PROTACs in cancer immunotherapy: a minireview

Abstract

The discovery of immune checkpoint blockade as a therapeutic strategy to induce immunogenic cancer cell elimination has shown great success in the treatment of various cancers. However, limited response rates highlight the need for further development in this field. Promising new preclinical developments include the discoveries of proteolysis-targeting chimeras (PROTACs) to interfere with tumor immune escape signaling. Pharmacological induction of targeted protein degradation by these chimeras has shown advantages in inhibiting non-enzymatic protein functions and difficult to target protein-protein interactions. Furthermore, the induced degradation was shown to promote changes in the major histocompatibility complex I ligandome, which can be leveraged for an immune stimulus, increasing the cancer immune response. In this minireview, we highlight the research efforts ongoing towards employing PROTACs in immunotherapy for cancer treatment. Specifically, we outline how the unique mechanism of action can be leveraged to enhance the immune response or inhibit immune suppression.

Keywords: cancer; immune response; ubiquitin ligases; ubiquitin proteasome system; ubiquitin signaling.

Figure 1. PROTACs and covalent strategies can introduce neoantigens targetable with antibodies.

(A) Jensen et al. [20] and Moser et al. [21] find degradation products enhanced presentation on MHC-I but these effects are too transient to induce T cell activation alone. (B) Massafara et al. [22] target degradation products by using bifunctional antibodies to recruit and activate T cells. (C) Covalent immune recruiters (CIR) directly recruit and activate T cells by forming covalent ternary complexes on their cell surfaces [23–25]. (D) Covalent ligands can form neo-haptens which are targetable by bispecific antibodies [26,27]. Figure created with Biorender.

Figure 2. Chemical structures of PROTACs to overcome tumor immune escape by targeted degradation of immunosuppressive protein.COX-1/2, cyclooxygenase-1/2; IDO-1, indoleamine 2,3-dioxygenase 1; PD-L1, programmed death ligand 1.

Figure 3. Schematic illustration of how the degradation character of PROTACs can dually benefit immunotherapy through proteolysis of immunosuppressive proteins and neoantigen creation. Figure created with Biorender.