药学学报

Strategy	Nanocarrier	Active drug	Result	Reference
Hyperbaric oxygen	-	O₂ and a-PD-1	Resume the extracellular matrix's components, promote a-PD-1 delivery and T cells infiltration	[16]
Blood substitute	Liposomes	Hemoglobin and doxorubicin	Reverse hypoxia-induced chemoresistance, promote cytotoxicity of doxorubicin	[17]
	Perfluorocarbon nanoemulsions	O₂ and porphyrin	Simultaneously deliver oxygen and photosensitizer, enhance the efficacy of photodynamic therapy	[20]
	Epidermal growth factor functionalized PLGA nanoparticles	O₂ and 5-fluorouracil	Relieve tumor hypoxia, enhance the efficacy of 5-fluorouracil	[21]
Supply O₂ in situ	CAT@Pt (Ⅳ)-liposome	CAT and Pt (Ⅳ)	Relieve tumor hypoxia, improve the efficacy of CAT@Pt (Ⅳ)-liposome	[24]
	CAT-THPP-PEG	CAT and THPP	Relieve tumor hypoxia, enhance the efficacy of photodynamic therapy	[25]
	PLGA-MnO₂ nanoparticles	MnO₂	Reduce hypoxia and decrease the expression of hypoxia-induced factor 1α	[26]
Vasculature normalization	-	Erlotinib	Increase accumulation and penetration of drugs, alter the immunosuppressive TME into immunosupportive	[27]
Depletation CAFs	αFAP-Z@FRT	ZnF₁₆Pc	Eliminate CAFs, improve antitumor efficacy	[33]
	FH-SSL-Nav	Nav	Eradicate CAFs, improve tumor growth inhibition	[34]
Inactivate CAFs	Nanoemulsions	Fraxinellone	Reduce the amount of CAFs and extracellular matrix deposition, enhance the anti-tumor immune response	[38]
	Gold nanoparticles	Gold	Reduce activation of pancreatic stellate cell and matrix deposition, enhance angiogenesis, inhibit tumor growth	[39]
	Liposomes	S-Nitroso-N-acetylpenicillamine	Inhibit the expression of TGF-β and the production of dense stroma, improve the tumor penetration ability of liposomes	[40]
	Cell penetrating peptide modified nanoparticles	siCXCL12	Inactive CAFs by down-regulating the expression of CXCL12, reshape the TME	[49]
Targeting extracellular matrix	-	Type I collagenase	Decrease interstitial fluid pressure, improve the accumulation of drugs	[51]
	Gold nanoparticles	Collagenase	Improve the delivery efficiency of drugs in tumor	[52]
	DEX-HAase nanoparticles	HAase	Loose the structure of extracellular matrix, enhance the penetration of oxygen and liposomes	[53]
	Liposomes	4-Methylumbelliferone	Reduce tumor extracellular matrix and improve the distribution of liposomes	[54]
	Gold nanorods	Gold	Increase the diffusion rate of inorganic nanoparticles	[55]
Reshaping TAMs	β-Cyclodextrin nanoparticles	R848	Alter the immune microenvironment towards an M1 phenotype, improve a-PD-1 immunotherapy response rates	[57]
	Mannose-modified PEGylated PLGA nanoparticles	Indocyanine green, titanium dioxide and ammonium bicarbonate	Reprogram TAMs, promote the recruitment of CTLs and enhance the anti-tumor response of memory T cell	[58]
Targeting DCs	LCP NPs	BRAF^V600E peptide	Drive DCs maturation for antigen presentation, produce IFN-γ	[59]
	Fe₃O₄-OVA nanocomposites	Fe₃O₄ NPs and OVA	Stimulate DCs maturation, activate T cells	[60]
	AC-NPs	TDPAs	Expand CD8⁺ cytotoxic T cells, increase both CD4⁺ T/Treg and CD8⁺ T/Treg ratios	[61]

Strategy	Nanocarrier	Active drug	Result	Reference
Hyperbaric oxygen	-	O₂ and a-PD-1	Resume the extracellular matrix's components, promote a-PD-1 delivery and T cells infiltration	[16]
Blood substitute	Liposomes	Hemoglobin and doxorubicin	Reverse hypoxia-induced chemoresistance, promote cytotoxicity of doxorubicin	[17]
	Perfluorocarbon nanoemulsions	O₂ and porphyrin	Simultaneously deliver oxygen and photosensitizer, enhance the efficacy of photodynamic therapy	[20]
	Epidermal growth factor functionalized PLGA nanoparticles	O₂ and 5-fluorouracil	Relieve tumor hypoxia, enhance the efficacy of 5-fluorouracil	[21]
Supply O₂ in situ	CAT@Pt (Ⅳ)-liposome	CAT and Pt (Ⅳ)	Relieve tumor hypoxia, improve the efficacy of CAT@Pt (Ⅳ)-liposome	[24]
	CAT-THPP-PEG	CAT and THPP	Relieve tumor hypoxia, enhance the efficacy of photodynamic therapy	[25]
	PLGA-MnO₂ nanoparticles	MnO₂	Reduce hypoxia and decrease the expression of hypoxia-induced factor 1α	[26]
Vasculature normalization	-	Erlotinib	Increase accumulation and penetration of drugs, alter the immunosuppressive TME into immunosupportive	[27]
Depletation CAFs	αFAP-Z@FRT	ZnF₁₆Pc	Eliminate CAFs, improve antitumor efficacy	[33]
	FH-SSL-Nav	Nav	Eradicate CAFs, improve tumor growth inhibition	[34]
Inactivate CAFs	Nanoemulsions	Fraxinellone	Reduce the amount of CAFs and extracellular matrix deposition, enhance the anti-tumor immune response	[38]
	Gold nanoparticles	Gold	Reduce activation of pancreatic stellate cell and matrix deposition, enhance angiogenesis, inhibit tumor growth	[39]
	Liposomes	S-Nitroso-N-acetylpenicillamine	Inhibit the expression of TGF-β and the production of dense stroma, improve the tumor penetration ability of liposomes	[40]
	Cell penetrating peptide modified nanoparticles	siCXCL12	Inactive CAFs by down-regulating the expression of CXCL12, reshape the TME	[49]
Targeting extracellular matrix	-	Type I collagenase	Decrease interstitial fluid pressure, improve the accumulation of drugs	[51]
	Gold nanoparticles	Collagenase	Improve the delivery efficiency of drugs in tumor	[52]
	DEX-HAase nanoparticles	HAase	Loose the structure of extracellular matrix, enhance the penetration of oxygen and liposomes	[53]
	Liposomes	4-Methylumbelliferone	Reduce tumor extracellular matrix and improve the distribution of liposomes	[54]
	Gold nanorods	Gold	Increase the diffusion rate of inorganic nanoparticles	[55]
Reshaping TAMs	β-Cyclodextrin nanoparticles	R848	Alter the immune microenvironment towards an M1 phenotype, improve a-PD-1 immunotherapy response rates	[57]
	Mannose-modified PEGylated PLGA nanoparticles	Indocyanine green, titanium dioxide and ammonium bicarbonate	Reprogram TAMs, promote the recruitment of CTLs and enhance the anti-tumor response of memory T cell	[58]
Targeting DCs	LCP NPs	BRAF^V600E peptide	Drive DCs maturation for antigen presentation, produce IFN-γ	[59]
	Fe₃O₄-OVA nanocomposites	Fe₃O₄ NPs and OVA	Stimulate DCs maturation, activate T cells	[60]
	AC-NPs	TDPAs	Expand CD8⁺ cytotoxic T cells, increase both CD4⁺ T/Treg and CD8⁺ T/Treg ratios	[61]

Strategy	Clinical trial identifier	Study drug	Phase	Cancer type
Hypoxia-activated prodrug	NCT01144455	Gemcitabine, TH-302	Phase Ⅱ	Locally advanced or metastatic pancreatic cancer
NCT01037556	PR104	Phase Ⅰ/II	Refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia
Targeting VEGF/VEGFR therapeutic agent	NCT00945139 and NCT00846612	Bevacizumab, liposomal doxorubicin	Phase Ⅱ	Platinum- and taxane-resistant ovarian cancer
NCT03048877	Bevacizumab	Phase Ⅲ	Thyroid cancer
NCT03278717	Olaparib, cediranib	Phase Ⅲ	Ovarian cancer
EudraCT (2008-001090-15)	Sorafenib, docetaxel	Phase Ⅱ	Metastatic breast cancer
NCT02898077	Ramucirumab, paclitaxel	Phase Ⅲ	Gastric adenocarcinoma
NCT03172299	Aflibercept	Phase Ⅲ	Ocular melanoma
NCT01206764	Everolimus	Phase Ⅳ	Renal cell carcinoma
Targeting CAF mediated immunosuppression	NCT03277209	Plerixafor	Phase Ⅰ	Pancreatic cancer
NCT02826486	BL-8040, pembrolizumab	Phase Ⅱ	Pancreatic cancer
-	S-3304	Phase Ⅰ	Advanced and refractory solid tumors
-	Bevacizumab	Phase Ⅲ	Pleural mesothelioma
-	Ruxolitinib, capecitabine	Phase Ⅱ	Metastatic pancreatic cancer
Targeting stromal depletion	NCT02715804	PEGPH20, gemcitabine, nab-paclitaxel	Phase Ⅲ	Pancreatic cancer
NCT02910882	PEGPH20, gemcitabine, radiation	Phase Ⅱ	Pancreatic cancer
NCT03481920	PEGPH20, avelumab	Phase Ⅰ	Pancreatic cancer
Targeting TAM mediated immunosuppression	NCT01804530	PXL7486	Phase Ⅰ	Advanced solid tumors
NCT02829723	BLZ945	Phase Ⅰ/II	Advanced solid tumors
NCT02880371	ARRY-382	Phase Ⅱ	Advanced solid tumors
NCT02890368	TTI-621	Phase Ⅰ	Relapsed and refractory solid tumors
NCT03013218	ALX148	Phase Ⅰ	Metastatic cancer, solid tumor, advanced cancer, or non-Hodgkin's lymphoma
NCT00319748	852A	Phase Ⅱ	Breast, ovarian, endometrial and cervical cancers
NCT02781805	Alendronate	Phase Ⅰ	Breast neoplasms
Natural DC vaccination	NCT02993315 and NCT02574377	gp100, tyrosinase, NY-ESO-1, MAGE-C2, MAGE-A3	Phase Ⅲ, Phase Ⅰ/II	Melanoma stage IIIB-C, melanoma stage III
NCT01690377	Gp100, tyrosinase	Phase Ⅰ	Melanoma stage IV

Strategy	Clinical trial identifier	Study drug	Phase	Cancer type
Hypoxia-activated prodrug	NCT01144455	Gemcitabine, TH-302	Phase Ⅱ	Locally advanced or metastatic pancreatic cancer
NCT01037556	PR104	Phase Ⅰ/II	Refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia
Targeting VEGF/VEGFR therapeutic agent	NCT00945139 and NCT00846612	Bevacizumab, liposomal doxorubicin	Phase Ⅱ	Platinum- and taxane-resistant ovarian cancer
NCT03048877	Bevacizumab	Phase Ⅲ	Thyroid cancer
NCT03278717	Olaparib, cediranib	Phase Ⅲ	Ovarian cancer
EudraCT (2008-001090-15)	Sorafenib, docetaxel	Phase Ⅱ	Metastatic breast cancer
NCT02898077	Ramucirumab, paclitaxel	Phase Ⅲ	Gastric adenocarcinoma
NCT03172299	Aflibercept	Phase Ⅲ	Ocular melanoma
NCT01206764	Everolimus	Phase Ⅳ	Renal cell carcinoma
Targeting CAF mediated immunosuppression	NCT03277209	Plerixafor	Phase Ⅰ	Pancreatic cancer
NCT02826486	BL-8040, pembrolizumab	Phase Ⅱ	Pancreatic cancer
-	S-3304	Phase Ⅰ	Advanced and refractory solid tumors
-	Bevacizumab	Phase Ⅲ	Pleural mesothelioma
-	Ruxolitinib, capecitabine	Phase Ⅱ	Metastatic pancreatic cancer
Targeting stromal depletion	NCT02715804	PEGPH20, gemcitabine, nab-paclitaxel	Phase Ⅲ	Pancreatic cancer
NCT02910882	PEGPH20, gemcitabine, radiation	Phase Ⅱ	Pancreatic cancer
NCT03481920	PEGPH20, avelumab	Phase Ⅰ	Pancreatic cancer
Targeting TAM mediated immunosuppression	NCT01804530	PXL7486	Phase Ⅰ	Advanced solid tumors
NCT02829723	BLZ945	Phase Ⅰ/II	Advanced solid tumors
NCT02880371	ARRY-382	Phase Ⅱ	Advanced solid tumors
NCT02890368	TTI-621	Phase Ⅰ	Relapsed and refractory solid tumors
NCT03013218	ALX148	Phase Ⅰ	Metastatic cancer, solid tumor, advanced cancer, or non-Hodgkin's lymphoma
NCT00319748	852A	Phase Ⅱ	Breast, ovarian, endometrial and cervical cancers
NCT02781805	Alendronate	Phase Ⅰ	Breast neoplasms
Natural DC vaccination	NCT02993315 and NCT02574377	gp100, tyrosinase, NY-ESO-1, MAGE-C2, MAGE-A3	Phase Ⅲ, Phase Ⅰ/II	Melanoma stage IIIB-C, melanoma stage III
NCT01690377	Gp100, tyrosinase	Phase Ⅰ	Melanoma stage IV

肿瘤微环境的靶向和重塑策略

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杨蒙蒙 ¹^,² , 韩晓鹏 ¹^,² , 秦超 ¹^,² , 杨磊 ¹^,² , 尹莉芳 ¹^,²^,^*

药学学报 | 综述 2022,57(1): 98-108

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药学学报 | 综述 2022, 57(1): 98-108

肿瘤微环境的靶向和重塑策略

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杨蒙蒙¹^,², 韩晓鹏¹^,², 秦超¹^,², 杨磊¹^,², 尹莉芳¹^,²^,^*

作者信息

1.中国药科大学药学院, 江苏南京 210009

2.江苏省缓释智能制剂及关键功能性辅料开发与评价工程研究中心, 江苏南京 210009

通讯作者:

*尹莉芳, Tel / Fax: 86-25-83271018, E-mail: lifangyin_@163.com

Strategies for targeting and remodeling tumor microenvironment

Meng-meng YANG¹^,², Xiao-peng HAN¹^,², Chao QIN¹^,², Lei YANG¹^,², Li-fang YIN¹^,²^,^*

Affiliations

1. School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China

2. Jiangsu Province Engineering Research Center for R & D and Evaluation of Intelligent Drugs and Key Functional Excipients, Nanjing 210009, China

出版时间: 2022-01-12 doi: 10.16438/j.0513-4870.2021-1232

文章导航

摘要

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肿瘤微环境(tumor microenvironment, TME) 由异常的肿瘤血管、细胞外基质组分、内皮细胞、周细胞、肿瘤相关成纤维细胞、平滑肌细胞和免疫细胞组成。TME在肿瘤的发生、生长和转移中起着至关重要的作用。TME中异常的肿瘤血管系统、细胞外基质组分及丰富的间质细胞等, 影响了药物在肿瘤组织的分布和渗透, 其免疫抑制状态也是导致包括免疫治疗在内的多种抗肿瘤失败的重要原因之一。近年来, 许多研究致力于通过靶向和重塑TME以提高治疗效果。本文综述了基于乏氧状态、肿瘤血管系统、肿瘤相关成纤维细胞、细胞外基质组分、肿瘤相关巨噬细胞和树突细胞的靶向和重塑策略最新研究进展, 并对其中存在的问题及未来的发展进行讨论。

关键词

肿瘤微环境 / 乏氧 / 肿瘤相关成纤维细胞 / 细胞外基质 / 肿瘤相关巨噬细胞

Abstract

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Tumor microenvironment (TME) is composed of abnormal tumor vasculature, extracellular matrix components, endothelial cells, pericytes, tumor associated fibroblasts, smooth muscle cells and immune cells, which is characterized by hypoxia, acidosis and high interstitial fluid pressure. Hypoxia and acidosis within the TME trigger an adjustment of the extracellular matrix (ECM), a response from neighbor stromal cells (e.g., fibroblasts) and immune cells (lymphocytes and macrophages), inducing tumor growth, angiogenesis, and ultimately, resulting in metastasis. What's more, the components of TME including abnormal tumor vasculature, rich composition of the ECM, and abundant stroma cells impair tumoral distribution and penetration of the drugs. At the same time, this stromal microenvironment plays a vital role in creating an immunosuppressive environment.Over the past years, more and more researches focus on targeting and remolding TME to improve therapeutic effects against tumors. Herein, we reviewed current strategies developed to target and remodel TME, including modulating tumor hypoxia, tumor vasculature, tumor associated fibroblasts, extracellular matrix components, tumor associated macrophage phenotypes and dendritic cells. Also, potential problems and future directions are pointed out in this review.

Key words

tumor microenvironment / hypoxia / tumor associated fibroblast / extracellular matrix / tumor associated macrophage

引用本文

杨蒙蒙, 韩晓鹏, 秦超, 杨磊, 尹莉芳. 肿瘤微环境的靶向和重塑策略. 药学学报, 2022 , 57 (1) : 98 -108 . DOI: 10.16438/j.0513-4870.2021-1232

Meng-meng YANG, Xiao-peng HAN, Chao QIN, Lei YANG, Li-fang YIN. Strategies for targeting and remodeling tumor microenvironment[J]. Acta Pharmaceutica Sinica, 2022 , 57 (1) : 98 -108 . DOI: 10.16438/j.0513-4870.2021-1232

正文

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恶性肿瘤仍然是威胁人类生命的最可怕的杀手之一, 因此迫切需要有效的治疗策略。早期大量的研究集中在肿瘤细胞和宿主细胞的研究上, 然而随着对肿瘤进展的不断了解, 肿瘤微环境(tumor microenvironment, TME) 已被证明在肿瘤进展、侵袭和转移过程中发挥关键作用^[1]。TME是指肿瘤细胞与浸润的免疫细胞、基质细胞、血管、细胞外基质和分泌因子等共同构成的在肿瘤发生发展过程中形成的一种特殊生物环境。TME中不成熟的脉管系统、高间质液体压力, 以及丰富的细胞外基质和肿瘤相关基质细胞等为肿瘤细胞构筑了高密度基质屏障, 而且肿瘤内部渗透压梯度丧失, 这些均能影响药物运输和渗透到肿瘤部位^[2]。从免疫上, TME主要由促瘤成分如肿瘤相关成纤维细胞(cancer associated fibroblasts, CAFs)、肿瘤血管、M2型肿瘤相关巨噬细胞(tumor associated macrophages, TAMs)、辅助性T细胞-2 (T helper-2, Th2) 细胞因子等和抑瘤成分如T细胞、自然杀伤(natural killer, NK) 细胞、M1型TAMs、Th1细胞因子等组成, 当促瘤成分在数量及功能上呈压倒性优势时, TME即呈现出严重的免疫抑制状态, 这也是导致包括免疫治疗在内的多种抗肿瘤失败的重要原因之一。

本综述拟阐述靶向和重塑肿瘤微环境的最新策略, 为肿瘤治疗提供新的思路。在这些策略中, 改善肿瘤乏氧、靶向肿瘤血管、靶向肿瘤相关成纤维细胞、靶向细胞外基质组分、靶向肿瘤相关巨噬细胞和靶向树突细胞通过减弱基质屏障或者改善免疫抑制微环境增强药物及内源性抗肿瘤免疫细胞的浸润, 增强抗肿瘤治疗效果。

1 肿瘤微环境

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TME不仅包括肿瘤细胞本身, 还有其周围的成纤维细胞、免疫细胞和胶质细胞, 同时也包括肿瘤细胞间质、微血管及其他物理因素(如pH值、氧气、间质液体压力等)^{[3, 4]}。这种复杂的TME为肿瘤早期发生、发展、侵袭和转移等过程提供了必要的物质基础。

1.1 物理因素

乏氧是TME典型生理特征, 促进肿瘤的侵袭和转移, 影响肿瘤细胞的基因表达、谱重排和表型重塑。50%~60%的实体肿瘤显示氧气水平下降(乏氧)^[3], 肿瘤的生长需要大量的能量, 但异常的肿瘤血管输送的氧气不足。乏氧不仅会影响远离血管的细胞, 还会影响转移过程不同阶段的多个基因表达谱^[5]。此外, 肿瘤内乏氧与肿瘤的侵袭性和转移性表型以及对传统放化疗的耐药性有关。因此改善乏氧环境可抑制肿瘤治疗耐药性的发生。

由于肿瘤细胞糖酵解率高, 在肿瘤进展过程中产生大量酸性物质, 弱酸性成为TME的另一个显著特征。此外, 乏氧环境会加剧这种弱酸性。与正常组织pH值7.4相比, 肿瘤组织pH值在6.5~7.2之间^[6], 而在亚细胞水平, 如晚期核内体和溶酶体, pH值在4.5~5.5之间^{[7, 8]}。

肿瘤血管的结构及功能异常导致局部血液渗漏, 进而使间质压(interstitial fluid pressure, IFP) 升高, IFP在肿瘤组织升高至(5~40) mmHg, 在某些病例中甚至升高到(75~130) mmHg, 而在正常组织中仅为(0~3) mmHg^[9]。高IFP使得肿瘤组织血流灌注进一步受到阻碍, 氧、营养物质及代谢产物的递送受到抑制, 加剧形成肿瘤细胞低氧、低pH和高IFP的肿瘤微环境。

1.2 肿瘤相关成纤维细胞

CAFs是一类重要的基质细胞, 在应激、炎症、癌细胞等刺激下CAFs发生表型转化(亦称为激活), 成为一种肌成纤维样细胞, 以表达α-平滑肌肌动蛋白、成纤维细胞活化蛋白(fibroblast activation protein, FAP) 为标志^[10]。CAFs与胶原、纤维和透明质酸等其他细胞外基质成分形成了肿瘤重要屏障, 限制药物及免疫细胞瘤内浸润。

此外, CAFs通过分泌转化生长因子-β (transforming growth factor beta, TGF-β) 等细胞因子, 在很大程度上调节TME至Th2表型(Th1/Th2平衡漂移中, Th2细胞占优势状态), 极大地抑制了效应T细胞的杀伤肿瘤能力, 促进了肿瘤的生长。CAFs可通过上调趋化因子CCL22和CCL28的表达招募骨髓来源免疫抑制细胞(myeloid-derived suppressor cells, MDSCs) 和调节性T细胞(regulatory T lymphocytes, Tregs), 进一步增强免疫抑制TME。当这些细胞进入TME, CAFs分泌的TGF-β等细胞因子能够促进Tregs的扩增。而抑制性免疫细胞也可调节CAFs, 从而加剧TME结缔组织形成。例如, M2巨噬细胞分泌C-X-C趋化因子配体12 (CXCL12), 使成纤维细胞更容易激活和分化^[11]。

CAFs还通过表达程序性死亡配体-1 (programmed death-ligand 1, PD-L1) 和PD-L2直接作用于T淋巴细胞, 诱导T细胞衰竭并且产生免疫耐受。CAFs抑制细胞毒性T淋巴细胞(cytotoxic T lymphocyte, CTL) 的活性, 导致免疫抑制细胞的聚集。综上所述, 肿瘤中活化的CAFs与肿瘤细胞间联系密切, 因此精准靶向肿瘤组织中活化的CAFs, 是提高肿瘤治疗效果的重要方向之一。

1.3 细胞外基质

细胞外基质(extracellular matrix, ECM) 包括胶原蛋白、纤连蛋白、整合素、弹性蛋白、微纤丝蛋白、蛋白多糖等细胞分泌的蛋白质, 在结构上和生物化学上支持邻近细胞^[12]。ECM位于基底膜和间质间隙的基质中, 为肿瘤细胞的增殖、分化和转移提供了天然屏障。对于抗肿瘤治疗而言, ECM的存在显著限制了抗肿瘤药物在肿瘤组织的浸润^[11]。

在ECM的组成成分中, 胶原蛋白是一个由至少28个成员组成的多样化的蛋白家族^[13]。完整的胶原蛋白及其分解代谢蛋白(被基质金属蛋白酶和其他蛋白酶分解) 在肿瘤的发生发展中发挥着重要作用。除了结构支持, 胶原蛋白还调节TGF-β/Smad、PI3K/Akt、MAPK、Wnt和NF-κB等信号通路。因此, 胶原蛋白可以作为肿瘤干预的潜在靶点。

1.4 免疫细胞

TME中有多种免疫细胞浸润, 其中CTL发挥肿瘤杀伤功能, 而Tregs减弱效应T细胞活性, 促进TME的免疫抑制。通常M1型巨噬细胞分泌Th1细胞因子, 发挥促炎和抗瘤作用, 但TME中的TAMs为M2型, 通过分泌Th2细胞因子促进血管生成和肿瘤侵袭。另一种能够杀伤肿瘤的免疫细胞—NK细胞, 通过释放颗粒酶和穿孔素或以其Fc段受体介导抗体依赖的细胞毒性作用杀伤靶细胞, 但在TME中富集的TGF-β会抑制其杀伤活性。树突细胞(dendritic cell, DC) 同样会受到TME中乏氧和炎症环境影响, 削弱其抗原提呈活性。而MDSCs作为TME中的免疫负调控因素, 能够抑制T细胞激活和多种免疫细胞活性^[14]。以下重点介绍肿瘤相关巨噬细胞和树突细胞。

1.4.1 肿瘤相关巨噬细胞

在原发和继发肿瘤中, 巨噬细胞被称为肿瘤相关巨噬细胞, 是肿瘤间质中细胞数量最多的群体, 约占细胞总数的30%~50%。根据功能表型不同, 巨噬细胞大致分为M1型(经典活化巨噬细胞) 和M2型(替代活化巨噬细胞)。根据活化因子类型的不同, M2型TAMs又分为M2a、M2b和M2c三个亚型。M1型巨噬细胞参与炎症反应, 清除体内病原体, 参与抗肿瘤免疫。而M2型巨噬细胞具有抗炎症反应、修复损伤的功能并促进肿瘤形成。在肿瘤微环境中, TAMs一般表现为M2型巨噬细胞的特征, 表达抗炎性细胞因子、清除受体、血管生成因子和蛋白酶的水平高于M1型巨噬细胞。这些抗炎性细胞因子可以诱导肿瘤免疫抑制微环境的形成, 进而促进肿瘤进展。靶向TAMs可能成为一种新的治疗肿瘤的方法。

1.4.2 树突细胞

DC作为免疫系统的核心成分, 主要参与适应性免疫反应。然而, 在TME中有双重功能: 一方面, 成熟的免疫原性树突状细胞通过抗原摄取、加工和呈递促进T细胞介导的抗肿瘤反应; 另一方面, 未成熟或部分分化的髓系树突状细胞不能诱导抗肿瘤免疫反应。相反, 作为调节性树突状细胞, 诱导TME的免疫抑制和耐受。

DC作为最有效的抗原呈递细胞, 对于抗肿瘤免疫应答的启动、进展和诱导至关重要。大量研究证明多种肿瘤类型中存在肿瘤浸润DC (TIDC)。然而, TIDC在TME中通常表现出数量和功能缺陷, 如成熟功能性DC的减少和未成熟或调节性DC的局部聚集。因此, 以DC为基础的治疗可以恢复TME中DC的功能, 从而在肿瘤治疗中显示出广阔的潜力。

2 肿瘤微环境靶向和重塑策略

收起

肿瘤存在的纤维间质增生以及强免疫抑制微环境抑制了药物在瘤体的分布和渗透, 极大削弱了药物疗效。调节TME可以减少药物递送的障碍, 并改善免疫抑制微环境。在本综述中, 主要总结了通过靶向肿瘤乏氧、肿瘤血管系统、肿瘤相关成纤维细胞、细胞外基质组分、肿瘤相关巨噬细胞和树突细胞, 从而重塑TME的策略, 以提高药物和疗法的靶向效率及治疗效果, 如图 1所示。

2.1 改善肿瘤乏氧微环境

乏氧是多数实体瘤的固有特征, 严重的肿瘤乏氧会导致肿瘤非手术治疗的疗效明显下降, 甚至导致肿瘤转移及产生耐药性。因此, 提高肿瘤组织中的含氧量, 改善肿瘤乏氧环境, 有望提高抗肿瘤作用。

目前提高肿瘤组织的含氧量主要有两种方式: 一是基于高压氧(hyperbaric oxygen, HBO) 或是血液代用品递送O₂至肿瘤组织内, 其中常见的血液代用品有全氟化碳、血红蛋白等; 二是设计能催化肿瘤内源性过氧化氢(H₂O₂) 分解产生O₂的药物递送系统, 例如基于二氧化锰(MnO₂) 或过氧化氢酶(catalase, CAT) 的纳米粒触发肿瘤内源性H₂O₂分解生成O₂^[15]。

2.1.1 将O₂递送至肿瘤组织的治疗方法

在现代医学治疗中, HBO治疗被广泛应用于各种病理状态下的辅助治疗, 现有研究证实了高压氧治疗联合手术、放疗、化疗和光动力治疗的疗效。虽然HBO尚未被批准用于癌症治疗, 但作为一种辅助治疗, HBO可以抑制肿瘤的生长, 且成本较低, 是一种理想的安全治疗方法。如Liu等^[16]首次使用HBO增强免疫检查点封锁抗体(a-PD-1) 的抗肿瘤疗效, 研究其机制发现HBO通过破坏缺氧介导的免疫抑制, 帮助a-PD-1触发强大的细胞毒性T淋巴细胞响应和持久的免疫记忆, 从而抑制肿瘤复发。

在人体中, 红细胞中的血红蛋白(hemoglobin, Hb) 将氧从肺运送到其他组织。因此, 将红细胞作为药物递送系统可以向肿瘤组织传送足够的氧以改善乏氧。然而, 红细胞的平均尺寸在5~7 μm内, 限制了其血管扩散能力, 因而很难到达肿瘤。红细胞的携氧能力是通过Hb, 一种存在于红细胞中的金属蛋白。因此, 在一些研究中, 使用Hb代替红细胞。Hb输送O₂的原理是依靠氧分子与血红素的铁原子之间形成稳定的局部化学配位键, 通过共价结合方式, 实现O₂的递送作用。Yang等^[17]构建了一种同时荷载Hb和抗肿瘤药物多柔比星(doxorubicin, DOX) 的多功能脂质体, 该递送系统可以高效负载氧气并将其递送至肿瘤部位, 通过逆转乏氧, 增强DOX的抗肿瘤作用。

全氟化碳(perfluorocarbon, PFC) 是碳氢化合物中的氢原子被氟原子取代后形成的有机分子, 是无色无味、无毒的透明液体, 其化学性质稳定, 但不溶于水, 需要经过乳化变为可溶性乳剂; 该乳剂具有良好的溶解非极性气体的功能, 可以作为O₂和CO₂的运送载体, 其原理是通过疏松、非定向的范德华力交互作用, 物理溶解O₂, 实现O₂递送作用^[18]。PFC由于其较高的氧亲和力和良好的生物相容性而被作为血液代用品, 在临床上应用于创伤、失血性休克和贫血等方面^[19]。Day等^[20]使用全氟化碳纳米乳剂来同时输送氧气和光敏剂, 提高了光动力疗法(photodynamic therapy, PDT) 的疗效。Wu等^[21]构建了一种表皮生长因子功能化的聚乳酸-羟基乙酸共聚物[poly(lactic-co-glycolic acid), PLGA] 纳米粒, 共同负载5-氟尿嘧啶和PFC, 用于结肠癌的靶向治疗。结果表明PFC通过向肿瘤输送氧气来缓解肿瘤乏氧, 提高了化疗药物的抑瘤效果。

2.1.2 肿瘤组织原位供氧

由于肿瘤组织的血管异常, 且多数肿瘤细胞处于远离肿瘤血管的位置, 导致氧运转不足。因此, 通过将O₂递送至肿瘤组织内以改善肿瘤乏氧微环境的方法具有一定局限性。近年来研究者致力于开发一类新型纳米递送系统, 该体系能催化肿瘤内源性H₂O₂分解产生O₂, 从而提高肿瘤组织的含氧量, 改善肿瘤乏氧微环镜。

肿瘤细胞因增殖过快和代谢异常产生大量活性氧(reactive oxygen species, ROS)。H₂O₂是ROS的一个重要成分, 而且H₂O₂分解产生的O₂能够提高肿瘤组织内含氧量, 从而改善肿瘤乏氧环境。目前有文献报道, CAT^[22]或MnO₂^[23]纳米粒可作为催化剂, 诱导肿瘤组织内H₂O₂分解产生O₂, 从而提高肿瘤组织含氧量, 改善肿瘤乏氧微环镜。

Zhang等^[24]将CAT包裹在顺铂(Ⅳ)-前药-脂质体中, 形成CAT@Pt (Ⅳ)-脂质体, 用于增强癌症的化疗-放疗联合治疗的疗效。结果表明, CAT被装载到脂质体内后, 能够触发肿瘤细胞产生的H₂O₂分解, 从而产生额外的氧气来缓解乏氧。最终显著改善了CAT@Pt (Ⅳ)-脂质体化疗-放疗联合治疗效果。此外, CAT纳米粒也可通过改善微环境乏氧缓解肿瘤对PDT的抵抗。Wang等^[25]通过原位自由基聚合对CAT进行改性, 以MESO-四(对羟基苯基) 卟啉(THPP) 为交联剂, 制备了包封CAT的纳米胶囊(CAT-THPP-PEG)。结果表明, CAT-THPP-PEG纳米粒在静脉注射后表现出增强的渗透和滞留(enhanced permeability and retention, EPR) 效应, 能够通过触发肿瘤内源性H₂O₂分解为氧气, 极大地缓解肿瘤乏氧。在光敏剂THPP的作用下, 进一步在体内进行PDT, 取得了显著的抗肿瘤治疗效果。近年来, 许多研究使用MnO₂纳米粒在乏氧肿瘤微环境中原位生成O₂。Murphy等^[26]将二氧化锰纳米粒(MnO₂ NPs) 包封在PLGA中, 制备所得粒子大小为116 nm, zeta电位为+17 mV (PLGA-MnO₂ NPs)。PLGA-MnO₂ NPs高效催化肿瘤组织H₂O₂的降解, 从而产生氧气。与未包封的MnO₂ NPs相比, PLGA-MnO₂ NPs具有更好的生物相容性和渗透效果, 在穿透肿瘤球后改善肿瘤乏氧, 继而降低缺氧诱导因子1α的表达。

2.2 靶向肿瘤血管

TME血管系统异常阻碍了肿瘤治疗的效果, 因此, 血管正常化不失为一种有前途的解决方案。肿瘤部位促血管生成因子与抑血管生成因子间的不一致是导致其血管异常的主要因素, 抗血管生成药物可通过调节混乱的信号传导过程, 使肿瘤新生血管暂时正常化。Chen等^[27]通过厄洛替尼[一种表皮生长因子受体(epidermal growth factor receptor, EGFR) 的特异性抑制剂] 使肿瘤血管正常化, 可以显著增强小鼠乳腺肿瘤、结直肠肿瘤和鳞状细胞癌肿瘤灌注和氧合状态。结果表明, 口服剂量为50 mg·kg^-1的厄洛替尼预处理组小鼠增加了载药纳米粒在肿瘤组织的分布和渗透, 显著提高了纳米药物的化疗疗效。此外, 厄洛替尼诱导的肿瘤血管正常化可进一步逆转免疫抑制微环境, 提高了a-PD-L1肿瘤免疫治疗效果。

虽然抗肿瘤血管生成药物可以调节肿瘤间质促血管生成因子和血管生成抑制因子恢复平衡, 逆转肿瘤血管异常结构, 从而使肿瘤血管及其微环境发生暂时的正常化。“正常化”的血管可使血管数量减少, 间质压降低, 肿瘤内氧含量升高, 改善肿瘤免疫抑制微环境, 有利于抗肿瘤药物进入到肿瘤组织内部, 增强其敏感性, 在该时间窗内联合抗肿瘤药物可取得较为明显的治疗效果。然而, 血管正常化窗口的出现与抗血管生成药物治疗的时机和剂量有关。大剂量或长期使用抗血管生成药物往往会导致肿瘤血管过度缩小, 从而缩短归一化窗口。这种现象被称为“肿瘤血管过度修剪”^[28]。因此, 抗血管生成药物只有使用适当的剂量和治疗周期才能延长血管正常化的窗口。

2.3 靶向肿瘤相关成纤维细胞

CAFs是肿瘤组织中主要的基质细胞。在某些肿瘤类型中, CAFs的含量可能占肿瘤间质的50%左右^[29]。CAFs不仅能通过旁分泌的方式分泌大量细胞因子促进肿瘤细胞的活化, 还能通过促进细胞间质的重塑、肿瘤微血管的生成及免疫抑制诱导肿瘤细胞的侵袭和转移。CAFs可以产生ECM, 包括Ⅰ型、Ⅲ型和Ⅴ型胶原蛋白和纤连蛋白。由于化疗或免疫调节药物等传统抗肿瘤药物的疗效受到限制药物扩散的基质屏障限制^[30], 调控CAFs可为抗肿瘤药物增敏提供一种有效的辅助方法。CAFs的靶向策略主要包括直接消耗CAFs及正常化CAFs。

2.3.1 清除CAFs

如前所述, 与正常成纤维细胞相比, CAFs中多种膜蛋白被上调, 这些膜蛋白可能充当潜在的靶标。由于FAP在绝大多数恶性肿瘤间质及其他增生性成纤维细胞上呈现高度特异性表达^[31], 目前清除CAFs的靶向递送策略主要是针对其表面标志物FAP。Zhen等^[32]报道了一种基于纳米粒的光免疫治疗(nano-PIT) 方法。该方法使用铁蛋白作为光敏剂载体, 并将FAP特异性单链可变片段(scFv) 偶联到铁蛋白表面。在光照射下, nano-PIT能有效地消除肿瘤中的CAFs, 并能有效抑制肿瘤生长。进一步研究其机制发现, nano-PIT抑制CXCL12的分泌, 显著增强T细胞浸润, 进而有效抑制肿瘤生长。Zhou等^[33]将负载ZnF16Pc的去铁铁蛋白纳米粒偶联scFv制备成αFAP-Z@FRT进行光动力治疗。研究发现, αFAP-Z@FRT光动力治疗可以有效根除肿瘤中的CAFs, 并在4T1乳腺癌小鼠模型中引发了系统性免疫, 有效地抑制了小鼠原位瘤及远端瘤的生长。除了针对FAP, Chen等^[34]构建了一种由FH肽修饰的Nav纳米脂质体(FH-SSL-Nav) 用于根除CAFs, FH-SSL-Nav与表达在CAFs表面的tenascin C特异性结合, Nav主要通过抑制抗凋亡蛋白BCL-2和BCL-XL的活性诱导CAFs细胞凋亡, 进而降低IFP和增强血液灌注, 促进多柔比星脂质体在肿瘤球体和肿瘤组织的渗透^[35]。

2.3.2 失活CAFs

尽管CAFs清除可以增强治疗药物对肿瘤的穿透性, 并改善免疫抑制微环境, 增强抗肿瘤免疫反应。但通常伴有严重的不良反应。首先, 大量间质成分的消除可能破坏TME的稳态, 增加了肿瘤转移和侵袭的风险。此外, 有研究报道, 包封DNA损伤药物的纳米递送系统用于CAFs靶向治疗, 可引起损伤反应程序分子的分泌, 如Wnt16, 从而触发化疗耐药, 诱导肿瘤细胞增殖^[36]。因此, 将CAFs还原为静息状态或赋予其肿瘤抑制表型可能是更好的治疗方法。

在肿瘤进展过程中, 正常成纤维细胞被多种细胞因子激活, 包括由癌细胞或其他基质细胞分泌的TGF-β、碱性成纤维细胞生长因子(basic fibroblast growth factor, bFGF)、结缔组织生长因子、白细胞介素-1b、血管内皮细胞生长因子、血小板衍生生长因子(platelet-derived growth factor, PDGF) 和sonic hedgehog等^[37]。因此, 通过药物或物理手段下调PDGF、TGF-β、bFGF等细胞因子的水平是另一种有前途的靶向CAFs的策略。Hou等^[38]将抗纤维化药物梣酮制备成纳米乳, 将其递送至CAFs, 用于逆转纤维增生性黑色素瘤免疫抑制微环境。系统给药后, 梣酮纳米乳显著地降低CAFs的量, 并通过增加自然杀伤细胞、细胞毒T细胞在肿瘤组织的浸润, 提高Th1细胞因子干扰素-γ (IFN-γ) 的分泌及抑制TGF-β、趋化因子CCL2和白细胞介素-6 (interleukin-6, IL-6) 的表达增强抗肿瘤免疫反应。Saha等^[39]研究表明, 20 nm的金纳米颗粒(AuNPs) 可以通过抑制胰腺癌细胞和胰腺星状细胞(pancreas stellate cells, PSCs) 之间的相互作用而将其转化为静息表型, 其中PDGF、TGF-β、bFGF均显著下调。通过抑制PSCs的活化, 重塑肿瘤微环境进而抑制肿瘤生长。此外, 最近的一项研究表明, 一氧化氮(nitric oxide, NO) 可以通过sGC-cGMP途径阻断TGF-β转导^[40]。NO供体负载脂质体(Lip-SNAP) 通过抑制TGF-β的表达及其下游促纤维化信号转导来抑制致密间质的产生, 从而提高了负载吉西他滨脂质体的肿瘤穿透能力。另外, 一些其他TGF-β抑制剂, 如吡非尼酮^[41]、LY2109761^[42]、α-山竹素^[43]、二甲双胍^[44]、曲尼司特^[45]、尼达尼布^[46]、氟富酮^[47]和minnelide^[48]等也被研究用于靶向CAFs。除了上述策略外, CAFs分泌的趋化因子具有支持肿瘤生长的作用, 也为肿瘤潜在的治疗靶点。如Lang等^[49]将CXCL12沉默siRNA (siCXCL12) 装载于细胞穿透肽[CPP, 9-精氨酸(R9)] 自组装纳米粒中, 并将成纤维细胞活化蛋白-α单克隆抗体(抗FAP-α单抗) 吸附在纳米粒表面形成PNP/siCXCL12/mAb, 构建了一个CAFs靶向siRNA纳米递送系统。该纳米递送系统通过下调CXCL12在CAFs中的表达, 有效地灭活CAFs, 重塑前列腺恶性肿瘤微环境, 从而显著抑制了肿瘤细胞的迁移、侵袭和肿瘤血管生成, 并进一步抑制了原位前列腺肿瘤的转移。

2.4 靶向细胞外基质组分

ECM是肿瘤部位主要的生理屏障, 阻碍了药物在肿瘤组织的渗透^[50]。因此, 下调ECM的表达或降解已生成的ECM将有助于提高递药系统在肿瘤组织的传递效率。作为ECM的主要组成成分, 胶原成为调节ECM的常用靶点。Kato等^[51]在荷瘤小鼠体内静脉注射胶原酶后, 肿瘤组织的胶原密度和IFP降低, 增强了脂质体在肿瘤组织的积累。Murty等^[52]进一步将胶原酶修饰到AuNPs上, 发现胶原酶修饰的AuNPs在A549肿瘤中的分布是对照组的1.35倍, 表明胶原酶修饰的AuNPs显著提高了药物在肿瘤组织的递送效率。透明质酸(hualuronic acid, HA) 是ECM的另一重要成分, Wang等^[53]将透明质酸酶(hyaluronidase, HAase) 通过酸敏感键修饰至生物相容性良好的右旋糖苷(dextran, DEX) 上制备成纳米粒DEX-HAase。经尾静脉注射后, DEX-HAase表现出较强的酶稳定性, 较低的免疫原性及较长的血浆半衰期。当其被动靶向至肿瘤组织后, DEX-HAase在酸性TME中发生解离, 释放出的HAase促进HA的分解, 使ECM结构疏松, 增强氧气和载有光敏剂的脂质体在肿瘤组织的渗透, 再通过联用a-PD-L1, 实现了较好的肿瘤免疫治疗的效果。

另外, 许多小分子药物可以抑制ECM的表达, 如4-甲基伞形酮(4-methylumbelliferone, 4-MU) 可直接抑制HA的合成, Kohli等^[54]将4-MU前药(4-MU-p) 装载到脂质体中, 以减少肿瘤ECM, 提高脂质体在肿瘤组织的分布。在乳腺肿瘤模型中, 将负载4-MU-p的脂质体与Doxil^®联合使用可显著减缓肿瘤生长, 延长小鼠生存期。

此外, 胶原变性也可以改善药物在肿瘤部位的递送。Raeesi等^[55]利用金纳米棒的光热效应使胶原变性。结果表明, 与未处理的胶原基质相比, 无机纳米粒(50和120 nm) 在变性胶原基质中的扩散率分别提高了14倍和21倍。

2.5 靶向肿瘤相关巨噬细胞

TAMs由多种细胞组成, 包括促炎的M1型(由脂多糖或IFN-γ激活) 和抗炎的M2型(由IL-4、IL-13或IL-10激活)。M1型TAMs具有引起炎症反应, 增强抗肿瘤免疫的能力; M2型TAMs则表现出肿瘤促进功能, 包括诱导肿瘤血管生成以及抑制肿瘤免疫反应等。研究表明将TAMs重新复极化为抗肿瘤M1型是一种有希望的治疗策略, 可激活抗肿瘤免疫反应, 抑制肿瘤生长、血管生成和转移扩散。细胞因子、趋化因子、生长因子与其受体的相互作用可指导TAMs极化程序^[56], 因此, 借助小分子、抗体和RNA重塑TAMs表型是一种常用的免疫调节策略, 可以单独或与其他策略(如经典化疗、免疫检查点抑制剂疗法等) 联合用于抗肿瘤治疗。

Toll样受体(Toll-like receptor, TLR) 是一种模式识别受体, 在先天免疫应答的激活中具有重要作用。Rodell等^[57]证明R848是TLR的激动剂, 其对TLR的激活能够诱导免疫反应, 使巨噬细胞趋向于促炎的M1表型。为了“重塑”TAMs, 作者使用β-环糊精负载R848制备成具有TAMs靶向功能的β-环糊精纳米粒(CDNP-R848)。作为一种单药疗法, CDNP-R848在小鼠的多种肿瘤模型中激发适应性免疫反应, 包括髓系表型的改变和最终IL-12水平的增加。CDNP-R848将TAMs复极化为M1表型, 从而抑制了肿瘤的生长并延长小鼠生存期。当与免疫检查点抑制剂a-PD-1联合使用时, 进一步提高了免疫应答率, 发现2/7小鼠肿瘤完全消退, 同时引发抗肿瘤记忆。另外, Shi等^[58]使用甘露糖修饰的聚乙二醇化PLGA纳米粒(MAN-PLGA-N) 将吲哚菁绿(indocyanine green, ICG)、NH₄HCO₃和二氧化钛(TiO₂) 递送至肿瘤。MAN-PLGA-N通过甘露糖介导的内吞作用在TAMs中积累。随后, NH₄HCO₃产生CO₂和NH₃破坏溶酶体, 释放到细胞质中的ICG和TiO₂在近红外光照射下产生ROS, 成功复极化TAMs至肿瘤抑制性M1表型。“重塑”后的TAMs促进CTL的募集, 并增强记忆T细胞对肿瘤的杀伤反应。该策略可以有效地根除肿瘤, 抑制转移, 并进一步防止其复发, 为实现有效的癌症免疫治疗提供了巨大的前景。

2.6 靶向树突细胞

DC是体内最强的抗原提呈细胞(antigen presenting cell, APC), 其在肿瘤免疫中具有重要的作用。有别于其他APC, DC既能诱导初级免疫反应, 又能诱导次级免疫反应, 是启动、调控并维持免疫应答的中心环节, 亦是目前发现的功能最强、唯一能激活静息T细胞的抗原提呈细胞。成熟的DC为T细胞提供必需的共刺激信号, 然而肿瘤内的免疫抑制微环境抑制了DC的功能。因此, DC的靶向治疗以促进其有效激活越来越受到关注。

一些研究通过将激活DC的药物包封在纳米粒中靶向DC, 以激活和成熟DC。如Liu等^[59]使用磷酸钙脂质纳米粒将特异性肿瘤抗原BRAFV600E肽通过抗原递呈递送到DC。这些脂质双分子层能够有效地穿透物理屏障, 防止药物的降解和聚集。结果表明, 纳米粒能够驱动DC成熟并显著增加了抗原特异性T细胞应答和IFN-γ的产生。最近的一项研究表明, 合成的超小Fe₃O₄纳米粒作为纳米免疫增强剂与卵清蛋白联合使用, 可以促进DC的成熟^[60], 作者首次发现这种Fe₃O₄纳米粒不仅可以作为递送系统, 还可以参与免疫治疗。Fe₃O₄的这种固有的免疫调节特性可能在癌症免疫治疗中具有极大的吸引力。然而, 由一种抗原引起的免疫反应是有限的, 需要更广泛的肿瘤抗原。Min等^[61]利用了抗原捕获纳米粒(AC-NPs), 可以通过多种机制捕获肿瘤源性蛋白抗原(TDPA), 包括离子相互作用、共价相互作用和非共价疏水-疏水相互作用。这些TDPA结合的AC-NPs有效地靶向DC, 并显著提高a-PD-1作用于B16F10黑色素瘤的疗效, 治愈率高达20%, 而在单独使用a-PD-1对照组中为0%。进一步研究其机制表明, AC-NPs可诱导更强大的CD8⁺细胞毒性T细胞应答, 且CD4⁺ T/Treg和CD8⁺ T/Treg比值均增加。AC-NPs与传统的单一或多种特异性抗原的免疫治疗不同, 可捕获多种肿瘤抗原, 放大治疗效果, 降低肿瘤异质性对肿瘤免疫治疗的影响。

DC作为免疫系统中最强大的APC, 在免疫中发挥着至关重要的作用, 因此DC靶向治疗的研究一直在进行。近年来, 通过传递抗原来增强抗肿瘤免疫的肿瘤疫苗越来越受到人们的关注。癌症疫苗的主要类型是基于细胞的疫苗, 这种疫苗耗时、昂贵, 并且由于自身免疫存在潜在的风险。纳米医学的发展提供了一个更好的选择。纳米粒可以特异性地将抗原或佐剂递送到DC中, 防止降解并促进DC的有效激活。然而, 纳米药物的治疗效果很大程度上取决于合适的载体和抗原。此外, DC亚群(如浆类或髓类) 的变异尚未完全阐明。因此, 需要进行更广泛的研究, 以阐明最合适的纳米粒设计和不同DC亚群的功能, 才能将其转化为临床实践^[62]。

3 总结和展望

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TME是肿瘤发展、侵袭和转移的关键, 是肿瘤靶向药物递送的主要障碍和潜在靶点, 其免疫抑制状态也显著影响了药物的抗肿瘤作用。如前所述, 许多研究者证实通过靶向重塑肿瘤微环境治疗策略, 可以取得更好的抗肿瘤效果, 如表 1^{[16, 17, 20, 21, 24-27, 33, 34, 38-40, 49, 51-55, 57-61]}所示。除了在临床前研究中显示出有益的抗肿瘤作用外, 在临床试验中也观察到TME重塑提高药物治疗效果的巨大潜力, 详见表 2。尽管TME重塑有增加抗肿瘤效果的潜力, 但在进一步的临床转化中面临着明显的瓶颈。首先, TME重塑是一把双刃剑。如肿瘤血管正常化虽然增强了血液灌注, 同时也降低了纳米粒的EPR效应和肿瘤渗透性。破坏肿瘤间质虽然克服药物的扩散屏障, 从而提高靶向效率, 但也增加了肿瘤迁移和转移的风险。这些矛盾和有争议的治疗方法强调了TME重塑的复杂性, 从而鼓励了对TME多方面特征的深入研究和分析; 其次, 肿瘤的异质性和复杂性也是TME调控的一大挑战^[63]。TME重塑的治疗效果取决于肿瘤个体的病理生理特征。只有低渗透性或致密间质的肿瘤类型可能从这种策略中受益显著; 同一肿瘤类型在不同人群中的病理生理特征或同一肿瘤在不同生理状态和部位的病理生理特征可能不同, 导致TME重塑的结果难以预测。因此, 全面评估个体肿瘤的类型、阶段和生理结构对于TME重塑策略的未来临床应用是必不可少的。而且, 仅仅通过单方面TME的调控来达到理想的肿瘤药物浸润效率始终是不够的。未来的研究应该强调开发多功能策略, 同时调控TME的多个方面。此外, 由于TME调控存在有效时间窗, 需要充分考虑TME调节药物与其他治疗药物的具体联合用药策略, 包括给药顺序和给药比例; 最后, 由于模型动物与人在临床试验中的差异, 很难根据动物模型的临床前治疗结果来推断患者的治疗效果。例如, 基于肿瘤细胞的皮下和原位异种移植缺乏患者肿瘤复杂的生物微环境^[64]。开发更合适的动物模型, 准确模拟人类肿瘤自然进展的病理特征是当务之急。例如, 患者源性肿瘤外植体模型^[65]将临床患者肿瘤组织或细胞移植到免疫缺陷小鼠中, 提供了更真实的人类肿瘤结构和微环境特征。值得注意的是, 目前的临床实践侧重于TME重塑策略与小分子药物或已批准的纳米药物的结合^[2]。系统输送小分子药物的潜在毒性可能是其临床应用的另一个负面影响。开发TME重塑与药物治疗相结合的智能纳米药物有望解决现有的不足。

作者贡献: 杨蒙蒙负责文献的整理及综述的撰写; 韩晓鹏、秦超和杨磊负责稿件质量把关并提出修改意见; 尹莉芳负责文章的整体设计并参与稿件修改。

利益冲突: 作者声明没有任何利益冲突。

基金

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国家自然科学基金资助项目(81871477)
国家自然科学基金资助项目(81673377)

参考文献

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2022年第57卷第1期

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doi: 10.16438/j.0513-4870.2021-1232

接收时间：2021-08-24
首发时间：2025-12-22
出版时间：2022-01-12

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收稿日期：2021-08-24
修回日期：2021-10-20

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国家自然科学基金资助项目(81871477)

国家自然科学基金资助项目(81673377)

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1.中国药科大学药学院, 江苏南京 210009

2.江苏省缓释智能制剂及关键功能性辅料开发与评价工程研究中心, 江苏南京 210009

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*尹莉芳, Tel / Fax: 86-25-83271018, E-mail: lifangyin_@163.com

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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

Strategy	Nanocarrier	Active drug	Result	Reference
Hyperbaric oxygen	-	O₂ and a-PD-1	Resume the extracellular matrix's components, promote a-PD-1 delivery and T cells infiltration	[16]
Blood substitute	Liposomes	Hemoglobin and doxorubicin	Reverse hypoxia-induced chemoresistance, promote cytotoxicity of doxorubicin	[17]
	Perfluorocarbon nanoemulsions	O₂ and porphyrin	Simultaneously deliver oxygen and photosensitizer, enhance the efficacy of photodynamic therapy	[20]
	Epidermal growth factor functionalized PLGA nanoparticles	O₂ and 5-fluorouracil	Relieve tumor hypoxia, enhance the efficacy of 5-fluorouracil	[21]
Supply O₂ in situ	CAT@Pt (Ⅳ)-liposome	CAT and Pt (Ⅳ)	Relieve tumor hypoxia, improve the efficacy of CAT@Pt (Ⅳ)-liposome	[24]
	CAT-THPP-PEG	CAT and THPP	Relieve tumor hypoxia, enhance the efficacy of photodynamic therapy	[25]
	PLGA-MnO₂ nanoparticles	MnO₂	Reduce hypoxia and decrease the expression of hypoxia-induced factor 1α	[26]
Vasculature normalization	-	Erlotinib	Increase accumulation and penetration of drugs, alter the immunosuppressive TME into immunosupportive	[27]
Depletation CAFs	αFAP-Z@FRT	ZnF₁₆Pc	Eliminate CAFs, improve antitumor efficacy	[33]
	FH-SSL-Nav	Nav	Eradicate CAFs, improve tumor growth inhibition	[34]
Inactivate CAFs	Nanoemulsions	Fraxinellone	Reduce the amount of CAFs and extracellular matrix deposition, enhance the anti-tumor immune response	[38]
	Gold nanoparticles	Gold	Reduce activation of pancreatic stellate cell and matrix deposition, enhance angiogenesis, inhibit tumor growth	[39]
	Liposomes	S-Nitroso-N-acetylpenicillamine	Inhibit the expression of TGF-β and the production of dense stroma, improve the tumor penetration ability of liposomes	[40]
	Cell penetrating peptide modified nanoparticles	siCXCL12	Inactive CAFs by down-regulating the expression of CXCL12, reshape the TME	[49]
Targeting extracellular matrix	-	Type I collagenase	Decrease interstitial fluid pressure, improve the accumulation of drugs	[51]
	Gold nanoparticles	Collagenase	Improve the delivery efficiency of drugs in tumor	[52]
	DEX-HAase nanoparticles	HAase	Loose the structure of extracellular matrix, enhance the penetration of oxygen and liposomes	[53]
	Liposomes	4-Methylumbelliferone	Reduce tumor extracellular matrix and improve the distribution of liposomes	[54]
	Gold nanorods	Gold	Increase the diffusion rate of inorganic nanoparticles	[55]
Reshaping TAMs	β-Cyclodextrin nanoparticles	R848	Alter the immune microenvironment towards an M1 phenotype, improve a-PD-1 immunotherapy response rates	[57]
	Mannose-modified PEGylated PLGA nanoparticles	Indocyanine green, titanium dioxide and ammonium bicarbonate	Reprogram TAMs, promote the recruitment of CTLs and enhance the anti-tumor response of memory T cell	[58]
Targeting DCs	LCP NPs	BRAF^V600E peptide	Drive DCs maturation for antigen presentation, produce IFN-γ	[59]
	Fe₃O₄-OVA nanocomposites	Fe₃O₄ NPs and OVA	Stimulate DCs maturation, activate T cells	[60]
	AC-NPs	TDPAs	Expand CD8⁺ cytotoxic T cells, increase both CD4⁺ T/Treg and CD8⁺ T/Treg ratios	[61]

Strategy

Nanocarrier

Active drug

Result

Reference

Hyperbaric oxygen

O₂ and a-PD-1

Resume the extracellular matrix's components, promote a-PD-1 delivery and T cells infiltration

[16]

Blood substitute

Liposomes

Hemoglobin and doxorubicin

Reverse hypoxia-induced chemoresistance, promote cytotoxicity of doxorubicin

[17]

Perfluorocarbon nanoemulsions

O₂ and porphyrin

Simultaneously deliver oxygen and photosensitizer, enhance the efficacy of photodynamic therapy

[20]

Epidermal growth factor functionalized PLGA nanoparticles

O₂ and 5-fluorouracil

Relieve tumor hypoxia, enhance the efficacy of 5-fluorouracil

[21]

Supply O₂ in situ

CAT@Pt (Ⅳ)-liposome

CAT and Pt (Ⅳ)

Relieve tumor hypoxia, improve the efficacy of CAT@Pt (Ⅳ)-liposome

[24]

CAT-THPP-PEG

CAT and THPP

Relieve tumor hypoxia, enhance the efficacy of photodynamic therapy

[25]

PLGA-MnO₂ nanoparticles

MnO₂

Reduce hypoxia and decrease the expression of hypoxia-induced factor 1α

[26]

Vasculature normalization

Erlotinib

Increase accumulation and penetration of drugs, alter the immunosuppressive TME into immunosupportive

[27]

Depletation CAFs

αFAP-Z@FRT

ZnF₁₆Pc

Eliminate CAFs, improve antitumor efficacy

[33]

FH-SSL-Nav

Nav

Eradicate CAFs, improve tumor growth inhibition

[34]

Inactivate CAFs

Nanoemulsions

Fraxinellone

Reduce the amount of CAFs and extracellular matrix deposition, enhance the anti-tumor immune response

[38]

Gold nanoparticles

Gold

Reduce activation of pancreatic stellate cell and matrix deposition, enhance angiogenesis, inhibit tumor growth

[39]

Liposomes

S-Nitroso-N-acetylpenicillamine

Inhibit the expression of TGF-β and the production of dense stroma, improve the tumor penetration ability of liposomes

[40]

Cell penetrating peptide modified nanoparticles

siCXCL12

Inactive CAFs by down-regulating the expression of CXCL12, reshape the TME

[49]

Targeting extracellular matrix

Type I collagenase

Decrease interstitial fluid pressure, improve the accumulation of drugs

[51]

Gold nanoparticles

Collagenase

Improve the delivery efficiency of drugs in tumor

[52]

DEX-HAase nanoparticles

HAase

Loose the structure of extracellular matrix, enhance the penetration of oxygen and liposomes

[53]

Liposomes

4-Methylumbelliferone

Reduce tumor extracellular matrix and improve the distribution of liposomes

[54]

Gold nanorods

Gold

Increase the diffusion rate of inorganic nanoparticles

[55]

Reshaping TAMs

β-Cyclodextrin nanoparticles

R848

Alter the immune microenvironment towards an M1 phenotype, improve a-PD-1 immunotherapy response rates

[57]

Mannose-modified PEGylated PLGA nanoparticles

Indocyanine green, titanium dioxide and ammonium bicarbonate

Reprogram TAMs, promote the recruitment of CTLs and enhance the anti-tumor response of memory T cell

[58]

Targeting DCs

LCP NPs

BRAF^V600E peptide

Drive DCs maturation for antigen presentation, produce IFN-γ

[59]

Fe₃O₄-OVA nanocomposites

Fe₃O₄ NPs and OVA

Stimulate DCs maturation, activate T cells

[60]

AC-NPs

TDPAs

Expand CD8⁺ cytotoxic T cells, increase both CD4⁺ T/Treg and CD8⁺ T/Treg ratios

[61]

Strategy	Clinical trial identifier	Study drug	Phase	Cancer type
Hypoxia-activated prodrug	NCT01144455	Gemcitabine, TH-302	Phase Ⅱ	Locally advanced or metastatic pancreatic cancer
NCT01037556	PR104	Phase Ⅰ/II	Refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia
Targeting VEGF/VEGFR therapeutic agent	NCT00945139 and NCT00846612	Bevacizumab, liposomal doxorubicin	Phase Ⅱ	Platinum- and taxane-resistant ovarian cancer
NCT03048877	Bevacizumab	Phase Ⅲ	Thyroid cancer
NCT03278717	Olaparib, cediranib	Phase Ⅲ	Ovarian cancer
EudraCT (2008-001090-15)	Sorafenib, docetaxel	Phase Ⅱ	Metastatic breast cancer
NCT02898077	Ramucirumab, paclitaxel	Phase Ⅲ	Gastric adenocarcinoma
NCT03172299	Aflibercept	Phase Ⅲ	Ocular melanoma
NCT01206764	Everolimus	Phase Ⅳ	Renal cell carcinoma
Targeting CAF mediated immunosuppression	NCT03277209	Plerixafor	Phase Ⅰ	Pancreatic cancer
NCT02826486	BL-8040, pembrolizumab	Phase Ⅱ	Pancreatic cancer
-	S-3304	Phase Ⅰ	Advanced and refractory solid tumors
-	Bevacizumab	Phase Ⅲ	Pleural mesothelioma
-	Ruxolitinib, capecitabine	Phase Ⅱ	Metastatic pancreatic cancer
Targeting stromal depletion	NCT02715804	PEGPH20, gemcitabine, nab-paclitaxel	Phase Ⅲ	Pancreatic cancer
NCT02910882	PEGPH20, gemcitabine, radiation	Phase Ⅱ	Pancreatic cancer
NCT03481920	PEGPH20, avelumab	Phase Ⅰ	Pancreatic cancer
Targeting TAM mediated immunosuppression	NCT01804530	PXL7486	Phase Ⅰ	Advanced solid tumors
NCT02829723	BLZ945	Phase Ⅰ/II	Advanced solid tumors
NCT02880371	ARRY-382	Phase Ⅱ	Advanced solid tumors
NCT02890368	TTI-621	Phase Ⅰ	Relapsed and refractory solid tumors
NCT03013218	ALX148	Phase Ⅰ	Metastatic cancer, solid tumor, advanced cancer, or non-Hodgkin's lymphoma
NCT00319748	852A	Phase Ⅱ	Breast, ovarian, endometrial and cervical cancers
NCT02781805	Alendronate	Phase Ⅰ	Breast neoplasms
Natural DC vaccination	NCT02993315 and NCT02574377	gp100, tyrosinase, NY-ESO-1, MAGE-C2, MAGE-A3	Phase Ⅲ, Phase Ⅰ/II	Melanoma stage IIIB-C, melanoma stage III
NCT01690377	Gp100, tyrosinase	Phase Ⅰ	Melanoma stage IV

Strategy

Clinical trial identifier

Study drug

Phase

Cancer type

Hypoxia-activated prodrug

NCT01144455

Gemcitabine, TH-302

Phase Ⅱ

Locally advanced or metastatic pancreatic cancer

NCT01037556

PR104

Phase Ⅰ/II

Refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia

Targeting VEGF/VEGFR therapeutic agent

NCT00945139 and NCT00846612

Bevacizumab, liposomal doxorubicin

Phase Ⅱ

Platinum- and taxane-resistant ovarian cancer

NCT03048877

Bevacizumab

Phase Ⅲ

Thyroid cancer

NCT03278717

Olaparib, cediranib

Phase Ⅲ

Ovarian cancer

EudraCT (2008-001090-15)

Sorafenib, docetaxel

Phase Ⅱ

Metastatic breast cancer

NCT02898077

Ramucirumab, paclitaxel

Phase Ⅲ

Gastric adenocarcinoma

NCT03172299

Aflibercept

Phase Ⅲ

Ocular melanoma

NCT01206764

Everolimus

Phase Ⅳ

Renal cell carcinoma

Targeting CAF mediated immunosuppression

NCT03277209

Plerixafor

Phase Ⅰ

Pancreatic cancer

NCT02826486

BL-8040, pembrolizumab

Phase Ⅱ

Pancreatic cancer

S-3304

Phase Ⅰ

Advanced and refractory solid tumors

Bevacizumab

Phase Ⅲ

Pleural mesothelioma

Ruxolitinib, capecitabine

Phase Ⅱ

Metastatic pancreatic cancer

Targeting stromal depletion

NCT02715804

PEGPH20, gemcitabine, nab-paclitaxel

Phase Ⅲ

Pancreatic cancer

NCT02910882

PEGPH20, gemcitabine, radiation

Phase Ⅱ

Pancreatic cancer

NCT03481920

PEGPH20, avelumab

Phase Ⅰ

Pancreatic cancer

Targeting TAM mediated immunosuppression

NCT01804530

PXL7486

Phase Ⅰ

Advanced solid tumors

NCT02829723

BLZ945

Phase Ⅰ/II

Advanced solid tumors

NCT02880371

ARRY-382

Phase Ⅱ

Advanced solid tumors

NCT02890368

TTI-621

Phase Ⅰ

Relapsed and refractory solid tumors

NCT03013218

ALX148

Phase Ⅰ

Metastatic cancer, solid tumor, advanced cancer, or non-Hodgkin's lymphoma

NCT00319748

852A

Phase Ⅱ

Breast, ovarian, endometrial and cervical cancers

NCT02781805

Alendronate

Phase Ⅰ

Breast neoplasms

Natural DC vaccination

NCT02993315 and NCT02574377

gp100, tyrosinase, NY-ESO-1, MAGE-C2, MAGE-A3

Phase Ⅲ,
Phase Ⅰ/II

Melanoma stage IIIB-C, melanoma stage III

NCT01690377

Gp100, tyrosinase

Phase Ⅰ

Melanoma stage IV