Biselective remodeling of the melanoma tumor microenvironment prevents metastasis and enhances immune activation in mouse models.

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.