Abstract
A previous study classifies solid tumors based on collagen deposition and immune infiltration abundance, identifying a refractory subtype termed armored & cold tumors, characterized by elevated collagen deposition and diminished immune infiltration. Beyond its impact on immune infiltration, collagen deposition also influences tumor angiogenesis. This study systematically analyzes the association between immuno-collagenic subtypes and angiogenesis across diverse cancer types. As a result, armored & cold tumors exhibit the highest angiogenic activity in lung adenocarcinoma (LUAD). Single-cell and spatial transcriptomics reveal close interactions and spatial co-localization of fibroblasts and endothelial cells. In vitro experiments demonstrate that collagen stimulates tumor cells to express vascular endothelial growth factor A (VEGFA) and directly enhances vessel formation and endothelial cell proliferation through sex determining region Y box 18 (SOX18) upregulation. Collagen inhibition via multiple approaches effectively suppresses tumor angiogenesis in vivo. In addition, armored & cold tumors display superior responsiveness to anti-angiogenic therapy in advanced LUAD cohorts. Post-immunotherapy resistance, the transformation into armored & cold tumors emerges as a potential biomarker for selecting anti-angiogenic therapy. In summary, collagen deposition is shown to drive angiogenesis across various cancers, providing a novel and actionable framework to refine therapeutic strategies combining chemotherapy with anti-angiogenic treatments.