Angiosarcomas are a group of vascular cancers that form malignant blood vessels. These malignancies are seemingly inflamed primarily due to their pathognomonic nature, which consists of irregular endothelium and tortuous blood channels. PIK3CA mutations are oncogenic and disrupt the PI3K pathway. In this study, we aimed to define the molecular and functional consequences of oncogenic PIK3CA mutations in angiosarcoma. We first generated two isogenic hemangiosarcoma cell lines harboring the H1047R hotspot mutations in PIK3CA gene using CRISPR/Cas9. We found PIK3CA-mutant cells established distinct molecular signatures in global gene expression and chromatin accessibility, which were associated with enrichment of immune cytokine signaling, including IL-6, IL-8, and MCP-1. These molecular processes were disrupted by the PI3K-α specific inhibitor, alpelisib. We also observed that the molecular distinctions in PIK3CA-mutant cells were linked to metabolic reprogramming in glycolytic activity and mitochondrial respiration. Our multi-omics analysis revealed that activating PIK3CA mutations regulate molecular machinery that contributes to phenotypic alterations and resistance to alpelisib. Furthermore, we identified potential therapeutic vulnerabilities of PIK3CA mutations in response to PI3K-α inhibition mediated by MAPK signaling. In summary, we demonstrate that PIK3CA mutations perpetuate PI3K activation and reinforce immune enrichment to promote drug resistance in vascular cancers.