Afratis et al. focused on disrupting key extracellular matrix (ECM) pathways in the TME by engineering dual-targeting decoys (glycosylated and non-glycosylated lysyl oxidase [LOX] propeptide-Fc) that simultaneously targeted the collagen cross-linking enzyme LOX and heat shock protein HSP70, both upregulated during melanoma progression in mouse and human models. Dual inhibition suppressed cancer-driven ECM organization and remodeling, resulting in decreased tumor burden and circulating melanoma cells by inhibiting proliferation and metastases, and enhancing neutrophil, B cell, and CD8+ T cell infiltration.
Contributed by Katherine Turner
ABSTRACT: The extracellular matrix (ECM) plays a crucial role in supporting metastasis in solid malignancies, yet effective ECM-targeted therapies remain scarce. Here, we introduce a dual-targeting strategy to combat melanoma by leveraging bispecific agents that disrupt key ECM and tumor-associated pathways. Building on the inhibitory properties of lysyl oxidase-propeptide (LOX-PP), we engineered biselective decoys that simultaneously target the collagen cross-linking enzyme LOX and heat shock protein 70 (HSP70), both of which are up-regulated during melanoma progression in both human and mouse models. This dual-targeting strategy offers a new avenue for disrupting ECM-driven tumor progression and enhancing therapeutic efficacy. Administered to mouse models of melanoma, the decoys reduced tumor burden and circulating melanoma cells by inhibiting proliferation and lung metastasis. Mechanistically, the decoys suppressed cancer-supporting ECM organization, inhibited ECM-remodeling pathways and associated enzymes, and reshaped the tumor immune microenvironment. The treatment modulated immune responses by enhancing neutrophil, B cell, and CD8(+) T cell infiltration. In combination with immune check point inhibitor, the decoys further promoted melanoma killing by CD8(+) T cells. The decoys efficiently bound multiple human tumors expressing LOX(+)/HSP70(+) ex vivo. These findings highlight the potential of dual inhibition as a potential strategy for remodeling melanoma and other tumor microenvironments and enhancing immunotherapy efficacy.
Author Info: (1) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 7610001, Israel. Department of Agricultural Development, Agrofood an
Author Info: (1) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 7610001, Israel. Department of Agricultural Development, Agrofood and Management of Natural Resources, National and Kapodistrian University of Athens, Evripos Campus, Psachna 34400, Greece. (2) Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. (3) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 7610001, Israel. (4) Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. (5) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 7610001, Israel. (6) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 7610001, Israel. (7) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 7610001, Israel. (8) Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. (9) Institute of Pathology, E. Wolfson Medical Center, Holon 58100, Israel. (10) Institute of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel. (11) Institute of Pathology, E. Wolfson Medical Center, Holon 58100, Israel. (12) Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel. (13) Institute of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel. Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. (14) Univ. Lyon, Institut de Chimie et Biochimie Molculaires et Supramolculaires (ICBMS), UMR 5246, University Lyon 1, CNRS, Villeurbanne F-69622, France. (15) Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. (16) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 7610001, Israel.
