https://orcid.org/0000-0002-4830-5626)
- Tuomas Tammela (ORCID: https://orcid.org/0000-0003-3675-6961)
- Clemens Hinterleitner (ORCID: https://orcid.org/0000-0003-2416-9399)
- Gabriel Dessotti Barretto (ORCID: https://orcid.org/0000-0002-4121-0990)
- Scott W. Lowe (ORCID: https://orcid.org/0000-0002-5284-9650)
- Rui Gardner (ORCID: https://orcid.org/0000-0002-7270-5136)
- Almudena Chaves Perez (ORCID: https://orcid.org/0000-0002-2663-4672)
- Matthew Joseph Bott (ORCID: https://orcid.org/0000-0003-0523-4028)
- Daniel A. Heller (ORCID: https://orcid.org/0000-0002-6866-0000)
- Xiang Li (ORCID: https://orcid.org/0000-0001-7422-251X)
- Aveline A. Filliol (ORCID: https://orcid.org/0000-0002-1345-8147)
- Valentin J.A. Barthet (ORCID: https://orcid.org/0000-0002-5396-3594)
- Maria Skamagki (ORCID: https://orcid.org/0000-0003-0332-4521)
- Wei Luan (ORCID: https://orcid.org/0000-0002-9988-0612)
- Charles M. Rudin (ORCID: https://orcid.org/0000-0001-5204-3465)
- Paul Bernard Romesser (ORCID: https://orcid.org/0000-0001-8268-2903)
- Stephen B. Ruiz (ORCID: https://orcid.org/0000-0002-1634-9798)
- Hannah C. Styers (ORCID: https://orcid.org/0009-0007-9339-4254)
- Yu-Jui Ho (ORCID: https://orcid.org/0000-0002-7540-024X)
- Domhnall McHugh (ORCID: https://orcid.org/0000-0002-0255-5873)
- Natasha Rekhtman (ORCID: https://orcid.org/0000-0001-5801-3144)
- Ana Marie Perea (ORCID: https://orcid.org/0000-0001-5931-8142)
- Xueqian Zhuang (ORCID: https://orcid.org/0000-0001-7012-3223)
- Sara Flowers
- Logan R. Hillger
- Janelle Simon (ORCID: https://orcid.org/0009-0004-8259-5016)
- Jadae T. Watson
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Howard Hughes Medical Institute (US)
- Cornell University (US)
- Tri-Institutional PhD Program in Chemical Biology (US)
- Weill Cornell Medicine (US)
Publication Details
- Journal
- Science
- Published
- 2026-09-24
- DOI
- https://doi.org/10.1126/science.aeg4791
- Primary Topic
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00