药学学报

Cell membrane source	Main characteristics
Red blood cell	Immune escape; long cycle
White blood cell
Macrophage	Targeted chemotaxis of inflammation
Cytotoxic T lymphocyte	Secretion of cytokines, high expression of adhesion molecules
Natural killer cell	Promote the maturation of antigen presenting cells and activate T cells
Dendritic cell	Antigen presentation, specific activation of T cells
Blood platelet	Through P-selectin interaction with CD44 receptor on circulating tumor cell; all 9 Toll-like receptors were expressed
Tumor cell	Homologous targeting
Bacteria	Strong immunogenicity

Cell membrane source	Main characteristics
Red blood cell	Immune escape; long cycle
White blood cell
Macrophage	Targeted chemotaxis of inflammation
Cytotoxic T lymphocyte	Secretion of cytokines, high expression of adhesion molecules
Natural killer cell	Promote the maturation of antigen presenting cells and activate T cells
Dendritic cell	Antigen presentation, specific activation of T cells
Blood platelet	Through P-selectin interaction with CD44 receptor on circulating tumor cell; all 9 Toll-like receptors were expressed
Tumor cell	Homologous targeting
Bacteria	Strong immunogenicity

Chemotherapeutic agent	Mechanism of action	Ref.
Carboplatin	Induce DNA damage and activate STING/TBK1/IRF3 pathway	[102]
Methotrexate	Increase adenosine content, thereby inhibiting neutrophil function and reducing the occurrence of inflammatory mediators; enhance antigen presentation function of dendritic cells (DCs)	[103, 104]
5-Fluorouracil	Significantly reduced MDSC in spleen and tumor	[105]
Doxorubicin	Promote the maturation of DCs; increased cytotoxic T cell infiltration; promotes recruitment of natural killer (NK) cells	[106, 107]
Cyclophosphamide	Activate recruitment of NK cells, macrophages and DCs; the number of Tregs was selectively inhibited; induction of pathogenic Th17 cell differentiation by altering intestinal flora	[108, 109]
Oxaliplatin	Promoting the production of IFN-γ and IL-2 by T cells; promote the maturation of marrow derived DCs and the expansion of CD8⁺ T cells	[110, 111]
Paclitaxel (PTX)	Selective reduction of Treg, promotion of CRT transduction, promotion of IFN-γ expression	[112, 113]

Chemotherapeutic agent	Mechanism of action	Ref.
Carboplatin	Induce DNA damage and activate STING/TBK1/IRF3 pathway	[102]
Methotrexate	Increase adenosine content, thereby inhibiting neutrophil function and reducing the occurrence of inflammatory mediators; enhance antigen presentation function of dendritic cells (DCs)	[103, 104]
5-Fluorouracil	Significantly reduced MDSC in spleen and tumor	[105]
Doxorubicin	Promote the maturation of DCs; increased cytotoxic T cell infiltration; promotes recruitment of natural killer (NK) cells	[106, 107]
Cyclophosphamide	Activate recruitment of NK cells, macrophages and DCs; the number of Tregs was selectively inhibited; induction of pathogenic Th17 cell differentiation by altering intestinal flora	[108, 109]
Oxaliplatin	Promoting the production of IFN-γ and IL-2 by T cells; promote the maturation of marrow derived DCs and the expansion of CD8⁺ T cells	[110, 111]
Paclitaxel (PTX)	Selective reduction of Treg, promotion of CRT transduction, promotion of IFN-γ expression	[112, 113]

纳米仿生型肿瘤疫苗的研究进展

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杨玥 ^# , 王海燕 ^# , 孙野 ^# , 孙涛 ^* , 蒋晨

药学学报 | 综述 2022,57(4): 963-975

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药学学报 | 综述 2022, 57(4): 963-975

纳米仿生型肿瘤疫苗的研究进展

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杨玥^#, 王海燕^#, 孙野^#, 孙涛^*, 蒋晨

作者信息

复旦大学药学院, 智能化递药教育部重点实验室/复旦大学附属闵行中心医院, 医学神经生物学国家重点实验室, 上海 201203

通讯作者:

*孙涛, Tel: 86-21-51980187, E-mail: sunt@fudan.edu.cn

Advances in the study of nano-biomimetic tumor vaccines

Yue YANG, Hai-yan WANG, Ye SUN, Tao SUN^*, Chen JIANG

Affiliations

Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203

出版时间: 2022-04-12 doi: 10.16438/j.0513-4870.2021-1069

文章导航

摘要

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肿瘤疫苗作为肿瘤免疫疗法的一种, 为癌症治疗提供了新策略。利用纳米仿生材料包被肿瘤抗原, 构建纳米仿生型肿瘤疫苗, 可实现抗原的靶向递释, 具有高效性和安全性等优点。因此, 纳米仿生型疫苗成为当今的研究热点。据此, 本文综述了新型纳米仿生肿瘤疫苗的研究进展, 并介绍了其临床应用及同其他疗法的联合应用情况。

关键词

肿瘤疫苗 / 免疫治疗 / 纳米仿生型材料 / 免疫佐剂 / 药物靶向递送

Abstract

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As a kind of tumor immunotherapy, tumor vaccine provides a new strategy for cancer treatment. With nano-biomimetic materials to encapsulate the tumor antigens, the construction of nano-biomimetic tumor vaccine can target the tumor and release antigens, with high efficiency and safety. Therefore, nano-biomimetic vaccine has become a hot research topic. Based on this review, several new nano-biomimetic nanoparticles are summarized, and the clinical applications of the nano-biomimetic vaccine combined with other therapeutic strategies are introduced.

Key words

tumor vaccine / immunotherapy / nano-biomimetic material / immune adjuvant / targeting drug delivery

引用本文

杨玥, 王海燕, 孙野, 孙涛, 蒋晨. 纳米仿生型肿瘤疫苗的研究进展. 药学学报, 2022 , 57 (4) : 963 -975 . DOI: 10.16438/j.0513-4870.2021-1069

Yue YANG, Hai-yan WANG, Ye SUN, Tao SUN, Chen JIANG. Advances in the study of nano-biomimetic tumor vaccines[J]. Acta Pharmaceutica Sinica, 2022 , 57 (4) : 963 -975 . DOI: 10.16438/j.0513-4870.2021-1069

正文

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手术切除肿瘤、放射疗法和化学药物治疗一直是肿瘤综合治疗的基本疗法, 近年来靶向药物也成为新的研究方向, 肿瘤治疗效果有了很大改善, 但仍具有易复发、易耐受和不良反应大等缺陷。随着分子生物学、免疫学基础研究的进展, 免疫疗法获得了2018年诺贝尔生理学或医学奖, 成为攻克癌症的主要研究方向。肿瘤免疫疗法通过作用于免疫细胞, 增强人体免疫系统对肿瘤细胞的杀伤作用, 减少肿瘤细胞免疫逃逸。免疫治疗包括细胞因子疗法、免疫检查点疗法(inhibitory checkpoint therapy)、淋巴细胞免疫疗法(CAR-T免疫疗法) 和肿瘤疫苗等^{[1, 2]}。但由于肿瘤较差的免疫原性, 并有肿瘤免疫逃避(tumor immune escape) 现象, 免疫系统难以分辨正常机体细胞和肿瘤细胞, 免疫疗法杀伤肿瘤效果不理想^[3]。

肿瘤疫苗(tumor vaccine) 作为一种新兴的免疫疗法, 是将肿瘤抗原、编码肿瘤抗原的基因、免疫细胞及分子等导入体内, 激活非特异性免疫应答杀灭肿瘤的方法。肿瘤细胞产生的抗原可以分为肿瘤特异性抗原(tumor-specific antigen, TSA) 和肿瘤非特异性抗原(tumor-associated antigen, TAA)。抗原呈递细胞(antigen presenting cells, APCs) 主要是树突状细胞(dendritic cells, DCs) 和巨噬细胞, 首先需要有效摄取并呈递肿瘤抗原^[4]。APCs将通过主要组织相容性复合体(major histocompatibility complex, MHC)-Ⅱ类分子将抗原呈递到细胞膜上, 激活CD4⁺ T细胞, 发生体液免疫应答; 或抗原逃逸至细胞质中, 被MHC-Ⅰ类分子呈递给CD8⁺ T细胞, 激活细胞免疫清除肿瘤细胞, 这种方式叫做交叉呈递^[5]。交叉呈递能够有效加强机体免疫系统。根据功能的不同, 肿瘤疫苗可以分为治疗性疫苗和预防性疫苗。按有效成分可分为DCs疫苗、基因疫苗、多肽疫苗和活载体疫苗等^[6]。将纳米技术与肿瘤疫苗相结合是当今的研究热点^[7-9]。

纳米粒是指粒径在1~1 000 nm的材料。在肿瘤疫苗中, 纳米材料具有包载抗原和免疫佐剂的作用。纳米仿生型肿瘤疫苗指的是利用生物来源材料, 通过静电作用、疏水-疏水作用、氢键和共价结合等方式, 构建成纳米平台, 实现对肿瘤抗原和佐剂的高效负载或包被, 继承生物来源材料固有的生物学行为, 实现在淋巴结组织的靶向蓄积及在抗原提呈细胞内的高效释放。纳米肿瘤疫苗的粒径分布范围一般在20~300 nm之间。纳米粒经过修饰能够具有与病原体相似的表面性质, 如: 粒径、电核、亲疏水性和有利于运载抗原的形状等, 调控疫苗与APCs之间的相互作用, 从而增加抗原被摄取的效率, 增加抗原免疫原性^{[10, 11]}。纳米材料能增强共刺激信号的表达, 促进DCs的成熟; 通过修饰增强肿瘤疫苗的靶向性, 促进肿瘤抗原交叉呈递; 高表达肿瘤相关组织相容物复合体; 增加DCs的内化等优点^{[12, 13]}。因此, 以纳米材料作为载体可以减少肿瘤疫苗对正常细胞的损伤, 提高杀灭肿瘤的能力。纳米仿生型疫苗应用新型的递送系统, 展现出了巨大的潜力。

1 细胞膜包被纳米粒

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细胞膜包被纳米粒指的是由纳米粒核心及外层细胞膜构成的仿生型纳米材料。细胞膜包被的纳米仿生型肿瘤疫苗使肿瘤疫苗能够得到源细胞的特性, 从而增强其免疫逃逸、肿瘤的靶向定位和促进抗肿瘤免疫等功能, 能够用于制备纳米仿生型肿瘤疫苗的细胞膜有红细胞(red blood cell, RBC) 膜、白细胞(white blood cell, WBC) 膜、血小板(blood platelet, PLT) 膜、肿瘤细胞膜和细菌膜等, 本部分综述了各种细胞膜的特性和其在纳米仿生型肿瘤疫苗制备中的优势, 以及细胞膜包被的纳米仿生型肿瘤疫苗的研究现状。

细胞膜包被的纳米仿生型肿瘤疫苗与真实的细胞结构相似, 具有细胞的自然特性, 毒性较小, 能够跨过生理障碍, 适应生物体内不同的生理环境, 以逃避自身免疫系统的识别与清除。不同细胞类型所显示的独特特性在很大程度上可以归因于其膜上存在的复杂抗原特征^[14], 因而不同的细胞膜的包被能够使肿瘤疫苗获得独特的源细胞特性和抗原特征(表 1), 以引起特定的免疫应答。总之, 细胞膜包被的纳米仿生型肿瘤疫苗是一个非常值得深入研究探索的领域。

1.1 RBC膜包被纳米粒

RBC是血液中数目最为丰富的一种血细胞, 也是运输氧气最主要的载体, 还参与体内的免疫过程, 且成熟的RBC没有细胞核和繁杂的细胞器, 易于进行膜的提取净化。RBC膜的包被能赋予纳米粒在体内长期循环的特点, 其免疫逃逸的机制主要与RBC膜表面的CD47 (cluster of differentiation 47, 整联素关联蛋白) 和巨噬细胞表达的信号调节蛋白α (signal regulatory proteins α, SIRPα) 之间的相互作用有关^[15], CD47和SIRPα结合后, 能抑制巨噬细胞对RBC的吞噬作用(图 1)。但RBC对恶性肿瘤缺乏一定的靶向功能, 可通过表面修饰、脂质插入靶向配体等方法进行改善。Guo等^[16]开发了一种由RBC膜包裹的聚合物纳米粒作为纳米疫苗, 研究结果表明, 其对小鼠黑色素瘤有预防效果, 并且抑制了肿瘤生长和转移, 还能增强干扰素γ (interferon-γ, IFN-γ) 的分泌和CD8⁺ T细胞的应答。Han等^[17]开发了一种RBC衍生的纳米红细胞体(nano-Ag@erythrosome), 将肿瘤细胞膜相关抗原与纳米红细胞体相融合, 在体内可引起抗原反应, 并发现与抗程序性死亡受体1 (programmed cell death protein 1, PD-1) 阻断剂相结合, 可抑制肿瘤生长。

1.2 WBC膜包被纳米粒

WBC是一类分布于血液、淋巴及各组织中的无色、有核的血细胞, 分为粒细胞、单核细胞和淋巴细胞3大类, 具体包含嗜酸粒细胞、嗜碱粒细胞、中性粒细胞、巨噬细胞、DCs、T细胞、B细胞和自然杀伤细胞(natural killer cells, NK) 等, WBC类群在机体发挥免疫功能的过程中有重要的作用。

巨噬细胞来源于单核细胞, 是具有噬菌功能的免疫细胞, 能吞噬并清除残留的细胞碎片和病原体, 刺激淋巴细胞或其他免疫细胞发挥免疫作用。巨噬细胞固有的炎症定向趋化能力使其能够对慢性炎症肿瘤组织靶向定位^[18], 且巨噬细胞是网状内皮系统(reticulo-endothelial system, RES) 的成员之一, 因此巨噬细胞膜涂层纳米粒也具有很好的免疫逃逸能力和生物相容性, 在仿生型纳米肿瘤疫苗的研究中具有很大潜力。

细胞毒性T淋巴细胞(cytotoxic T lymphocyte, CTL) 属于特异性T细胞, 能够产生穿孔素、干扰素和肿瘤坏死因子等, 发挥特定的免疫功能。CTL作为WBC的一种, 能高表达黏附分子, 从而准确有效地靶向肿瘤部位, 并在肿瘤部位招募此类细胞, 此外, 还具有血液循环时间长的特点。Zhang等^[19]开发的一种CTL膜涂层纳米粒既保留了其长血液循环的特点, 又能很好地在肿瘤部位累积, 辅以低剂量辐照还能显著提高其靶向肿瘤组织的能力。

NK是淋巴细胞中的一类, 不依赖抗体也没有MHC限制, 能促进APC的成熟, 从而激活T细胞杀死肿瘤细胞^[20]。NK膜上活性受体, 如NKp30、NKp44、NKp46、DNAM-1 (CD226) 和NKG2D, 与肿瘤识别和肿瘤杀伤密切相关^[21]。因此, NK细胞膜有望帮助纳米疫苗逃避免疫监测, 识别、靶向肿瘤细胞, 促进免疫原性细胞死亡, 抑制肿瘤生长, 并激活体内的其他抗肿瘤免疫反应。Deng等^[20]发现NK细胞膜包被的纳米粒(NK-NPs) 能定位肿瘤细胞、增强M1型巨噬细胞极化, 触发体内抗肿瘤免疫应答, 抑制肿瘤细胞的生长。

成熟的DCs膜具有DCs的抗原呈递功能, 并能特异性激活T细胞, 包括记忆T细胞和初始T细胞, DCs膜还可表达共刺激分子和黏附分子, 介导细胞黏附, 从而促进DCs与T细胞的相互作用^[21]。Ochyl等^[22]的实验结果表明, 纳米粒径的树突状细胞膜囊泡(DC-MV) 能有效输送抗原肽疫苗, 激活抗原特异性T细胞的反应, 是一个很有发展潜力的肿瘤疫苗载体。

1.3 PLT膜包被纳米粒

PLT是从骨髓成熟的巨核细胞胞浆脱落下来的小块胞质, 循环寿命约为7~10天, 对损伤血管有超强的黏附性^[23]。PLT能够通过P-选择素与循环肿瘤细胞(circulating tumor cell, CTC) 上的CD44受体相互作用, 从而靶向肿瘤组织(图 2)^[24]。还有研究发现PLT表达所有9种Toll样受体, 能够激活机体的免疫应答^[25]。因此, PLT膜的包被能够保护纳米疫苗逃避巨噬细胞的内吞作用, 延长循环时间, 且能够靶向肿瘤细胞, 并调节免疫反应。Wang等^[24]开发了PLT膜功能化的多孔纳米粒, 利用静电吸引力来稳定PLT膜包被纳米粒, 并表现出很好的生物相容性, 由于PLT膜表面的P-选择素和肿瘤细胞上的CD44受体的相互作用, 能够靶向并蓄积于肿瘤组织, 降低全身毒性。总之, PLT膜在制备纳米仿生型肿瘤疫苗方面也是很有发展前景的材料。

PLT膜包被材料的制备方法一般包含3个步骤: ①制备纳米载体核心(可通过乳化溶剂挥发法等); ②制备PLT膜: 首先提取PLT, 将富含PLT的血浆加入EDTA抗凝后, 离心除去RBC, 取上清液, 加入前列环素, 以抑制PLT的激活; 之后高速离心, 利用含蛋白酶抑制剂的缓冲液重悬, 以得到PLT; 再利用反复冻融法制备PLT膜。液氮速冻PLT后室温溶解、离心, 然后利用加入蛋白酶抑制剂的缓冲液反复洗涤重悬, 得到PLT膜; ③将第1个步骤中得到的纳米载体核心加入到新鲜制备的PLT膜中, 超声处理制备得到PLT膜包被的纳米材料。

1.4 肿瘤细胞膜包被纳米粒

肿瘤细胞本身就来源于体内的正常细胞, 但与体内正常的细胞相比, 肿瘤细胞具有其独特的特征, 例如不断增殖的能力、迁移性、接触抑制丧失和同源靶向能力等, 已有研究表明肿瘤细胞膜上存在TAA^[14], 能够向APC呈递TAA (图 3), 此外, 肿瘤细胞坏死后会释放损伤相关模式分子(damage associated molecular patterns, DAMPs), 可通过Toll样受体、RIG-1样受体或NOD样受体等模式识别受体, 使其具有更强的免疫原性, 诱导自身免疫或免疫耐受^[26]。因此, 肿瘤细胞膜包被纳米粒, 能更有效地靶向恶性肿瘤, 触发或增强体内免疫系统的应答。

Fang等^[14]用小鼠黑色素瘤细胞的细胞膜与纳米多聚体结合, 制成癌细胞膜涂层纳米粒, 所制的纳米粒与源癌细胞有非常相似的抗原特性和外观特征。通过研究发现, 该癌细胞膜涂层纳米粒不仅有一定的免疫原性能呈递TAA, 还与源癌细胞有足够的亲和力从而实现癌细胞的同型靶向, 有利于癌细胞的定位、判断癌细胞的转移倾向及抗癌药物的靶向递送。Kang等^[27]将癌细胞膜蛋白(cancer cell membrane protein, CM)、HSP70功能肽(heat shock protein 70s, HSP70s) 和寡脱氧核苷酸(oligodeoxynucleotide, CpG) 合成一个仿生型人工坏死癌细胞膜纳米疫苗。该纳米疫苗在体外可诱导骨髓衍生树突状细胞(bone marrow-derived dendritic cell, BMDC) 的成熟, 在体内能诱导多表位特异性T细胞反应, 且可被有效输送至淋巴结。而HSP70s能增强DAMP信号, 激活NK细胞和DC细胞, CpG寡脱氧核苷酸也能刺激强大的宿主免疫反应^[27]。结果显示, 将该疫苗与抗PD-1抗体联合使用, 小鼠的黑色素瘤完全消退, 还能产生长期效应记忆T细胞。

1.5 细菌膜包被纳米粒

对于肿瘤疫苗来说, 拥有一定的免疫原性能显著增强体内免疫系统的抗肿瘤应答。细菌膜的包被使得肿瘤疫苗拥有强烈的免疫原性, 能够更好地捕获肿瘤新抗原, 刺激或增强免疫系统的抗肿瘤免疫应答。Patel等^[28]从一种具有强烈免疫原性的非致病菌株—小分枝杆菌(Mycobacterium smegmatis, MS) 中提取出细菌膜, 开发了一种细菌膜涂层纳米粒(bacterial nanolayered coating nanoparticle, BNP)。研究表明, BNP能捕获肿瘤新抗原, 增强DC细胞对其摄取并促进交叉呈递, 以刺激抗肿瘤T细胞反应。此外, 革兰阴性细菌分泌的细菌外膜囊泡也是一种有用的肿瘤疫苗运载工具, 能有效地诱导长期抗肿瘤免疫反应, 有望完全根除肿瘤细胞, 而没有明显毒性^[29]。

1.6 仿生体肿瘤疫苗

Wang等^[30]研究了一种配体介导的靶向DC细胞的texosomes仿生体作为肿瘤疫苗的载体, 将肿瘤抗原肽或其与热休克蛋白的复合物包裹在载体中, 对DC细胞具有很高的靶向性, 能增强疫苗的免疫原性, 克服肿瘤免疫逃逸, 还能刺激T细胞转化为CTL细胞, 使机体产生主动免疫, 抑制肿瘤的生长。

从体内正常细胞特别是参与免疫系统功能的细胞中提取细胞膜能够使肿瘤疫苗具有很好的免疫逃逸功能和生物相容性, 且毒性较低。肿瘤细胞膜因其同源靶向能力能够使肿瘤疫苗有较好的靶向定位能力。而细菌膜能够使得肿瘤疫苗具有强大的免疫原性以诱导体内长期而强烈的抗肿瘤免疫。还能够将不同的细胞膜进行融合使用, 目前已经有RBC和PLT混合膜^[31]、RBC和肿瘤细胞混合膜^[32]等涂层纳米粒的研究, 能够使纳米肿瘤疫苗同时获得不同的细胞特性和功能。

细胞膜包被的仿生型纳米肿瘤疫苗具有很好的免疫逃逸功能、肿瘤细胞靶向能力和激活患者本身的抗肿瘤免疫功能, 且临床研究过程中也有一定的良好反馈, 有望成为有效的治疗恶性肿瘤的方法。最好从患者自身的健康细胞或肿瘤细胞中提取细胞膜, 能够大大降低毒性, 更好的逃避自身免疫系统的清除, 也是一种个性化肿瘤疫苗的研究方向。

2 自组装蛋白

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机体中一般的可溶性蛋白难以被APCs摄取, 而将蛋白质修饰成与病原体类似大小和表面性质则可以提高蛋白质-抗原复合物的免疫原性与靶向性。目前研究较多的蛋白质载体包括病毒样颗粒(virus-like particles, VLPs) 及载脂蛋白。

2.1 VLPs

VLPs是由病毒蛋白在空间中重复堆积、排列形成的具有规则空间结构的中空蛋白质结构, 能被APCs通过MHC-Ⅱ类分子呈递给CD4⁺ T细胞或VLPs经过溶酶体逃逸, 通过MHC-Ⅰ类分子呈递给CD8⁺ T细胞。进而刺激并活化CTL和辅助型T细胞, 促进分泌细胞因子杀伤肿瘤细胞^{[33, 34]}。另外, 由于VLPs一般具有连续重复的抗原表位和规则的几何结构, 被看作高效的病原相关分子模式(pathogen-associated molecular patterns, PAMP) 能有效交联B细胞表位, 激活B细胞分化成熟^{[35, 36]}。VLPs具有以下优点: ①虽然VLPs具有较强的免疫原性, 但是其缺少病毒核酸结构, 不能复制和感染, 相对比较安全^[36]; ② VLPs在体内存在天然的靶向性, 能在致癌病毒聚集的部位浓集^{[36, 37]}; ③具有空腔结构和较强的重组能力, 便于包载药物; ④易进行功能化改造, 并大规模可控的生产^[38]。

VLPs可通过化学键等与肿瘤抗原进行融合修饰, 组装成新型高效肿瘤疫苗。Simons等^[39]将两种前列腺癌特异性肿瘤抗原: 前列腺酸性磷酸酶(PAP-1、PAP-2) 和前列腺干细胞抗原(prostate stem cell antigen, PSCA), 以及前列腺癌特异性癌特异性T细胞刺激物(stimulator of prostatic adenocarcinoma specific T cells, SPAS-1) 修饰的牛乳头瘤病毒L1蛋白, 与病毒表面的半胱氨酸的游离巯基形成二硫键, 组装成能应用于转移性潜力腺癌患者的新型肿瘤疫苗。Campbell等^[40]研究用VLPs装载多种抗原共同呈递治疗乳腺癌。VLPs来源于兔出血症病毒, 由180个病毒衣壳蛋白VP60组成, VP60可表达小鼠凋亡抑制蛋白。VLPs通过二硫键与肿瘤细胞特有的异常糖基化黏蛋白-1 (MUC-1) 肽段结合, 同时以CpG为佐剂组成肿瘤疫苗。结果显示, 通过VLPs共呈递肿瘤抗原能够产生强大的抗肿瘤免疫效应, 肿瘤疫苗共呈递抗原是未来研究的新方向。

近年来, 通过基因工程技术, 将VLPs多肽结构的基因与其他功能多肽基因片段相融合, 高效构建肿瘤疫苗成为纳米仿生型疫苗中的研究热点。Zheng等^[41]通过将表面抗原分化簇274 (cluster of differentiation 274, CD274) 的siRNA导入人乳头瘤病毒L1蛋白质(HPV16 L1), 与阻断免疫检查点疗法结合, 构建肿瘤疫苗。siRNA可显著降低CD274的表达, 组织肿瘤组织逃避免疫监视; HPV L1作为肿瘤抗原激活Ⅰ型干扰素(interferon, IFN) 介导的先天免疫, 实现协同治疗肿瘤。

2.2 载脂蛋白修饰的纳米疫苗

一直以来, 有关抗原呈递过程的研究重点都在于增强DCs的胞吞作用, 却忽视了DCs的巨胞饮途径在摄取内源性抗原中发挥的重要作用。以载脂蛋白作为搭建肿瘤疫苗的载体能通过激发巨胞饮增加抗原呈递效率, 有效激活免疫系统。Zhou等^[42]用磷脂膜包裹抗原肽(αOVA) 和重组人ApoE3蛋白, 构建具有核衣壳结构的纳米仿生肿瘤疫苗。实验证明, 皮下注射后, 经载脂蛋白修饰后的肿瘤疫苗能靶向淋巴结的DCs, 显著提高巨胞饮作用, 增加固有免疫和适应性免疫应答。载脂蛋白生物相容性比较好, 体内稳定性好, 作为一种天然纳米载体, 在靶向递送药物领域有很大研究价值。

2.3 脂质体纳米仿生疫苗

脂质体是将磷脂分散在水中后形成的生物仿生体, 分为被单层磷脂双分子层包裹的单室脂质体和被水分开的同心多室脂质体^{[43, 44]}。脂质体具有亲脂膜和亲水核, 可包裹水溶性和脂溶性抗原和佐剂, 使其应用范围变广, 还可通过改变配基或靶点改变脂质体的表面性质, 使其能靶向运载释放药物^[45]。另外, 研究发现, 表面聚乙二醇化的脂质体能够减少血浆蛋白的结合, 延长循环时间, 引起立体稳定效应^[46]。因此, 脂质体具有保护免疫抗原与佐剂; 增强抗原的免疫原性, 有效激活免疫反应; 在体内易降解, 减少炎症发生; 能包裹大量抗原等优点^[43]。

Affandi等^[47]利用神经节苷脂体外修饰的脂质体包裹肿瘤抗原和Toll样受体, 靶向运载到高表达CD169的APCs, 包括单核来源树突状细胞(monocyte-derived dendritic cells, moDCs) 和Axl⁺ DCs。神经节苷脂是CD169的内源性天然配体, 能够增加脂质体的靶向性和免疫原性。最终结果显示, 神经节苷脂修饰的纳米仿生型疫苗能够促进细胞因子的释放, 增加T细胞分化成熟; 由于包裹Toll样受体, 活化CD169⁺ moDCs并促进抗原的交叉呈递, 进而活化CD8⁺ T细胞。

近些年来, 阳离子脂质体受到了广泛的关注。阳离子脂质体表面的正电荷能够加速APCs的摄取, 保护装载的阴离子抗原被降解, 并且能与细胞膜相互作用, 加速释放装载的抗原, 显著提高免疫反应的速度和程度^{[48, 49]}。研究发现, 阳离子脂质体能诱导活性氧(reactive oxygen species, ROS), 进而引起的细胞杀伤作用^[50]。研究最多的阳离子脂质体包括(2, 3-二油氧基丙基) 三甲基氯化铵(1, 2-dioleoyl-3-trimethylammonium propane, DOTAP) 和二油酰丙基氯化三甲铵(N-(1-[2, 3-dioleyloxy]propyl)-N, N, N-trimethylammonium chloride, DOTMA)。Talesh等^[51]将带正电的DOTAP与胆固醇融合形成脂质膜, 包裹HER2/Neu的P5肽段作为肿瘤抗原和聚胞啶酸[polyribocytidylic acid, poly (I∶C)] 作为免疫佐剂形成肿瘤疫苗。这种疫苗在体内外均明显增强免疫系统: 促进CD8⁺ T细胞释放IFN-γ, 活化Th1细胞, 释放细胞因子, 活化大量CTL, 杀伤肿瘤细胞。

随着对脂质体的研究, 其在纳米仿生型疫苗中的应用有良好的前景。但是由于脂质体制备难度高、价格贵和不稳定等缺点, 限制了脂质体的广泛应用。这是未来研究工作的瓶颈, 需对肿瘤疫苗进行更加深入的研究。

2.4 外泌体(exosomes) 仿生纳米粒

外泌体来源于细胞膜系统的脂质膜囊泡, 能在细胞间运输蛋白质、RNA和其他分子, 在细胞间交流和疾病发生发展过程中起到了重要作用^[52]。相比较于其他纳米粒, 外泌体有较好的生物相容性和可降解性, 能装载肿瘤抗原和配体, 近些年来广泛应用于诊断和靶向治疗疾病^{[53, 54]}。Wang等^[55]通过将肿瘤相关外泌体(tumor-associated exosomes, TAEs) 同肿瘤细胞溶解产物(tumor cell lysates, TCLs) 进行对比, 发现TAEs能降低DCs表达细胞程序性死亡配体1 (programmed cell death 1 ligand 1, PD-L1), 进而降低肿瘤细胞的免疫抑制作用, 减少Tregs的表达。由于在肿瘤引流淋巴结和脾脏中CD8⁺ T细胞聚集, Tregs减少, 使得TAEs装载的肿瘤疫苗能抑制肿瘤增长, 并延长小鼠的存活时间。Liu等^[56]将来自经过热疗小鼠的血清外泌体与黑磷量子点(black phosphorus quantum dots, BPQDs) 相结合, 构建热敏肿瘤疫苗。结果显示, 外泌体和BPQDs搭建的纳米结构能有效被DCs吞噬, 促进Th1释放细胞因子。以外泌体作为搭建疫苗的载体有如下优点: ①保护BPQD, 避免被肾脏清除体外; ②来自患肺癌小鼠的外泌体承载多种肿瘤抗原, 能增强免疫反应; ③脂质体表面表达一系列配基包括CD11b和CD18, 能实现靶向运载。但其具体对人体的毒性还需进一步研究。

3 纳米仿生型肿瘤疫苗的临床研究与应用

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3.1 纳米仿生型肿瘤疫苗作为预防性疫苗

癌症的预防分为3个等级, 其中二级预防是指在尽可能早的阶段识别疾病并阻止其发展为恶性肿瘤^[57]。而接种肿瘤预防性疫苗正是在此步骤中降低癌症的发病率。研究显示, 无论是动物实验还是临床试验, 接种肿瘤预防性疫苗均可有效降低肿瘤发生率和病死率^{[58, 59]}。目前较为成熟多用的预防性疫苗主要是通过预防致癌病原体, 达到避免诱发癌症的目的^[60]。这是由于病原体(如病毒) 具有较高的免疫原性, 可有效刺激人体免疫系统产生针对这些外来颗粒的抗体, 常见的预防性疫苗包括人乳头瘤病毒疫苗、乙肝疫苗等。

持续感染高危人乳头瘤病毒(human papilloma virus, HPV) 易导致包括宫颈癌在内的多种癌症^[61]。目前多种针对HPV的疫苗, 均可有效防止宫颈癌的发生, 已在全球得到推广。为改善HPV疫苗靶蛋白HPV16型E7表位肽存在的一系列分子质量小、易降解等缺点, Tang等^[62]选用pORF9-mGMCSF质粒和细胞穿膜肽HIV-1Tat49-57融合制成纳米粒, 对靶蛋白进行装载; Zheng等^[63]利用生物材料聚乳酸-羟基乙酸共聚物[poly(lactic-co-glycolic acid), PLGA] 负载HPV16mE7蛋白, 包封为纳米疫苗悬液。以上两种纳米仿生疫苗在稳定性提高的同时, 利用纳米仿生载体的靶向作用和缓释作用^[64], 显著提高了CTL反应的强度, 在体外实验和动物实验中获得了可观的疗效。

乙型肝炎病毒(hepatitis B virus, HBV) 是导致肝硬化和肝癌的主要原因之一^[65], 研究表明接种乙肝疫苗可明显预防传播感染和肝癌发生^[66]。在传统乙肝预防疫苗的基础上, Wang等^[67]结合仿生纳米平台, 设计了一种基于仿生纳米铁蛋白材料的NP-preS1 (纳米粒-乙肝病毒前S1抗原) 疫苗, 通过协同靶向不同的SIGNR1⁺抗原呈递细胞(SIGNR1⁺ APC), 提高了HBV表面蛋白preS1结构域的免疫原性, 增强抗体产生, 在慢性HBV小鼠模型中获得良好的预防和功能性治愈效果(图 4)。

由于绝大多数癌症无法追溯到病原体, 开发针对TAA或TSA的预防性疫苗是必要的。但是, 肿瘤细胞具有多种免疫逃逸机制, 包括抗原表达的丢失^[68]、抗原内吞^[69]和类似病毒的抗原漂移^[70]等, 以逃避免疫系统的监视和攻击。如果疫苗诱导有限单一的免疫防御, 反应效力将不够充分^[71], 提示了非病毒性癌症预防中多价疫苗的重要性; 同时, 抗原可能会遭到体内核酸酶等酶的水解^{[72, 73]}, 这要求载体有较好的保护作用; 最后, 作为预防性疫苗, 要求其精准趋向至淋巴器官或APC的同时, 不伤害正常细胞^[9], 暗示了其靶向功能的必要性。使用仿生纳米技术构建的肿瘤疫苗理论上能较好地解决以上问题^{[74, 75]}。目前已有MUC1糖蛋白、细胞周期蛋白B1 (cyclin B1) 和人表皮生长因子受体2等少数肿瘤抗原可显示出一定的保护效果^{[16, 20, 76-85]}。但目前存在的较大开发障碍是如何避免正常组织中TAA免疫, 降低接种效率^[86]。虽然这些抗原采用仿生纳米平台进行递送的报道较少, 研究还存在一定的局限, 但联合后在某些癌症高危人群的防护中必将发挥有效作用。

3.2 纳米仿生型肿瘤疫苗作为治疗性疫苗

成功的抗肿瘤纳米疫苗需要能够将肿瘤相关抗原和佐剂有效地递送至APC, 治疗效果的好坏取决于CTL反应响应的强度^[86]。与传统非纳米疫苗相比, 仿生纳米粒本身既具有一定的免疫刺激性, 又具有较高的安全性^{[9, 87]}。上述所提到的细胞膜包被纳米粒、纳米化蛋白质等仿生纳米疫苗技术已经在各体外实验和动物模型中被证实具有较好抑制肿瘤生长的效果^{[80, 88]}。如Cheng等^[89]构建了一种由DCs膜涂层负载IL-2的PLGA纳米疫苗, 对卵巢癌模型鼠接种后观察到其效应T细胞和血清中的IFN-γ和IFN-α含量有了明显提高; 此外, 以RBC膜^[90]、WBC膜^[91]、NK膜^[92]、细菌外膜囊泡^{[93, 94]}、巨噬细胞膜^[95]和癌细胞膜^{[96, 97]}包被的纳米粒运载体也在多项研究中证实了其效力。上文中提到的自组装蛋白质纳米化物(铁蛋白、病毒非感染性蛋白颗粒等)^{[98, 99]}、纳米阳离子脂质体^{[100, 101]}和外泌体^[102-104]等同样在递送抗原方面潜力巨大。

此外, 利用纳米仿生平台装载自体全肿瘤细胞裂解物(tumor lysate supernatants, TCL) 可较好地达到多价疫苗的目标, 相较于临床结果不佳的传统TCL疗法, 显示出更可靠的安全性和更有效的免疫效力^{[105, 106]}。

3.3 联合疗法

联合治疗是目前癌症治疗的重要手段之一。虽然仿生纳米肿瘤疫苗单独的临床应用仍然存在一些困难, 但在联合其他疗法对癌症进行多靶点个性化治疗方面显示出巨大的潜力, 远优于单药治疗效果, 在一定程度上提高了联合治疗方法的临床转化率^{[107, 108]}。

其他疗法与仿生纳米疫苗联用的机制主要分为两种(图 5): 一方面, 疫苗和其他疗法可互相补充其缺点(如化疗存在的耐药性), 根据原有机制分别对肿瘤细胞进行杀伤; 另一方面, 即采用免疫原性细胞死亡(induced cell death, ICD) 治疗模式: 利用化疗、放疗等手段诱导肿瘤细胞凋亡或杀死细胞, 释放各种DAMPs, 从而改善肿瘤微环境, 提高机体对某些肿瘤细胞抗原(如出现T细胞浸润不良或PD-L1表达较少的冷肿瘤) 的免疫敏感性, 便于加强后续疫苗和检查点阻断等方法的工作效力^[109-111]。

3.3.1 与化疗联用

化疗药物与仿生纳米疫苗的联用方法主要有以下两种构建模型: 基于相同纳米递送平台的多内容物(抗原及化疗药物) 系统, 也称靶向双纳米药物系统; 或不同递送平台(纳米递送系统和普通系统联用或双纳米递送系统) 的单内容物。大部分研究集中在共同递送系统和纳米-普通系统联用中。表 2^[102-113]列出了一些具有免疫调节作用的化疗药物。

在靶向双纳米模型的研究上, Byeon等^[114]开发了一种透明质酸标记的纳米粒HA-PLGA-NP, 封装化疗药物紫杉醇(paclitaxel, PTX) 和作为核酸疫苗的黏着斑激酶(FAK) siRNA, 用以对抗耐药的卵巢癌, 在卵巢癌PDX模型中表现出显著的抑制肿瘤生长能力; 在仿生纳米疫苗与普通化疗制剂联用的研究上, Lu等^[115]发现姜黄素-聚乙二醇胶束(CUR-PEG) 与仿生纳米疫苗Trp2在晚期黑色素瘤动物模型上有协同抗癌活性, 疗效好于单药分开使用的对照组。

基于ICD的化疗免疫联合疗法具有良好的利用潜力, 并且仿生纳米递送平台可克服传统递送系统存在的一系列缺点, 包括保留有限、肿瘤细胞摄取受限和循环时间不足等^[95], 因而显示出更好的应用活力。为避免ICD治疗模式中免疫细胞被化疗药物杀死的可能, Bao等^[116]将化疗和免疫疗法以一定的先后顺序结合, 将多柔比星(doxorubicin, DOX) 作为前药激活免疫系统, 同时通过降低天然调节性Treg标志物Foxp3的表达水平以抑制Tregs, 调节免疫抑制微环境(tumor immune microenvironment, TIME)。作者指出, 这种策略可上调淋巴结中DCs和CTL活性, 增加相关细胞因子分泌。这种疗法与单独给药相比, 提高了黑色素瘤模型鼠对仿生纳米疫苗RBC-NPs的敏感度, 表现出强大的治疗和防复发效果, 具有良好的临床转化意义^[116]。

3.3.2 与放疗联用

电离放射疗法(radiation therapy, RT) 也可通过ICD途径, 将死亡肿瘤细胞转化为良好的呈递抗原^[117], 同时辐射促进靶向纳米仿生疫苗引发的T细胞更好地进入肿瘤^[118]。此外, 辐射可以增强死亡的肿瘤细胞释放DNA, 从而激活STING通路的刺激物, 诱导DCs产生Ⅰ型干扰素, 最终导致抗肿瘤T细胞的启动^[119-121]。若患者体内很少或不存在CD8⁺ T细胞, 即使是靶向性良好的仿生纳米疫苗, 接种也将难以获得有效响应, 而放疗正是为疫苗接种消除了T细胞浸润不足的问题^[122]; 并且高靶向的仿生纳米粒—如PLGA核壳纳米载体^[123], 可以在一定程度上提高放疗的疗效。因此, 虽然放疗与仿生纳米疫苗联用可能存在一些技术上的不足, 但仍有一定的联合应用价值。

3.3.3 与其他免疫疗法联用: 以检查点阻断法为例

以抗细胞毒性T淋巴细胞相关蛋白4 (cytotoxic T-lymphocyte-associated protein 4, CTLA-4) 和抗PD-1为首的免疫检查点阻断法(immuno-checkpoint blockade, ICB) 是近些年较为热门有效的癌症免疫疗法之一, 可在某些癌症患者体内引发持久显著的免疫反应^[124]。纳米仿生肿瘤疫苗可以与检查点阻断法联合使用, 加强了免疫反应响应。PD-1阻断主要通过诱导肿瘤浸润CD8⁺ T细胞耗竭的扩张来驱动抗肿瘤反应。在此基础上, 癌细胞膜包被的黑色素瘤纳米仿生疫苗αHSP70p-CM-CaP^[27]、NP-R@MM^[9]等都在与PD-1阻断法联用研究中表现出了强大的控制肿瘤效力。CTLA-4阻断法的原理则是在PD-1阻断法的基础上, 进一步诱导了CD4⁺效应区的扩张, 而仿生纳米疫苗B16.OVA^[125]、多表位sHDL纳米圆盘疫苗^[126]及载有MUC1 mRNA的LCP^[127]可与抗CTLA-4法进行协同, 分别提高了对侵袭性黑色素瘤和三阴性乳腺癌的治疗效果。总体而言, 这种双免疫治疗策略虽然能在一定程度抑制癌症复发, 但对于严重转移性患者效力不足, 因此仍具有较大的发展空间, 需要在实际情况下进行权衡^[128]。

3.3.4 与光热疗法联用

肿瘤的光热疗法(photothermal therapy, PTT) 是指在近红外激光照射下, 利用光热剂(photothermal agents, PTA) 的光热效应, 破坏浅表肿瘤细胞膜和细胞骨架同时抑制其DNA合成, 来达到杀死肿瘤细胞的治疗方法^{[129, 130]}。

光热疗法与仿生纳米肿瘤疫苗联用时(图 6), 一方面, 光热疗法提高了疫苗产生的免疫反应: 如Zhou等^[131]利用牛血清蛋白(bovine serum albumin, BSA) 和仿生金纳米棒(gold nanorods, GNRs) 构建mPEG-GNRs@BSA/R837疫苗, 联合PTT疗法后, 对肿瘤模型小鼠具有明显抑制肿瘤生长和复发的优势; 另一方面, 疫苗改善了光热反应只能杀伤浅表肿瘤的缺陷, 且由于仿生纳米材料的高靶向性, 提高了治疗精准度: 如Li等^[132]开发的一种基于荧光团脂质体的疫苗IR-7-lipo/HA-CpG, 改善了光热疗法的区域局限性, 有效根除了小鼠肿瘤。因此, 光热协同疫苗免疫治疗有着互补的协同优势, 在癌症治疗方面具有较大的意义。

4 总结与展望

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面向肿瘤的纳米仿生型疫苗具有较高的临床转化意义, 但是处于体外细胞实验、动物实验等实验室阶段的研究多, 已进入临床试验的少, 所以在人体中的安全性和有效性仍需验证。同时, 此类纳米粒的工业化生产也是一个挑战, 需要在确保安全质量的同时, 保证有效的产量。最后, 协同疗法的临床效果仍需进一步评估。总的来说, 纳米仿生型肿瘤疫苗在癌症治疗方面有着光明的未来。

作为肿瘤免疫疗法中的一种, 肿瘤疫苗同样面对着无法消除肿瘤免疫抑制的困难^{[133, 134]}。并且, 肿瘤疫苗搭载的抗原免疫原性不足, 难以激活机体免疫系统, 甚至激活Treg或MDSCs而加强免疫抑制^[135-137]。

纳米肿瘤疫苗作为一种新型“杂交”型疫苗, 可高效被树突状细胞摄取, 从而实现肿瘤抗原和佐剂的高效递释, 诱发强免疫反应。目前, 大多数研究均在多种小鼠肿瘤模型中得到了效果验证, 有效抑制肿瘤复发, 并产生持久的保护力, 延长了小鼠生存期。此外, 纳米肿瘤疫苗可在多种实体瘤中都有应用潜力, 具有广阔的临床应用前景。所以, 选择合适的肿瘤抗原或表位、减少肿瘤抑制、诱导抗原的交叉呈递, 是肿瘤疫苗发展中巨大的挑战。为了进一步的临床转化, 未来还需进一步研究纳米材料电荷、粒径、组成、电荷和抗原负载能力等对其性能的影响, 还要进一步研究纳米佐剂与机体细胞和器官之间的相互作用, 靶向设计纳米粒, 开发高效、安全的纳米仿生型肿瘤疫苗^[138]。纳米技术与肿瘤疫苗相融合是当前的热点问题, 能增强肿瘤疫苗的效果, 增加靶向性, 减少不良反应。但是在进入临床之前, 如何根据需求选择合适、安全的纳米载体及如何实现从实验动物到临床应用的转化等一系列问题还需要进一步研究。

作者贡献: 杨玥、王海燕和孙野分别独立完成了本综述不同章节; 孙涛和蒋晨对本综述进行了指导。

利益冲突: 本文作者声明无利益冲突。

基金

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国家自然科学基金资助项目(92059110)
国家自然科学基金资助项目(81872808)
复旦大学2025卓学计划(to T.S.)
上海学科带头人计划(2018SHZDZX01)
中国科学院上海药物研究所融合基金项目(FU-SIMM-20182006)

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2022年第57卷第4期

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doi: 10.16438/j.0513-4870.2021-1069

接收时间：2021-07-19
首发时间：2025-12-22
出版时间：2022-04-12

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收稿日期：2021-07-19
修回日期：2021-08-06

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国家自然科学基金资助项目(92059110)

国家自然科学基金资助项目(81872808)

复旦大学2025卓学计划(to T.S.)

上海学科带头人计划(2018SHZDZX01)

中国科学院上海药物研究所融合基金项目(FU-SIMM-20182006)

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复旦大学药学院, 智能化递药教育部重点实验室/复旦大学附属闵行中心医院, 医学神经生物学国家重点实验室, 上海 201203

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*孙涛, Tel: 86-21-51980187, E-mail: sunt@fudan.edu.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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TxT

Cell membrane source	Main characteristics
Red blood cell	Immune escape; long cycle
White blood cell
Macrophage	Targeted chemotaxis of inflammation
Cytotoxic T lymphocyte	Secretion of cytokines, high expression of adhesion molecules
Natural killer cell	Promote the maturation of antigen presenting cells and activate T cells
Dendritic cell	Antigen presentation, specific activation of T cells
Blood platelet	Through P-selectin interaction with CD44 receptor on circulating tumor cell; all 9 Toll-like receptors were expressed
Tumor cell	Homologous targeting
Bacteria	Strong immunogenicity

Cell membrane source

Main characteristics

Red blood cell

Immune escape; long cycle

White blood cell

Macrophage

Targeted chemotaxis of inflammation

Cytotoxic T lymphocyte

Secretion of cytokines, high expression of adhesion molecules

Natural killer cell

Promote the maturation of antigen presenting cells and activate T cells

Dendritic cell

Antigen presentation, specific activation of T cells

Blood platelet

Through P-selectin interaction with CD44 receptor on circulating tumor cell; all 9 Toll-like receptors were expressed

Tumor cell

Homologous targeting

Bacteria

Strong immunogenicity

Chemotherapeutic agent	Mechanism of action	Ref.
Carboplatin	Induce DNA damage and activate STING/TBK1/IRF3 pathway	[102]
Methotrexate	Increase adenosine content, thereby inhibiting neutrophil function and reducing the occurrence of inflammatory mediators; enhance antigen presentation function of dendritic cells (DCs)	[103, 104]
5-Fluorouracil	Significantly reduced MDSC in spleen and tumor	[105]
Doxorubicin	Promote the maturation of DCs; increased cytotoxic T cell infiltration; promotes recruitment of natural killer (NK) cells	[106, 107]
Cyclophosphamide	Activate recruitment of NK cells, macrophages and DCs; the number of Tregs was selectively inhibited; induction of pathogenic Th17 cell differentiation by altering intestinal flora	[108, 109]
Oxaliplatin	Promoting the production of IFN-γ and IL-2 by T cells; promote the maturation of marrow derived DCs and the expansion of CD8⁺ T cells	[110, 111]
Paclitaxel (PTX)	Selective reduction of Treg, promotion of CRT transduction, promotion of IFN-γ expression	[112, 113]

Chemotherapeutic agent

Mechanism of action

Ref.

Carboplatin

Induce DNA damage and activate STING/TBK1/IRF3 pathway

[102]

Methotrexate

Increase adenosine content, thereby inhibiting neutrophil function and reducing the occurrence of inflammatory mediators; enhance antigen presentation function of dendritic cells (DCs)

[103, 104]

5-Fluorouracil

Significantly reduced MDSC in spleen and tumor

[105]

Doxorubicin

Promote the maturation of DCs; increased cytotoxic T cell infiltration; promotes recruitment of natural killer (NK) cells

[106, 107]

Cyclophosphamide

Activate recruitment of NK cells, macrophages and DCs; the number of Tregs was selectively inhibited; induction of pathogenic Th17 cell differentiation by altering intestinal flora

[108, 109]

Oxaliplatin

Promoting the production of IFN-γ and IL-2 by T cells; promote the maturation of marrow derived DCs and the expansion of CD8⁺ T cells

[110, 111]

Paclitaxel (PTX)

Selective reduction of Treg, promotion of CRT transduction, promotion of IFN-γ expression

[112, 113]