Adaptable peptide-based therapeutics modulating tumor microenvironment for combinatorial radio-immunotherapy.

Radiotherapy is one of the conventional tumor treatments, while its abscopal therapeutic efficacy is severely hampered by the immunosuppressive tumor microenvironment. To address this challenge, we herein report on the morphology-adaptable peptide-based therapeutics for efficiently reversing the immunosuppression in the combinatorial radio-immunotherapy through simultaneous checkpoint blocking and induction of immunogenic cell death. The peptide-based therapeutics were created via co-assembling a pentapeptide containing a 4-amino proline residue with its derivatives containing IDO-1 inhibitor NLG919. The resulting therapeutics underwent pH-adaptable morphological transformation between nanofibrils and nanoparticles and released NLG919 upon GSH cleavage. In vivo studies confirmed that the pH-adaptable morphologies of the therapeutics facilitated their tumor accumulation and retention at tumor sites compared to morphology-persistent counterparts, thus resulting in efficient delivery of IDO-1 inhibitors. Simultaneously treating the tumor-bearing mice with the therapeutics and external γ-ray radiation boosted the tumor immunogenicity via inducing ICD cascade of the tumor cells and reverse the immunosuppressive tumor microenvironment due to the inhibition of IDO-1 for depletion of tryptophan. Our findings strongly demonstrate that the morphology-adaptable peptide-based therapeutics exhibit the capability to reverse the immunosuppressive tumor microenvironment during irradiation, thus providing a new strategy for the combinatorial radio-immunotherapy. [Display omitted] • Creation of peptide-based therapeutics adopting pH-dependent morphologies. • Efficient delivery of inhibitor NLG919 arising from pH-adaptable morphologies. • Reverse immunosuppression via simultaneous IDO-1 inhibition and induced ICD. • Combining γ-radiation with the therapeutics allows for reliable tumor therapy. [ABSTRACT FROM AUTHOR]