Insights into therapeutic peptides in the cancer-immunity cycle: Update and challenges

Abstract

Immunotherapies hold immense potential for achieving durable potency and long-term survival opportunities in cancer therapy. As vital biological mediators, peptides with high tissue penetration and superior selectivity offer significant promise for enhancing cancer immunotherapies (CITs). However, physicochemical peptide features such as conformation and stability pose challenges to their on-target efficacy. This review provides a comprehensive overview of recent advancements in therapeutic peptides targeting key steps of the cancer-immunity cycle (CIC), including tumor antigen presentation, immune cell regulation, and immune checkpoint signaling. Particular attention is given to the opportunities and challenges associated with these peptides in boosting CIC within the context of clinical progress. Furthermore, possible future developments in this field are also discussed to provide insights into emerging CITs with robust efficacy and safety profiles.

Keywords: Cancer immunotherapy; Cancer-immunity cycle; Immune checkpoint blockade; Oncolytic peptide; Peptide mimotope; Peptide neoantigen vaccine; Peptide-major histocompatibility complex; Synthetic long peptide vaccine.

Graphical abstract

Figure 1

Schematic symphony of peptides in cancer-immunity cycle (CIC). CIC can be divided into seven steps (numbered 1–7): 1) antigens release from dying tumor cells, 2) APCs uptake tumor antigens, 3) T-cell priming and activation in local lymph nodes, 4) trafficking of T cells to tumors via blood vessels, 5) infiltration of T cells into tumor tissues, 6) recognition of tumor cells by T cells, and 7) T-cell-mediated killing of tumor cells in the tumor microenvironment; then, dying tumor cells further contribute to a new round of CIC. Among them, peptides are mainly involved in four steps of the above cycle: (A) therapeutic vaccines, (B) improving APC activation, (C) enhancing T-cell response, and (D) strengthening T-cell recognition.

Figure 2

Structures of the human TLR2/TLR6-Pam₂CSK₄ complex (PDB: 3A79), human TLR2/TLR1-Pam₃CSK₄ complex (PDB: 2z7x), and SUP3. TLR1, TLR2, and TLR6 are depicted in blue, grey, and green respectively. Additionally, the Pam₂CSK₄ and Pam₃CSK₄ are shown by sticks in yellow and pink. The hydrogen bonds are marked by red dotted lines and their interaction residues are labeled accordingly.

Figure 3

Signaling pathways induced by Clec9a, Clec10a, TLR2/TLR1, and TLR2/TLR6. (A) Clec9a possesses a hemi-immunoreceptor tyrosine-based activation motif (HITAM) cytoplasmic tail in the signaling pathway that contains a highly conserved tyrosine. Upon phosphorylation of this tyrosine, it facilitates the recruitment and binding of spleen tyrosine kinase (SYK). Consequently, the phagocytosed dead cell fragments are transported to a recycling endosome compartment. (B) TLR2 specifically triggers the MyD88-dependent pathway, recruiting interleukin-1 receptor-associated kinases (IRAKs) to the TLR1/TLR2 and TLR2/TLR6 complexes. Subsequently, phosphorylated and activated IRAK binds to tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), thereby activating the IκB kinase (IKK) complex for promoting NF-κB translocation into the cell nucleus. Additionally, activation of the mitogen-activated protein kinase (MAPK) pathway can also occur, facilitating AP-1 activation. Ultimately, these aforementioned signaling molecules induce inflammatory cytokines and chemokines in a concerted manner. (C) When combined with GalNAc ligands, human Clec10a can trigger extracellular regulated protein kinase (ERK)-dependent pathways, leading to the phosphorylation of ERK and subsequent activation of p90-RSK, cAMP, and response-element binding protein (CREB). This cascade ultimately enhances the secretion of IL-12 and TNF-α.

Figure 4

Binding of epitope peptides to the classic MHC I and MHC II molecules. The human MHC I class molecule (HLA-A∗0201, blue) and MHC II class molecule (HLR-DR1, purple) are bound to the peptide LLFGYPVYV (left, PDB ID:1HHK) and the peptide PKYVKQNTLKLAT (right, PDB ID:1FYT), respectively. Stick views of peptides are used to display their binding grooves with MHC I and MHC II molecules. The arrows indicate the critical positions for binding with MHC molecules (in pink) and binding to TCRs (in rose red), numbered P1–P9. The function of the unnumbered pockets depends on the specific MHC molecules. Figures were generated by PyMOL.

Figure 5

Peptides targeting immune checkpoints. There are three pairs of immune checkpoints in the interaction between APCs and T cells: 1) PD-L1 or PD-L2/PD-1, 2) LAG-3/MHC, and 3) CD28/CTLA-4. Regarding the interaction between T cells and tumor cells, five pairs of immune checkpoints associated with peptides are shown. Among them, 4) VISTA/VSIG-3, 5) TIGIT/CD155, and 6) BTLA/HVEM are new immune checkpoints. In addition, 7) CD47/SIRPα represents a pair of immune checkpoints in the interaction between macrophages and tumor cells. The plus sign (pink) indicates a positive effect on the antitumor response, while the minus sign (gray) indicates an inhibitory effect. The peptides targeting these immune checkpoints are highlighted in yellow.