The roles of TGF-I3 and VEGF pathways in the suppression of antitumor immunity in melanoma and other solid tumors

Immune checkpoint blockade (ICB) has become well-known in cancer therapy, strengthening the body's antitu-mor immune response rather than directly targeting cancer cells. Therapies targeting immune inhibitory check-points, such as PD-1, PD-L1, and CTLA-4, have resulted in impressive clinical responses across different types of solid tumors. However, as with other types of cancer treatments, ICB-based immunotherapy is hampered by both innate and acquired drug resistance. We previously reported the enrichment of gene signatures associated with wound healing, epithelial-to-mesenchymal, and angiogenesis processes in the tumors of patients with in-nate resistance to PD-1 checkpoint antibody therapy; we termed these the Innate Anti-PD-1 Resistance Signa-tures (IPRES). The TGF-I3 and VEGFA pathways emerge as the dominant drivers of IPRES-associated processes. Here, we review these pathways' functions, their roles in immunosuppression, and the currently available ther-apies that target them. We also discuss recent developments in the targeting of TGF-I3 using a specific antibody class termed trap antibody. The application of trap antibodies opens the promise of localized targeting of the TGF-I3 and VEGFA pathways within the tumor microenvironment. Such specificity may offer an enhanced therapeutic window that enables suppression of the IPRES processes in the tumor microenvironment while sparing the nor-mal homeostatic functions of TGF-I3 and VEGFA in healthy tissues.(c) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).