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.

放射治疗是一种传统的肿瘤治疗方法，但其远距离治疗效果受到免疫抑制性肿瘤微环境的严重阻碍。为了应对这一挑战，我们在此报告了基于形态适应性肽的疗法，通过同时阻断检查点和诱导免疫原性细胞死亡，有效逆转组合放射免疫疗法中的免疫抑制。基于肽的疗法是通过将含有 4-氨基脯氨酸残基的五肽与其含有 IDO-1 抑制剂 NLG919 的衍生物共组装而产生的。由此产生的治疗剂在纳米纤维和纳米颗粒之间经历了 pH 适应性的形态转变，并在 GSH 裂解后释放 NLG919。体内研究证实，与形态持久性对应物相比，治疗剂的 pH 适应性形态促进了它们在肿瘤部位的肿瘤积累和保留，从而导致 IDO-1 抑制剂的有效传递。用治疗剂和外部γ射线辐射同时治疗荷瘤小鼠，通过诱导肿瘤细胞的ICD级联反应增强肿瘤免疫原性，并由于抑制IDO-1消耗色氨酸而逆转免疫抑制性肿瘤微环境。我们的研究结果有力地证明了基于形态适应性的肽疗法表现出在照射过程中逆转免疫抑制性肿瘤微环境的能力，从而为组合放射免疫疗法提供了一种新策略。