Available online 14 May 2022, 108211

Immune checkpoint blockade (ICB) has become well-known in cancer therapy, strengthening the body’s anti-tumor immune response rather than directly targeting cancer cells. Therapies targeting immune inhibitory checkpoints, 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 the wound healing, epithelial-to-mesenchymal, and angiogenesis processes in the tumors of patients with innate resistance to PD-1 checkpoint antibody therapy; we termed these the Innate Anti-PD-1 Resistance (IPRES) signatures. Based on gene signatures, the TGF-β 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 therapies that target them. We also discuss recent developments in the targeting of TGF-β using a specific antibody class called the trap antibody. The application of trap antibodies opens the promise of localized targeting of the TGF-β and VEGFA pathways within the tumor microenvironment. Such specificity may offer an enhanced therapeutic window that allows suppression of the IPRES processes in the tumor while sparing the normal homeostatic functions of the TGF-β and VEGFA in normal tissues.

Immune checkpoint blockade resistance

VEGF

VEGFA

TGF-β

Bispecific antibody

Trap antibody

Small molecule inhibitors

Angiogenesis

Immunosuppressive tumor microenvironment

IPRES

© 2022 The Authors. Published by Elsevier Inc.