Engineering Bioinspired Nanomedicines to Mitigate the Resistance to Cancer Immunotherapy,Accounts of Materials Research

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Engineering Bioinspired Nanomedicines to Mitigate the Resistance to Cancer Immunotherapy
Accounts of Materials Research ( IF 14.0 ) Pub Date : 2022-05-31 , DOI: 10.1021/accountsmr.2c00042
Jiayi Ye _{1,

2} , Bo Hou _{1,

3} , Madiha Saeed ₁ , Zhiai Xu ₃ , Haijun Yu _{1,

2}

Affiliation

The current era has witnessed the success of immunotherapy, in particular, immune checkpoint blockade (ICB) therapy, at an unprecedented pace. However, immunotherapy often fails to unleash the antitumor immune response because of the paucity of appropriate therapeutic targets in the complex tumor microenvironment (TME) and the occurrence of intrinsic and adaptive immune resistance of tumor cells. In recent years, we have rationally engineered a set of bioinspired stimuli-activatable nanotherapeutics to circumvent cancer immune resistance and potentiate cancer immunotherapy. To prompt the development of nanomedicine-based cancer immunotherapy, in this Account we first introduced the mechanisms of intrinsic and adaptive immune resistance from a tumor cell perspective. We then summarized the bioinspired nanomedicine strategies exploited in our laboratory in the past few years to circumvent both the intrinsic and adaptive immune resistance. These nanoparticles were rationally engineered for highly tumor-specific drug delivery of the immunotherapeutics by responding to the endogenous signals of TME including extracellular/intracellular acidity, overexpressed enzymes, glutathione, and reactive species. These nanoparticles caused the intrinsic immune resistance to migrate by restoring tumor-associated antigen presentation on the surface of tumor cells, repolarizing the tumor-associated macrophages, and eliciting antitumor immunogenicity via the induction of the immunogenetic cell death of tumor cells. Meanwhile, these nanoparticles were also loaded with small molecular or macromolecular immune inhibitors to relieve the inducible expression of the immune checkpoints (e.g., programmed cell death of ligand 1 and indolamine 2,3-dioxygenase 1), thereby relieving the adaptive immune resistance. Overviews of the nanomedicine strategies used to cause the immune resistance to migrate by regulating lactate metabolism and lipid peroxidation were also provided. Furthermore, we suggested rational combination strategies according to diverse cancers to mitigate multiple immune resistance. These tactics can be adopted to perpetuate the cancer immunity cycle for clinical therapy of immune-resistant cancer. It is envisaged that TME-activatable bioinspired nanomedicines to bypass immunosuppressive signaling pathways may broaden the clinical impact of cancer immunotherapy.

中文翻译：

工程仿生纳米药物以减轻对癌症免疫疗法的抵抗力

当前时代见证了免疫疗法的成功，特别是免疫检查点阻断（ICB）疗法以前所未有的速度取得了成功。然而，由于复杂的肿瘤微环境（TME）中缺乏合适的治疗靶点，以及肿瘤细胞存在固有和适应性免疫抗性，免疫治疗往往无法释放出抗肿瘤免疫反应。近年来，我们合理地设计了一套受生物启发的可刺激激活的纳米疗法，以规避癌症免疫抗性并增强癌症免疫疗法。为促进基于纳米医学的癌症免疫疗法的发展，在本文中，我们首先从肿瘤细胞的角度介绍了内在和适应性免疫抵抗的机制。然后，我们总结了过去几年在我们的实验室中利用的仿生纳米医学策略，以规避内在和适应性免疫抗性。这些纳米颗粒通过响应 TME 的内源信号（包括细胞外/细胞内酸度、过表达的酶、谷胱甘肽和活性物质）来合理地设计用于免疫治疗剂的高度肿瘤特异性药物递送。这些纳米颗粒通过恢复肿瘤细胞表面的肿瘤相关抗原呈递，使肿瘤相关巨噬细胞复极化，并通过诱导肿瘤细胞的免疫原性细胞死亡来引发抗肿瘤免疫原性，从而导致内在免疫抗性迁移。同时，这些纳米颗粒还装载了小分子或大分子免疫抑制剂，以减轻免疫检查点的诱导表达（例如，配体1和吲哚胺2,3-双加氧酶1的程序性细胞死亡），从而减轻适应性免疫抵抗。还概述了用于通过调节乳酸代谢和脂质过氧化来引起免疫抗性迁移的纳米药物策略。此外，我们根据不同的癌症提出了合理的组合策略，以减轻多重免疫抗性。这些策略可用于延长癌症免疫周期，用于免疫抗性癌症的临床治疗。设想 TME 可激活的仿生纳米药物绕过免疫抑制信号通路可能会扩大癌症免疫治疗的临床影响。

更新日期：2022-05-31

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