Microenvironment-specific modulation of macrophage function and tumour progression by ADAMTS1 through Syndecan-4 shedding

Recent studies have emphasized the role of ADAMTS proteases in inflammation and immunity, particularly in the context of tumour progression. Since inflammatory cells can either constrain or promote tumour growth, understanding how ADAMTS proteases influence immune cell behaviour is crucial. Using syngeneic tumour models-B16F1 melanoma and Lewis Lung Carcinoma (LLC)-in Adamts1 knockout (Ats1-KO) mice, we observed model-specific outcomes underscoring the complexity of ADAMTS1 function in cancer. Transcriptomic and functional analyses revealed broad alterations in the matrisome and immune-related pathways across both tumour types. Strikingly, while tumour progression was impaired in B16F1-derived tumours, the LLC model-characterized by a stronger myeloid component-showed no dependency on Adamts1 . To investigate this apparent resistance, we experimentally depleted macrophages and uncovered a profound functional defect in this population in Ats1-KO mice. In vitro assays confirmed reduced macrophage phagocytic activity. Mechanistically, we identified the transmembrane heparan sulfate proteoglycan syndecan-4 (SDC4), a known ADAMTS1 substrate, as a key mediator of this activity. Together, these findings reveal a previously unrecognized ADAMTS1-SDC4 axis that links extracellular matrix remodelling to macrophage phagocytosis, ultimately shaping tumour cell clearance and tumour progression.