Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer
(1) Hinterleitner C (2) Barthet VJA (3) Goldberg HV (4) Vogt KC (5) Perea AM (6) Hillger LR (7) Ruiz S (8) McHugh D (9) Ho YJ (10) Chaves-Perez A (11) Skamagki M (12) Flowers S (13) Styers HC (14) Rekhtman N (15) Zhuang X (16) Dessotti Barretto G (17) Li X (18) Watson JT (19) Luan W (20) Simon J (21) Tammela T (22) Gardner R (23) Rudin CM (24) Romesser PB (25) Bott MJ (26) Filliol A (27) Heller DA (28) Lowe SW
Hinterleitner, Barthet, and Goldberg et al. showed that senescent-like cells in fibrotic human and mouse tissues expressed P-selectin, and the team developed fucoidan-based senescence-modulating nanoparticles (SMNPs) to target these cells. SMNPs selectively depleted P-selectin+ senescent-like macrophages (Sen+MP) and reduced liver and lung fibrosis with limited toxicities. In fibrotic liver and lung tumor models, SMNPs remodeled stromal and myeloid barriers, increased DC and T cell infiltration, and improved response to ICB. P-selectin+ Sen+MP were enriched in immune-excluded human tumors and correlated with poor response to neoadjuvant ICB plus chemotherapy.
Contributed by Shishir Pant
(1) Hinterleitner C (2) Barthet VJA (3) Goldberg HV (4) Vogt KC (5) Perea AM (6) Hillger LR (7) Ruiz S (8) McHugh D (9) Ho YJ (10) Chaves-Perez A (11) Skamagki M (12) Flowers S (13) Styers HC (14) Rekhtman N (15) Zhuang X (16) Dessotti Barretto G (17) Li X (18) Watson JT (19) Luan W (20) Simon J (21) Tammela T (22) Gardner R (23) Rudin CM (24) Romesser PB (25) Bott MJ (26) Filliol A (27) Heller DA (28) Lowe SW
Hinterleitner, Barthet, and Goldberg et al. showed that senescent-like cells in fibrotic human and mouse tissues expressed P-selectin, and the team developed fucoidan-based senescence-modulating nanoparticles (SMNPs) to target these cells. SMNPs selectively depleted P-selectin+ senescent-like macrophages (Sen+MP) and reduced liver and lung fibrosis with limited toxicities. In fibrotic liver and lung tumor models, SMNPs remodeled stromal and myeloid barriers, increased DC and T cell infiltration, and improved response to ICB. P-selectin+ Sen+MP were enriched in immune-excluded human tumors and correlated with poor response to neoadjuvant ICB plus chemotherapy.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info:
(1) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Cancer Biology and Genetics Program, Sloan Ketter
ing Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA. (4) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (5) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Cancer Engineering Program, Gerstner Sloan Kettering School for Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (6) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (7) Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (8) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (9) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (10) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (11) Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (12) Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (13) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Cancer Engineering Program, Gerstner Sloan Kettering School for Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (14) Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (15) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (16) Flow Cytometry Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (17) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (18) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (19) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (20) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (21) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (22) Flow Cytometry Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (23) Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (24) Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Early Drug Development Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (25) Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (26) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (27) Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (28) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
