Advancement and Applications of Nanotherapy for Cancer Immune Microenvironment

Abstract

Cancer treatment has evolved rapidly due to major advances in tumor immunity research. However, due to the complexity, heterogeneity, and immunosuppressive microenvironment of tumors, the overall efficacy of immunotherapy is only 20%. In recent years, nanoparticles have attracted more attention in the field of cancer immunotherapy because of their remarkable advantages in biocompatibility, precise targeting, and controlled drug delivery. However, the clinical application of nanomedicine also faces many problems concerning biological safety, and the synergistic mechanism of nano-drugs with immunity remains to be elucidated. Our study summarizes the functional characteristics and regulatory mechanisms of nanoparticles in the cancer immune microenvironment and how nanoparticles activate and long-term stimulate innate immunity and adaptive immunity. Finally, the current problems and future development trends regarding the application of nanoparticles are fully discussed and prospected to promote the transformation and application of nanomedicine used in cancer treatment.

Keywords

nanotherapy / tumor microenvironment / immunotherapy

References

[1] XiaC, DongX, LiH, et al.. Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J (Engl), 2022, 135(5): 584-590

[2] SiegelRL, MillerKD, FuchsHE, et al.. Cancer statistics, 2022. CA Cancer J Clin, 2022, 72(1): 7-33

[3] DeVitaVT, ChuE. A history of cancer chemotherapy. Cancer Res, 2008, 68(21): 8643-8653

[4] ChandraRA, KeaneFK, VonckenFEM, et al.. Contemporary radiotherapy: present and future. Lancet, 2021, 398(10295): 171-184

[5] WaldmanAD, FritzJM, LenardoMJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol, 2020, 20(11): 651-668

[6] WangZ, CaoYJ. Adoptive Cell Therapy Targeting Neoantigens: A Frontier for Cancer Research. Front Immunol, 2020, 11: 176

[7] SaxenaM, van der BurgSH, MeliefCJM, et al.. Therapeutic cancer vaccines. Nat Rev Cancer, 2021, 21(6): 360-378

[8] SinghAK, McGuirkJP. CAR T cells: continuation in a revolution of immunotherapy. Lancet Oncol, 2020, 21(3): e168-e178

[9] PostowMA, CallahanMK, WolchokJD. Immune Checkpoint Blockade in Cancer Therapy. J Clin Oncol, 2015, 33(17): 1974-1982

[10] BagchiS, YuanR, EnglemanEG. Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance. Annu Rev Pathol, 2021, 16: 223-249

[11] PetroskyE, BocchiniJAJr, HaririS, et al.. Use of 9-valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations of the advisory committee on immunization practices. MMWR Morb Mortal Wkly Rep, 2015, 64(11): 300-304

[12] Paz-AresL, CiuleanuTE, CoboM, et al.. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol, 2021, 22(2): 198-211

[13] HellmannMD, Paz-AresL, Bernabe CaroR, et al.. Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. N Engl J Med, 2019, 381(21): 2020-2031

[14] HodiFS, Chiarion-SileniV, GonzalezR, et al.. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol, 2018, 19(11): 1480-1492

[15] HouAJ, ChenLC, ChenYY. Navigating CAR-T cells through the solid-tumour microenvironment. Nat Rev Drug Discov, 2021, 20(7): 531-550

[16] GoldbergMS. Improving cancer immunotherapy through nanotechnology. Nat Rev Cancer, 2019, 19(10): 587-602

[17] IrvineDJ, DaneEL. Enhancing cancer immunotherapy with nanomedicine. Nat Rev Immunol, 2020, 20(5): 321-334

[18] MatsumuraY, MaedaH. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res, 1986, 46(12): 6387-6392Pt 1

[19] IyerAK, KhaledG, FangJ, et al.. Exploiting the enhanced permeability and retention effect for tumor targeting. Drug Discov Today, 2006, 11(17–18): 812-818

[20] WangJ, ZhangB, SunJ, et al.. Nanomedicine-Enabled Modulation of Tumor Hypoxic Microenvironment for Enhanced Cancer Therapy. Adv Ther (Weinh), 2020, 3(1): 1900083

[21] JinMZ, JinWL. The updated landscape of tumor microenvironment and drug repurposing. Signal Transduct Target Ther, 2020, 5(1): 166

[22] ShieldsC4th, WangLL, EvansMA, et al.. Materials for Immunotherapy. Adv Mater, 2020, 32(13): e1901633

[23] ThomasPD, KahnM. Kat3 coactivators in somatic stem cells and cancer stem cells: biological roles, evolution, and pharmacologic manipulation. Cell Biol Toxicol, 2016, 32(1): 61-81

[24] ZhouJ, WangG, ChenY, et al.. Immunogenic cell death in cancer therapy: Present and emerging inducers. J Cell Mol Med, 2019, 23(8): 4854-4865

[25] KroemerG, GalluzziL, KeppO, et al.. Immunogenic cell death in cancer therapy. Annu Rev Immunol, 2013, 31: 51-72

[26] BanstolaA, JeongJH, YookS. Immunoadjuvants for cancer immunotherapy: A review of recent developments. Acta Biomater, 2020, 114: 16-30

[27] MohamedSIA, JantanI, HaqueMA. Naturally occurring immunomodulators with antitumor activity: An insight on their mechanisms of action. Int Immunopharmacol, 2017, 50: 291-304

[28] MitchellMJ, BillingsleyMM, HaleyRM, et al.. Engineering precision nanoparticles for drug delivery. Nat Rev Drug Discov, 2021, 20(2): 101-124

[29] KuaiR, YuanW, SonS, et al.. Elimination of established tumors with nanodisc-based combination chemoimmunotherapy. Sci Adv, 2018, 4(4): eaao1736

[30] DingY, SunZ, GaoY, et al.. Plasmon-Driven Catalytic Chemotherapy Augments Cancer Immunotherapy through Induction of Immunogenic Cell Death and Blockage of IDO Pathway. Adv Mater, 2021, 33(34): e2102188

[31] FengB, ZhouF, HouB, et al.. Binary Cooperative Prodrug Nanoparticles Improve Immunotherapy by Synergistically Modulating Immune Tumor Microenvironment. Adv Mater, 2018, 30(38): e1803001

[32] MuQG, LinG, JeonM, et al.. Iron oxide nanoparticle targeted chemo-immunotherapy for triple negative breast cancer. Mater Today (Kidlington), 2021, 50: 149-169

[33] de SouzaASC, GoncalvesLB, LepiqueAP, et al.. The Role of Autophagy in Tumor Immunology-Complex Mechanisms That May Be Explored Therapeutically. Front Oncol, 2020, 10: 603661

[34] WangX, LiM, RenK, et al.. On-Demand Autophagy Cascade Amplification Nanoparticles Precisely Enhanced Oxaliplatin-Induced Cancer Immunotherapy. Adv Mater, 2020, 32(32): e2002160

[35] LiW, YangJ, LuoL, et al.. Targeting photodynamic and photothermal therapy to the endoplasmic reticulum enhances immunogenic cancer cell death. Nat Commun, 2019, 10(1): 3349

[36] YanS, ZengX, TangY, et al.. Activating Antitumor Immunity and Antimetastatic Effect Through Polydopamine-Encapsulated Core-Shell Upconversion Nanoparticles. Adv Mater, 2019, 31(46): e1905825

[37] ChenC, NiX, JiaS, et al.. Massively Evoking Immunogenic Cell Death by Focused Mitochondrial Oxidative Stress using an AIE Luminogen with a Twisted Molecular Structure. Adv Mater, 2019, 31(52): e1904914

[38] HeC, DuanX, GuoN, et al.. Core-shell nanoscale coordination polymers combine chemotherapy and photodynamic therapy to potentiate checkpoint blockade cancer immunotherapy. Nat Commun, 2016, 7: 12499

[39] XuC, JiangY, HuangJ, et al.. Second Near-Infrared Light-Activatable Polymeric Nanoantagonist for Photothermal Immunometabolic Cancer Therapy. Adv Mater, 2021, 33(36): e2101410

[40] ShaoD, ZhangF, ChenF, et al.. Biomimetic Diselenide-Bridged Mesoporous Organosilica Nanoparticles as an X-ray-Responsive Biodegradable Carrier for ChemoImmunotherapy. Adv Mater, 2020, 32(50): e2004385

[41] SongR, LiT, YeJ, et al.. Acidity-Activatable Dynamic Nanoparticles Boosting Ferroptotic Cell Death for Immunotherapy of Cancer. Adv Mater, 2021, 33(31): e2101155

[42] SuZ, XiaoZ, WangY, et al.. Codelivery of Anti-PD-1 Antibody and Paclitaxel with Matrix Metalloproteinase and pH Dual-Sensitive Micelles for Enhanced Tumor Chemoimmunotherapy. Small, 2020, 16(7): e1906832

[43] ZhouP, QinJ, ZhouC, et al.. Multifunctional nanoparticles based on a polymeric copper chelator for combination treatment of metastatic breast cancer. Biomaterials, 2019, 195: 86-99

[44] HuCM, ZhangL, AryalS, et al.. Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic delivery platform. Proc Natl Acad Sci USA, 2011, 108(27): 10980-10985

[45] KrollAV, FangRH, ZhangL. Biointerfacing and Applications of Cell Membrane-Coated Nanoparticles. Bioconjug Chem, 2017, 28(1): 23-32

[46] BahmaniB, GongH, LukBT, et al.. Intratumoral immunotherapy using platelet-cloaked nanoparticles enhances antitumor immunity in solid tumors. Nat Commun, 2021, 12(1): 1999

[47] Kroll AV, Fang RH, Jiang Y, et al. Nanoparticulate Delivery of Cancer Cell Membrane Elicits Multiantigenic Antitumor Immunity. Adv Mater, 2017,29(47)

[48] LiuWL, ZouMZ, LiuT, et al.. Expandable Immunotherapeutic Nanoplatforms Engineered from Cytomembranes of Hybrid Cells Derived from Cancer and Dendritic Cells. Adv Mater, 2019, 31(18): e1900499

[49] DengG, SunZ, LiS, et al.. Cell-Membrane Immunotherapy Based on Natural Killer Cell Membrane Coated Nanoparticles for the Effective Inhibition of Primary and Abscopal Tumor Growth. ACS Nano, 2018, 12(12): 12096-12108

[50] CaoH, DanZ, HeX, et al.. Liposomes Coated with Isolated Macrophage Membrane Can Target Lung Metastasis of Breast Cancer. ACS Nano, 2016, 10(8): 7738-7748

[51] ChenQ, BaiH, WuW, et al.. Bioengineering Bacterial Vesicle-Coated Polymeric Nanomedicine for Enhanced Cancer Immunotherapy and Metastasis Prevention. Nano Lett, 2020, 20(1): 11-21

[52] KimOY, ParkHT, DinhNTH, et al.. Bacterial outer membrane vesicles suppress tumor by interferon-gamma-mediated antitumor response. Nat Commun, 2017, 8(1): 626

[53] MinY, RocheKC, TianS, et al.. Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy. Nat Nanotechnol, 2017, 12(9): 877-882

[54] WangB, AnJ, ZhangH, et al.. Personalized Cancer Immunotherapy via Transporting Endogenous Tumor Antigens to Lymph Nodes Mediated by Nano Fe₃O₄. Small, 2018, 14(38): e1801372

[55] LeiK, KurumA, TangL. Mechanical Immunoengineering of T cells for Therapeutic Applications. Acc Chem Res, 2020, 53(12): 2777-2790

[56] ZhouZ, ZhangB, ZaiW, et al.. Perfluorocarbon nanoparticle-mediated platelet inhibition promotes intratumoral infiltration of T cells and boosts immunotherapy. Proc Natl Acad Sci USA, 2019, 116(24): 11972-11977

[57] YinQ, YuW, GrzeskowiakCL, et al.. Nanoparticle-enabled innate immune stimulation activates endogenous tumor-infiltrating T cells with broad antigen specificities. Proc Natl Acad Sci USA, 2021, 118(21): e2016168118

[58] XuC, JiangY, HanY, et al.. A Polymer Multicellular Nanoengager for Synergistic NIR-II Photothermal Immunotherapy. Adv Mater, 2021, 33(14): e2008061

[59] VoskoboinikI, WhisstockJC, TrapaniJA. Perforin and granzymes: function, dysfunction and human pathology. Nat Rev Immunol, 2015, 15(6): 388-400

[60] ZhaoQ, GongZ, LiZ, et al.. Target Reprogramming Lysosomes of CD8+ T Cells by a Mineralized Metal-Organic Framework for Cancer Immunotherapy. Adv Mater, 2021, 33(17): e2100616

[61] BaeJ, ParayathN, MaW, et al.. BCMA peptide-engineered nanoparticles enhance induction and function of antigen-specific CD8(+) cytotoxic T lymphocytes against multiple myeloma: clinical applications. Leukemia, 2020, 34(1): 210-223

[62] JiangY, KrishnanN, ZhouJ, et al.. Engineered Cell-Membrane-Coated Nanoparticles Directly Present Tumor Antigens to Promote Anticancer Immunity. Adv Mater, 2020, 32(30): e2001808

[63] AiL, XuA, XuJ. Roles of PD-1/PD-L1 Pathway: Signaling, Cancer, and Beyond. Adv Exp Med Biol, 2020, 1248: 33-59

[64] BrahmerJR, TykodiSS, ChowLQ, et al.. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med, 2012, 366(26): 2455-2465

[65] ZhongY, MaZ, WangF, et al.. In vivo molecular imaging for immunotherapy using ultra-bright near-infrared-IIb rare-earth nanoparticles. Nat Biotechnol, 2019, 37(11): 1322-1331

[66] WangD, WangT, YuH, et al.. Engineering nanoparticles to locally activate T cells in the tumor microenvironment. Sci Immunol, 2019, 4(37): eaau6584

[67] LangT, LiuY, ZhengZ, et al.. Cocktail Strategy Based on Spatio-Temporally Controlled Nano Device Improves Therapy of Breast Cancer. Adv Mater, 2019, 31(5): e1806202

[68] ChiangCS, LinYJ, LeeR, et al.. Combination offucoidan-based magnetic nanoparticles and immunomodulators enhances tumour-localized immunotherapy. Nat Nanotechnol, 2018, 13(8): 746-754

[69] HongJ, KangM, JungM, et al.. T-Cell-Derived Nanovesicles for Cancer Immunotherapy. Adv Mater, 2021, 33(33): e2101110

[70] AlhallakK, SunJ, WasdenK, et al.. Nanoparticle T-cell engagers as a modular platform for cancer immunotherapy. Leukemia, 2021, 35(8): 2346-2357

[71] ParayathNN, StephanSB, KoehneAL, et al.. In vitro-transcribed antigen receptor mRNA nanocarriers for transient expression in circulating T cells in vivo. Nat Commun, 2020, 11(1): 6080

[72] TangL, ZhengY, MeloMB, et al.. Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery. Nat Biotechnol, 2018, 36(8): 707-716

[73] GaudinoSJ, KumarP. Cross-Talk Between Antigen Presenting Cells and T Cells Impacts Intestinal Homeostasis, Bacterial Infections, and Tumorigenesis. Front Immunol, 2019, 10: 360

[74] SchuijsMJ, HammadH, LambrechtBN. Professional and ‘Amateur’ Antigen-Presenting Cells In Type 2 Immunity. Trends Immunol, 2019, 40(1): 22-34

[75] LindenberghMFS, StoorvogelW. Antigen Presentation by Extracellular Vesicles from Professional Antigen-Presenting Cells. Annu Rev Immunol, 2018, 36: 435-459

[76] ChoNH, CheongTC, MinJH, et al.. A multifunctional core-shell nanoparticle for dendritic cell-based cancer immunotherapy. Nat Nanotechnol, 2011, 6(10): 675-682

[77] KranzLM, DikenM, HaasH, et al.. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature, 2016, 534(7607): 396-401

[78] NuhnL, De KokerS, Van LintS, et al.. Nanoparticle-Conjugate TLR7/8 Agonist Localized Immunotherapy Provokes Safe Antitumoral Responses. Adv Mater, 2018, 30(45): e1803397

[79] LiuY, CroweWN, WangL, et al.. An inhalable nanoparticulate STING agonist synergizes with radiotherapy to confer long-term control of lung metastases. Nat Commun, 2019, 10(1): 5108

[80] AtukoralePU, RaghunathanSP, RaguveerV, et al.. Nanoparticle Encapsulation of Synergistic Immune Agonists Enables Systemic Codelivery to Tumor Sites and IFNbeta-Driven Antitumor Immunity. Cancer Res, 2019, 79(20): 5394-5406

[81] PanY, YuY, WangX, et al.. Tumor-Associated Macrophages in Tumor Immunity. Front Immunol, 2020, 11: 583084

[82] MehlaK, SinghPK. Metabolic Regulation of Macrophage Polarization in Cancer. Trends Cancer, 2019, 5(12): 822-834

[83] LocatiM, CurtaleG, MantovaniA. Diversity, Mechanisms, and Significance of Macrophage Plasticity. Annu Rev Pathol, 2020, 15: 123-147

[84] YunnaC, MengruH, LeiW, et al.. Macrophage M1/M2 polarization. Eur J Pharmacol, 2020, 877: 173090

[85] NoyR, PollardJW. Tumor-associated macrophages: from mechanisms to therapy. Immunity, 2014, 41(1): 49-61

[86] CassettaL, PollardJW. Tumor-associated macrophages. Curr Biol, 2020, 30(6): R246-R248

[87] ZhangM, HeY, SunX, et al.. A high M1/M2 ratio of tumor-associated macrophages is associated with extended survival in ovarian cancer patients. J Ovarian Res, 2014, 7: 19

[88] MantovaniA, AllavenaP. The interaction of anticancer therapies with tumor-associated macrophages. J Exp Med, 2015, 212(4): 435-445

[89] ZhouJ, TangZ, GaoS, et al.. Tumor-Associated Macrophages: Recent Insights and Therapies. Front Oncol, 2020, 10: 188

[90] LiC, XuX, WeiS, et al.. Tumor-associated macrophages: potential therapeutic strategies and future prospects in cancer. J Immunother Cancer, 2021, 9(1): e001341

[91] ZanganehS, HutterG, SpitlerR, et al.. Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues. Nat Nanotechnol, 2016, 11(11): 986-994

[92] RongL, ZhangY, LiWS, et al.. Iron chelated melaninlike nanoparticles for tumor-associated macrophage repolarization and cancer therapy. Biomaterials, 2019, 225: 119515

[93] ZhangF, ParayathNN, EneCI, et al.. Genetic programming of macrophages to perform anti-tumor functions using targeted mRNA nanocarriers. Nat Commun, 2019, 10(1): 3974

[94] GaoX, LiS, DingF, et al.. A Virus-Mimicking Nucleic Acid Nanogel Reprograms Microglia and Macrophages for Glioblastoma Therapy. Adv Mater, 2021, 33(9): e2006116

[95] RodellCB, ArlauckasSP, CuccareseMF, et al.. TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy. Nat Biomed Eng, 2018, 2(8): 578-588

[96] MajetiR, ChaoMP, AlizadehAA, et al.. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell, 2009, 138(2): 286-299

[97] ChaoMP, AlizadehAA, TangC, et al.. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell, 2010, 142(5): 699-713

[98] WillinghamSB, VolkmerJP, GentlesAJ, et al.. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A, 2012, 109(17): 6662-6667

[99] FengM, JiangW, KimBYS, et al.. Phagocytosis checkpoints as new targets for cancer immunotherapy. Nat Rev Cancer, 2019, 19(10): 568-586

[100] AdvaniR, FlinnI, PopplewellL, et al.. CD47 Blockade by Hu5F9-G4 and Rituximab in Non-Hodgkin’s Lymphoma. N Engl J Med, 2018, 379(18): 1711-1721

[101] RaoL, WuL, LiuZ, et al.. Hybrid cellular membrane nanovesicles amplify macrophage immune responses against cancer recurrence and metastasis. Nat Commun, 2020, 11(1): 4909

[102] RaoL, ZhaoSK, WenC, et al.. Activating Macrophage-Mediated Cancer Immunotherapy by Genetically Edited Nanoparticles. Adv Mater, 2020, 32(47): e2004853

[103] ApostolopoulosV, McKenzieIF. Role of the mannose receptor in the immune response. Curr Mol Med, 2001, 1(4): 469-474

[104] AzadAK, RajaramMV, SchlesingerLS. Exploitation of the Macrophage Mannose Receptor (CD206) in Infectious Disease Diagnostics and Therapeutics. J Cytol Mol Biol, 2014, 1(1): 1000003

[105] KangM, LeeSH, KwonM, et al.. Nanocomplex-Mediated In Vivo Programming to Chimeric Antigen Receptor-M1 Macrophages for Cancer Therapy. Adv Mater, 2021, 33(43): e2103258

[106] ZhengC, WangQ, WangY, et al.. In Situ Modification of the Tumor Cell Surface with Immunomodulating Nanoparticles for Effective Suppression of Tumor Growth in Mice. Adv Mater, 2019, 31(32): e1902542

[107] JiT, LangJ, NingB, et al.. Enhanced Natural Killer Cell Immunotherapy by Rationally Assembling Fc Fragments of Antibodies onto Tumor Membranes. Adv Mater, 2019, 31(6): e1804395

[108] KimKS, HanJH, ParkJH, et al.. Multifunctional nanoparticles for genetic engineering and bioimaging of natural killer (NK) cell therapeutics. Biomaterials, 2019, 221: 119418

[109] BiberG, SabagB, RaiffA, et al.. Modulation of intrinsic inhibitory checkpoints using nano-carriers to unleash NK cell activity. EMBO Mol Med, 2022, 14(1): e14073

[110] GaoS, LiT, GuoY, et al.. Selenium-Containing Nanoparticles Combine the NK Cells Mediated Immunotherapy with Radiotherapy and Chemotherapy. Adv Mater, 2020, 32(12): e1907568

[111] Wei Z, Yi Y, Luo Z, et al. Selenopeptide Nanomedicine Activates Natural Killer Cells for Enhanced Tumor Chemoimmunotherapy. Adv Mater, 2022:e2108167

[112] NakamuraT, SatoT, EndoR, et al.. STING agonist loaded lipid nanoparticles overcome anti-PD-1 resistance in melanoma lung metastasis via NK cell activation. J Immunother Cancer, 2021, 9(7): e002852

[113] VegliaF, SansevieroE, GabrilovichDI. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat Rev Immunol, 2021, 21(8): 485-498

[114] GabrilovichDI. Myeloid-Derived Suppressor Cells. Cancer Immunol Res, 2017, 5(1): 3-8

[115] LedoAM, SassoMS, BronteV, et al.. Co-delivery of RNAi and chemokine by polyarginine nanocapsules enables the modulation of myeloid-derived suppressor cells. J Control Release, 2019, 295: 60-73

[116] DingD, ZhongH, LiangR, et al.. Multifunctional Nanodrug Mediates Synergistic Photodynamic Therapy and MDSCs-Targeting Immunotherapy of Colon Cancer. Adv Sci (Weinh), 2021, 8(14): e2100712

[117] ZhangP, MiskaJ, Lee-ChangC, et al.. Therapeutic targeting of tumor-associated myeloid cells synergizes with radiation therapy for glioblastoma. Proc Natl Acad Sci U S A, 2019, 116(47): 23714-23723

[118] ZhangN, LiuS, ShiS, et al.. Solubilization and delivery of Ursolic-acid for modulating tumor microenvironment and regulatory T cell activities in cancer immunotherapy. J Control Release, 2020, 320: 168-178

[119] OuW, ThapaRK, JiangL, et al.. Regulatory T cell-targeted hybrid nanoparticles combined with immunocheckpoint blockage for cancer immunotherapy. J Control Release, 2018, 281: 84-96