利用纳米技术提高癌症免疫治疗效果的研究进展

Advances in enhancing cancer immunotherapy by nanotechnology

免疫治疗是一种通过增强免疫应答反应,或解除免疫抑制作用来治疗癌症的方法.利用纳米技术能够防止抗原、免疫刺激分子等降解,提高免疫刺激分子等药物在肿瘤部位的富集,改善其生物分布和释放动力学,同时使其靶向作用于肿瘤微环境内的基质细胞、肿瘤细胞和免疫细胞,进行局部免疫调节,从而更有效地治疗癌症和预防全身免疫毒性.本文主要对免疫治疗的现状以及利用纳米技术提高免疫治疗效果的研究进行了总结,并对纳米技术在免疫治疗中应用的挑战进行了分析与展望.

To date, the preliminary research for understanding the underlying cancer etiology has made great progress. However, due to the heterogeneity of cancer and the complexity of tumor microenvironment, as well as the evasion of tumor cells from the immune surveillance, only a few people are rehabilitated with the eradicative cancer therapy so far. In the recent few years, the immunotherapy to stimulate the immune response or inhibit the immunosuppression against cancer has achieved unprecedented efficacy in refractory patients. There are two main streams of the immunoregulation for cancer treatment, immune checkpoint monoclonal antibodies （mAbs） and adoptive cell therapy （ACT）. Nowadays, three kinds of checkpoints-blockade inhibitors, cytotoxic T lymphocyte antigen-4 （CTLA-4） and programmed cell death protein-1 （PD-1）/PD-L1 mAbs, have been approved by the United States Food and Drug Administration （FDA） to treat several types of cancer in clinic, including melanoma, non-small cell lung cancer, renal cell carcinoma and leukemia. Although the current cancer immunotherapy can successfully lead to durable outcomes, the therapeutic effect is still limited and patients are even suffering from the adverse reactions. Thus, it is urgent to develop a localized and efficient immunoregulation strategy against cancer. Encouragingly, nanotechnology is a promising tool to optimize the tumor co-localization, bio-distribution and pharmacokinetics for the molecular probes, cytotoxic pharmaceuticals, immunostimulators, various ligands （e.g., antibodies or aptamers） and other biological agents. The conventional cancer treatment with nanoparticle administration is to increase the cancer cellular uptake by enhanced permeation and retention （EPR） effect, which is a kind of passive accumulation due to the leaky vasculature but is proven somewhat elusive. In contrast, leukocytes of immune system in vivo can actively trace through chemokine gradients to the tumor cells, and then recognize and kill them by binding to the the tu- mor specific antigens. Besides, secondary lymphoid organs do not exhibit physical barriers as tumor microenvironment. Owing to the similar size to pathogens, nanoparticles are also able to accumulate in these fenestrated structures and read- ily uptaken by antigen-presenting cells （APCs）, such as dendritic cells （DCs） and other natural phagocytes. The most typical application of nanotechnology on immunotherapy is cancer vaccines, and the nanoparticles are serving as antigen reservoirs to mimic both prime and boost injections after a single administration. The nanovaccines are able to induce robust DCs or CD8＋ T cells response and confer cross-priming efficacy observed in preclinical animal models, which is an important breakthrough in the development of the soluble vector-free cancer vaccines. In addition, nanotechnologymediated immunotherapy can enhance the treatment efficacy in combination with other approaches, such as surgery, ra- dio-/chemo-therapy or ablation therapy. Meanwhile, there are numerous novel nanotechnology-based strategies for the regulation of both immune system and tumor microenvironment. For example, polymer scaffold can be implanted in vivo to establish a condition for the T-cell engineering; nanocarriers are intended to increase the intercellular avidity by tar- geting the circulating T cells, macrophages and cancer cells; drug-loaded nanoparticles will deliver DNase to destroy the neutrophil extracellular trappings （NETs）. Looking ahead, the field of enhancing immunotherapy by nanotechnology will be developed to permit the analysis of multiple cell subtypes or immune cell activation state. What is more important, the researchers should take the responsibility to place an emphasis on the study of profound theory for immunology, innovative biomaterials for nanoparticles and clinical translation for engineered immunotherapeutic products. Hence, the nanotechnol- ogy-enhanced immunotherapy will enable the evaluation of treatment suitability and consequently improve the personalized immunotherapy. In conclusion, the concentrated immune response realized by nanotechnology can not only lower the drug dose and improve the efficacy, but also prevent the systemic toxicity in patients. It will definitely become the mainstay in immunotherapy in clinic. Therefore, this review is going to summarize the current situation of immunotherapy, and to analyze the opportunities, challenges and development of nanotechnology-enhanced immunotherapy in the future.