SHC Adaptor Protein 1 Drives Cancer-Associated Fibroblast-Mediated Immune Exclusion and Notch-Dependent Angiogenesis

Research shows that SHC Adaptor Protein 1 (SHC1) can undergo liquid-liquid phase separation (LLPS) in vitro. This study aims to explore the role of SHC1 in tumor angiogenesis and the tumor microenvironment in lung adenocarcinoma (LUAD). An optimal LLPS-risk signature was developed using 101 machine learning algorithm combinations. Functional enrichment, immune infiltration, and drug sensitivity analyses were performed to assess the biological and clinical relevance of the LLPS-risk signature. High-risk LUAD patients showed poorer prognosis, lower immune infiltration, and reduced response to immunotherapy. SHC1 expression was validated by single-cell transcriptomics and multiplex immunohistochemistry (mIHC). SHC1 was found to be a hub gene in the signature, associated with cancer-associated fibroblast (CAF) infiltration, tumor-derived endothelial cell (TEC) formation, and immune exclusion. SHC1 mediated vascular cell proliferation, migration, angiogenesis, and drug resistance in vitro. Zebrafish experiments confirmed SHC1's pro-angiogenic effects in vivo. RNA sequencing and Western blotting showed SHC1 regulates angiogenesis via the Notch pathway. This LLPS signature is a reliable biomarker for predicting survival and immunotherapy outcomes, with SHC1 as a key regulator of angiogenesis and the immune microenvironment.