In particular, anti-PD-1/anti-PD-L1 peptide-modified nanoparticles containing chemotherapeutic drugs elicited potent antitumor immune responses by inducing ICD and disruption of PD-1/PD-L1 interactions 19. Compared to mAbs for blockade of PD-1/PD-L1 interactions, these peptide antagonists have some advantages of amenability to chemical synthesis for design of various nanomedicine loading accurate contents due to their modifiable structure, and low production cost 16.

To overcome these drawbacks, anti-PD-1 or anti-PD-L1 peptides have broadly adopted to multifunctional nanomedicines, such as polymeric nanoparticles, liposomes and dendrimers 15 - 18. However, such PD-1/PD-L1 binding peptides have shown unfavorable therapeutic efficacy owing to the extensive proteolytic cleavage and short half-lives in vivo 14. In addition, antagonist peptide of PD-L1 (CLQKTPKQC) effectively blocked the PD-1/PD-L1 interactions via high binding affinity to PD-L1 and reinvigorated the T lymphocytes, thereby inducing potent ICB immunotherapy when combined with ICD-inducing chemotherapeutic drugs 13.

For example, small peptide, NP-12, was reported as an anti-PD-1 peptide with 29 amino acid sequence to synergize with ICD for effective ICB immunotherapy 12. In addition, immunogenicity of mAbs for ICB immunotherapy increase the risk of uncontrolled autoimmune toxicities, the so-called immune-related adverse events (irAEs), which are unpredictable, possibly permanent and occasionally fatal in almost every organ 9, 10.ĭue to the potential ability to block the PD-1/PD-L1 interactions, small molecular PD-1/PD-L1 binding peptides have been received much attention in cancer immunotherapy 11. However, poor cancer-specificity of chemotherapeutic drugs can induce systemic toxicities as well as bone marrow suppression and damage to the host immune system, resulting in serious side effects and low response rate of patients 8. These cascade events of ICD turn the immunosuppressive tumor microenvironment (ITM) to the immune-responsive tumors, leading to increase the ICB immunotherapy efficiency 6, 7. The underlying mechanism is that dying cells by ICD-inducing chemotherapeutic drugs release damage-associated molecular patterns (DAMPs) to promote the cross-presentation of tumor-associated antigens to the dendritic cells (DCs), and thus provokes DC maturation and T lymphocyte infiltration 3 - 6. Furthermore, the therapeutic outcomes of ICB immunotherapy have dramatically improved when combined with immunogenic cell death (ICD)-inducing chemotherapeutic drugs in pre-clinical and clinical studies 2. Immune checkpoint blockade (ICB) immunotherapy has provided significant clinical advances to combat a variety of cancers, which provokes an antitumor immune response via monoclonal antibodies (mAbs) against programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) 1. In tumor models, PD-NPs accumulate within tumor tissues via enhanced permeability and retention (EPR) effect and induce immune-responsive tumors by recruiting a large amount of immune cells.Ĭonclusions: Collectively, targeted tumor delivery of anti-PD-L1 peptide and DOX via PD-NPs efficiently inhibit tumor progression with minimal side effects. Concurrently, PD-L1 blockade by PD-NPs disrupt the immune-suppressing pathway of cancer cells, resulting in proliferation and reinvigoration of T lymphocytes. Results: The PD-NPs are taken up by PD-L1 receptor-mediated endocytosis and then induce ICD in cancer cells by DOX release.

The antitumor efficacy and immune responses with minimal side effects by PD-NPs combining PD-L1 blockade and ICD are evaluated in breast tumor models. Methods: The functional peptide, consisted of anti-PD-L1 peptide and cathepsin B-specific cleavable peptide, is conjugated to a doxorubicin (DOX), resulting in prodrug nanoparticles of PD-NPs via intermolecular interactions. In this study, we propose anti-PD-L1 peptide-conjugated prodrug nanoparticles (PD-NPs) to overcome these obstacles of current cancer immunotherapy. However, such combination therapeutic regimen has suffered from severe toxicity of both drugs and low response rate of patients. Rationale: Cancer immunotherapy combining immune checkpoint blockade (ICB) with chemotherapeutic drugs has provided significant clinical advances.

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