Clemens Hinterleitner, Valentin J A Barthet, Hailey V Goldberg, 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, Matthew J Bott, Aveline Filliol, Daniel A Heller, Scott W Lowe
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.