Novel Therapeutic Approaches for Cutaneous Angiosarcoma, Particularly Focusing on Immune Checkpoint Inhibitors.

Background/Objectives: Cutaneous angiosarcoma (CAS) is a rare and aggressive endothelial malignancy with a high rate of local recurrence and distant metastasis. In advanced cases, where surgical resection is not feasible, systemic therapy remains the cornerstone of treatment. This review aims to summarize the current landscape of systemic therapies for unresectable or metastatic CAS and discuss emerging strategies, particularly focusing on immune checkpoint inhibitors (ICIs). Methods: A comprehensive review of the literature was conducted, including clinical trials, retrospective studies, and case series focusing on systemic treatments for advanced CAS. Therapeutic approaches covered include cytotoxic chemotherapy, molecular targeted therapies, and ICIs, as well as combination strategies. Special attention was given to biomarker studies and ongoing clinical trials. Results: Taxane-based chemotherapy, particularly paclitaxel, has demonstrated clinical activity and remains a standard option. Molecular targeted agents such as pazopanib have yielded modest efficacy. Recent trials of ICIs, including the SWOG S1609 DART and AngioCheck studies, have shown encouraging results in select subgroups, especially tumors from sun-exposed regions associated with high tumor mutational burden (TMB). Although AngioCheck did not meet its predefined response criteria, a subset of patients achieved disease control. Biomarkers such as TMB, PD-L1 expression, and tumor-infiltrating lymphocytes are under investigation to guide patient selection. Combination therapies with ICIs and tyrosine kinase inhibitors (TKIs) are being actively explored. Conclusions: While systemic therapies for CAS remain limited in efficacy, ICIs-particularly in combination with TKIs-represent a promising avenue. Future trials should emphasize biomarker-driven, CAS-specific strategies to improve clinical outcomes in this challenging malignancy.