Combating cancer immunotherapy resistance: a nano-medicine perspective

Abstract

Cancer immunotherapy offers renewed hope for treating this disease. However, cancer cells possess inherent mechanisms that enable them to circumvent each stage of the immune cycle, thereby evading anti-cancer immunity and leading to resistance. Various functionalized nanoparticles (NPs), modified with cationic lipids, pH-sensitive compounds, or photosensitizers, exhibit unique physicochemical properties that facilitate the targeted delivery of therapeutic agents to cancer cells or the tumor microenvironment (TME). These NPs are engineered to modify immune activity. The crucial signal transduction pathways and mechanisms by which functionalized NPs counteract immunotherapy resistance are outlined, including enhancing antigen presentation, boosting the activation and infiltration of tumor-specific immune cells, inducing immunogenic cell death, and counteracting immunosuppressive conditions in the TME. Additionally, this review summarizes current clinical trials involving NP-based immunotherapy. Ultimately, it highlights the potential of nanotechnology to advance cancer immunotherapy.

Keywords

Cancer immunotherapy / drug delivery system / drug resistance / nanomedicine

References

[1] Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell. 2017; 168(4): 707–23.

[2] Vesely MD, Zhang T, Chen L. Resistance Mechanisms to Anti-PD Cancer Immunotherapy. Annu Rev Immunol. 2022; 40: 45–74.

[3] Guo X, Guo M, Cai R, Hu M, Rao L, Su W, et al. mRNA compartmentalization via multimodule DNA nanostructure assembly augments the immunogenicity and efficacy of cancer mRNA vaccine. Sci Adv. 2024; 10(47): eadp3680.

[4] Gan J, Lei J, Li Y, Lu M, Yu X, Yu G. Manganese Oxide-Incorporated Hybrid Lipid Nanoparticles Amplify the Potency of mRNA Vaccine via Oxygen Generation and STING Activation. J Am Chem Soc. 2024; 146(47): 32689–700.

[5] Xu B, Lei H, Tong T, Guan Y, Wang Y, Li B, et al. Acidity-Actuated Polymer/Calcium Phosphate Hybrid Nanomotor (PCaPmotor) for Penetrating Drug Delivery and Synergistic Anticancer Immunotherapy. Nano Lett. 2024; 24(35): 10724–33.

[6] Xie P, Rong X, Qin X, Li M, Zuo Y, Liu B, et al. A Highly Potent Os@Au-TPA Coordination Structure-Based Sonosensitizer for Tumor Sono-Immunotherapies. Adv Funct Mater. 2025; 35(2): 2412564.

[7] Yang Y. Cancer immunotherapy: harnessing the immune system to battle cancer. J Clin Invest. 2015; 125(9): 3335–7.

[8] Zhang Y, Zhang Z. The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol Immunol. 2020; 17(8): 807–21.

[9] Chen Daniel S, Mellman I. Oncology Meets Immunology: The Cancer-Immunity Cycle. Immunity. 2013; 39(1): 1–10.

[10] Xu Y, Xiong J, Sun X, Gao H. Targeted nanomedicines remodeling immunosuppressive tumor microenvironment for enhanced cancer immunotherapy. Acta Pharm Sin B. 2022; 12(12): 4327–47.

[11] Sayour EJ, Boczkowski D, Mitchell DA, Nair SK. Cancer mRNA vaccines: clinical advances and future opportunities. Nat Rev Clin Oncol. 2024; 21(7): 489–500.

[12] Yi M, Li T, Niu M, Zhang H, Wu Y, Wu K, et al. Targeting cytokine and chemokine signaling pathways for cancer therapy. Signal Transduct Target Ther. 2024; 9(1): 176.

[13] Dufour JH, Dziejman M, Liu MT, Leung JH, Lane TE, Luster AD. IFN-γ-Inducible Protein 10 (IP-10; CXCL10)-Deficient Mice Reveal a Role for IP-10 in Effector T Cell Generation and Trafficking1. J Immunol. 2002; 168(7): 3195–204.

[14] Datar I, Sanmamed MF, Wang J, Henick BS, Choi J, Badri T, et al. Expression Analysis and Significance of PD-1, LAG-3, and TIM-3 in Human Non–Small Cell Lung Cancer Using Spatially Resolved and Multiparametric Single-Cell Analysis. Clini Cancer Res. 2019; 25(15): 4663–73.

[15] Feng M, Jiang W, Kim BYS, Zhang CC, Fu Y-X, Weissman IL. Phagocytosis checkpoints as new targets for cancer immunotherapy. Nat Rev Cancer. 2019; 19(10): 568–86.

[16] Ahmed A, Tait SWG. Targeting immunogenic cell death in cancer. Mol Oncol. 2020; 14(12): 2994–3006.

[17] Jin Y, Huang Y, Ren H, Huang H, Lai C, Wang W, et al. Nano-enhanced immunotherapy: Targeting the immunosuppressive tumor microenvironment. Biomaterials. 2024; 305: 122463.

[18] Tan M, Cao G, Wang R, Cheng L, Huang W, Yin Y, et al. Metal-ion-chelating phenylalanine nanostructures reverse immune dysfunction and sensitize breast tumour to immune checkpoint blockade. Nat Nanotechnol. 2024; 19(12): 1903–13.

[19] Xia J, Chen X, Dong M, Liu S, Zhang L, Pan J, et al. Antigen self-presenting dendrosomes swallowing nanovaccines boost antigens and STING agonists codelivery for cancer immunotherapy. Biomaterials. 2025; 316: 122998.

[20] Khan I, Saeed K, Khan I. Nanoparticles: Properties, applications and toxicities. Arabian J Chem. 2019; 12(7): 908–31.

[21] Carvalho MR, Barata D, Teixeira LM, Giselbrecht S, Reis RL, Oliveira JM, et al. Colorectal tumor-on-a-chip system: A 3D tool for precision onco-nanomedicine. Sci Adv. 2019; 5(5): eaaw1317.

[22] Liu X-Y, Wang J-Q, Ashby CR, Zeng L, Fan Y-F, Chen Z-S. Gold nanoparticles: synthesis, physiochemical properties and therapeutic applications in cancer. Drug Discov Today. 2021; 26(5): 1284–92.

[23] Ajinkya N, Yu X, Kaithal P, Luo H, Somani P, Ramakrishna S. Magnetic Iron Oxide Nanoparticle (IONP) Synthesis to Applications: Present and Future. Materials (Basel). 2020; 13(20): 4644.

[24] Hou L, Tian C, Yan Y, Zhang L, Zhang H, Zhang Z. Manganese-Based Nanoactivator Optimizes Cancer Immunotherapy via Enhancing Innate Immunity. ACS Nano. 2020; 14(4): 3927–40.

[25] Yang H, Liu H-S, Hou W, Gao J-X, Duan Y, Wei D, et al. An NIR-responsive mesoporous silica nanosystem for synergetic photothermal-immunoenhancement therapy of hepatocellular carcinoma. J Mater Chem B. 2020; 8(2): 251–9.

[26] Zhou F, Wang M, Luo T, Qu J, Chen WR. Photo-activated chemo-immunotherapy for metastatic cancer using a synergistic graphene nanosystem. Biomaterials. 2021; 265: 120421.

[27] Liu Q, Fan T, Zheng Y, Yang S-L, Yu Z, Duo Y, et al. Immunogenic exosome-encapsulated black phosphorus nanoparticles as an effective anticancer photo-nanovaccine. Nanoscale. 2020; 12(38): 19939–52.

[28] Butreddy A, Gaddam RP, Kommineni N, Dudhipala N, Voshavar C. PLGA/PLA-Based Long-Acting Injectable Depot Microspheres in Clinical Use: Production and Characterization Overview for Protein/Peptide Delivery. Int J Mol Sci. 2021; 22(16): 8884.

[29] Zhao D, Zhu T, Li J, Cui L, Zhang Z, Zhuang X, et al. Poly(lactic-co-glycolic acid)-based composite bone-substitute materials. Bioact Mater. 2021; 6(2): 346–60.

[30] Fumoto S, Nishida K. Co-delivery Systems of Multiple Drugs Using Nanotechnology for Future Cancer Therapy. Chem Pharm Bull. 2020; 68(7): 603–12.

[31] Wang J, Zhu M, Nie G. Biomembrane-based nanostructures for cancer targeting and therapy: From synthetic liposomes to natural biomembranes and membrane-vesicles. Adv Drug Deliv Rev. 2021; 178: 113974.

[32] Yuan Z, Gottsacker C, He X, Waterkotte T, Park YC. Repetitive drug delivery using Light-Activated liposomes for potential antimicrobial therapies. Adv Drug Deliv Rev. 2022; 187: 114395.

[33] Kotta S, Aldawsari HM, Badr-Eldin SM, Nair AB, Yt K. Progress in Polymeric Micelles for Drug Delivery Applications. Pharmaceutics. 2022; 14(8): 1636.

[34] Blaya-Cánovas JL, Griñán-Lisón C, Blancas I, Marchal JA, Ramírez-Tortosa C, López-Tejada A, et al. Autologous patient-derived exhausted nano T-cells exploit tumor immune evasion to engage an effective cancer therapy. Mol Cancer. 2024; 23(1): 83.

[35] Xu C, Hong H, Lee Y, Park KS, Sun M, Wang T, et al. Efficient Lymph Node-Targeted Delivery of Personalized Cancer Vaccines with Reactive Oxygen Species-Inducing Reduced Graphene Oxide Nanosheets. ACS Nano. 2020; 14(10): 13268–78.

[36] Mei Y, Solovev AA, Sanchez S, Schmidt OG. Rolled-up nanotech on polymers: from basic perception to self-propelled catalytic microengines. Chem Soc Rev. 2011; 40(5): 2109–19.

[37] Shao S, Zhou Q, Si J, Tang J, Liu X, Wang M, et al. A non-cytotoxic dendrimer with innate and potent anticancer and anti-metastatic activities. Nat Biomed Eng. 2017; 1(9): 745–57.

[38] Qu L, Cui G, Sun Y, Ye R, Sun Y, Meng F, et al. A Biomimetic Autophagosomes-Based Nanovaccine Boosts Anticancer Immunity. Adv Mater. 2024; 36(40): 2409590.

[39] Lan J, Zeng R, Li Z, Yang X, Liu L, Chen L, et al. Biomimetic Nanomodulators With Synergism of Photothermal Therapy and Vessel Normalization for Boosting Potent Anticancer Immunity. Adv Mater. 2024; 36(40): 2408511.

[40] Moon S, Jung M, Go S, Hong J, Sohn HS, Kim C, et al. Engineered Nanoparticles for Enhanced Antitumoral Synergy Between Macrophages and T Cells in the Tumor Microenvironment. Adv Mater. 2024; 36(44): 2410340.

[41] Wu Y, Liu B, Yan Y, Gong C, Wang K, Liu N, et al. Thermal-responsive activation of engineered bacteria to trigger antitumor immunity post microwave ablation therapy. Nat Commun. 2024; 15(1): 10503.

[42] Dai X, Liu Z, Zhao X, Guo K, Ding X, Xu F-J, et al. NIR-II-Responsive Hybrid System Achieves Cascade-Augmented Antitumor Immunity via Genetic Engineering of Both Bacteria and Tumor Cells. Adv Mater. 2024; 36(40): 2407927.

[43] Wang J, Wang X, Xiong Q, Gao S, Wang S, Zhu S, et al. A dual-STING-activating nanosystem expands cancer immunotherapeutic temporal window. Cell Rep Med. 2024; 5(11): 101797.

[44] Wang R, Li H, He S, Feng Y, Liu C, Hao K, et al. Spatiotemporal Nano-Regulator Unleashes Anti-Tumor Immunity by Overcoming Dendritic Cell Tolerance and T Cell Exhaustion in Tumor-Draining Lymph Nodes. Adv Mater. n/a(n/a): 2412141.

[45] Lang F, Schrörs B, Löwer M, Türeci Ö, Sahin U. Identification of neoantigens for individualized therapeutic cancer vaccines. Nat Rev Drug Discov. 2022; 21(4): 261–82.

[46] Hamouda AEI, Filtjens J, Brabants E, Kancheva D, Debraekeleer A, Brughmans J, et al. Intratumoral delivery of lipid nanoparticle-formulated mRNA encoding IL-21, IL-7, and 4-1BBL induces systemic anti-tumor immunity. Nat Commun. 2024; 15(1): 10635.

[47] Shi K, Fu W, Farhadi Sabet Z, Ye J, Liang S, Liu T, et al. Hydrogel-Mediated Jamming of Exosome Communications That Counter Tumor Adaption in the Tumor Immune Microenvironment. ACS Nano. 2024; 18(48): 33042–57.

[48] Yang W, Feng Z, Lai X, Li J, Cao Z, Jiang F, et al. Calcium nanoparticles target and activate T cells to enhance anti-tumor function. Nat Commun. 2024; 15(1): 10095.

[49] Dong L, Zhu Y, Zhang H, Gao L, Zhang Z, Xu X, et al. Open-Source Throttling of CD8+ T Cells in Brain with Low-Intensity Focused Ultrasound-Guided Sequential Delivery of CXCL10, IL-2, and aPD-L1 for Glioblastoma Immunotherapy. Adv Mater. 2024; 36(44): 2407235.

[50] Qin S, Liu Y, He G, Yang J, Zeng F, Lu Q, et al. Spatiotemporal Delivery of Dual Nanobodies by Engineered Probiotics to Reverse Tumor Immunosuppression via Targeting Tumor-Derived Exosomes. ACS Nano. 2024; 18(39): 26858–71.

[51] Wang Y, Chen P, Wen H, Gui Y, Yan D, Huang D, et al. Advanced Nanoplatform Mediated by CRISPR-Cas9 and Aggregation-Induced Emission Photosensitizers to Boost Cancer Theranostics. ACS Nano. 2024; 18(48): 33168–80.

[52] Yue H, Li Y, Yang T, Wang Y, Bao Q, Xu Y, et al. Filamentous phages as tumour-targeting immunotherapeutic bionanofibres. Nat Nanotechnol. 2025; 20(1): 167–76.

[53] Ding X, Zhang J, Wan S, Wang X, Wang Z, Pu K, et al. Non-discriminating engineered masking of immuno-evasive ligands on tumour-derived extracellular vesicles enhances tumour vaccination outcomes. Nat Nanotechnol. 2025; 20(1): 156–66.

[54] Xie Y, Jiang T, Li L, Wang M, Chen S, Zhao G, et al. Fucoidan-Modified Au Nanocups With Tumor Targeting Inhibits CD24-Mediated Immune Escape and Epithelial Mesenchymal Transition Through Precise Controlled Release of Anti-CD24 Antibodies. Adv Funct Mater. n/a(n/a): 2415120.

[55] Wan X, Zhang Y, Wan Y, Xiong M, Xie A, Liang Y, et al. A Multifunctional Biomimetic Nanoplatform for Dual Tumor Targeting-Assisted Multimodal Therapy of Colon Cancer. ACS Nano. 2024; 18(39): 26666–89.

[56] Xiong M, Zhang Y, Zhang H, Shao Q, Hu Q, Ma J, et al. A Tumor Environment-Activated Photosensitized Biomimetic Nanoplatform for Precise Photodynamic Immunotherapy of Colon Cancer. Adv Sci. 2024; 11(28): 2402465.

[57] He C, Zhu N, Chen Y, Zheng Y, Chen S, Wu Z, et al. Reshaping Immunosuppressive Tumor Microenvironment Using Ferroptosis/Cuproptosis Nanosensitizers for Enhanced Radioimmunotherapy. Adv Funct Mater. 2024; 34(51): 2409966.

[58] Chen X, Zhang X, Liu Y, Chen Y, Zhao Y. Upconversion Nanoparticle-Anchored Metal–Organic Framework Nanostructures for Remote-Controlled Cancer Optogenetic Therapy. J Am Chem Soc 2024; 146(50): 34475–90.

[59] Liu Y, Zhao H, Wang S, Niu R, Bi S, Han W-K, et al. A Wurster-Type Covalent Organic Framework with Internal Electron Transfer-Enhanced Catalytic Capacity for Tumor Therapy. J Am Chem Soc. 2024; 146(40): 27345–61.

[60] Zu H, Wu Y, Meng H, Cheng X, Wang Y, Zhang LW, et al. Tumor Metabolism Aiming Cu2–xS Nanoagents Mediate Photothermal-Derived Cuproptosis and Immune Activation. ACS Nano. 2024; 18(35): 23941–57.

[61] Cheng Y, Zhong W, Chen Y, Tan BSN, Zhao Y, Guo J, et al. Bimetal-Biligand Frameworks for Spatiotemporal Nitric Oxide-Enhanced Sono-Immunotherapy. Adv Mater. 2024; 36(45): 2408242.

[62] Jin X-K, Zhang S-K, Zhang S-M, Liang J-L, Yan X, Lin Y-T, et al. Disrupting Intracellular Homeostasis by Copper-Based Nanoinducer with Multiple Enzyme-Mimicking Activities to Induce Disulfidptosis-Enhanced Pyroptosis for Tumor Immunotherapy. Adv Mater. 2025; 37(1): 2410957.

[63] Han C, Xiao S, Xing Z, Xu X, Wang M, Han X, et al. NADPH Oxidases-Inspired Reactive Oxygen Biocatalysts with Electron-Rich Pt Sites to Potently Amplify Immune Checkpoint Blockade Therapy. Adv Mater. n/a(n/a): 2407644.

[64] Ren L, Wan J, Li X, Yao J, Ma Y, Meng F, et al. Mitochondrial rewiring with small-molecule drug-free nanoassemblies unleashes anticancer immunity. Nat Commun. 2024; 15(1): 7664.

[65] Chen J, Hu S, Sun M, Shi J, Zhang H, Yu H, et al. Recent advances and clinical translation of liposomal delivery systems in cancer therapy. Eur J Pharm Sci. 2024; 193: 106688.

[66] Li X, Gao M-L, Wang S-S, Hu Y, Hou D, Liu P-N, et al. Nanoscale covalent organic framework-mediated pyroelectrocatalytic activation of immunogenic cell death for potent immunotherapy. Sci Adv. 2024; 10(48): eadr5145.

[67] Yang M, Li J, Gu P, Fan X. The application of nanoparticles in cancer immunotherapy: Targeting tumor microenvironment. Bioact Mater. 2021; 6(7): 1973–87.

[68] Pan Y, Liu L, Mou X, Cai Y. Nanomedicine Strategies in Conquering and Utilizing the Cancer Hypoxia Environment. ACS Nano. 2023; 17(21): 20875–924.

[69] Chen Q, Liu G, Liu S, Su H, Wang Y, Li J, et al. Remodeling the Tumor Microenvironment with Emerging Nanotherapeutics. Trends Pharmacol Sci. 2018; 39(1): 59–74.

[70] Wu J, Wang X, Chen L, Wang J, Zhang J, Tang J, et al. Oxygen microcapsules improve immune checkpoint blockade by ameliorating hypoxia condition in pancreatic ductal adenocarcinoma. Bioact Mater. 2023; 20: 259–70.

[71] Yuan C-S, Teng Z, Yang S, He Z, Meng L-Y, Chen X-G, et al. Reshaping hypoxia and silencing CD73 via biomimetic gelatin nanotherapeutics to boost immunotherapy. J Control Release. 2022; 351: 255–71.

[72] Zhang Y, Liao Y, Tang Q, Lin J, Huang P. Biomimetic Nanoemulsion for Synergistic Photodynamic-Immunotherapy Against Hypoxic Breast Tumor. Angew Chem Int Ed. 2021; 60(19): 10647–53.

[73] Gowd V, Ahmad A, Tarique M, Suhail M, Zughaibi TA, Tabrez S, et al. Advancement of cancer immunotherapy using nanoparticles-based nanomedicine. Semin Cancer Biol. 2022; 86(Pt 2): 624–44.

[74] Li Z, Li X, Lu Y, Zhu X, Zheng W, Chen K, et al. Novel Photo-STING Agonists Delivered by Erythrocyte Efferocytosis-Mimicking Pattern to Repolarize Tumor-Associated Macrophages for Boosting Anticancer Immunotherapy. Adv Mater. 2024; 36(47): 2410937.

[75] Liu J, Zhao H, Gao T, Huang X, Liu S, Liu M, et al. Glypican-3-targeted macrophages delivering drug-loaded exosomes offer efficient cytotherapy in mouse models of solid tumours. Nat Commun. 2024; 15(1): 8203.

[76] Zanganeh S, Hutter G, Spitler R, Lenkov O, Mahmoudi M, Shaw A, et al. Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues. Nat Nanotechnol. 2016; 11(11): 986–94.

[77] Sang Y, Deng Q, Cao F, Liu Z, You Y, Liu H, et al. Remodeling Macrophages by an Iron Nanotrap for Tumor Growth Suppression. ACS Nano. 2021; 15(12): 19298–309.

[78] Zhang Y, Chen Y, Li J, Zhu X, Liu Y, Wang X, et al. Development of Toll-like Receptor Agonist-Loaded Nanoparticles as Precision Immunotherapy for Reprogramming Tumor-Associated Macrophages. ACS Appl Mater Interfaces. 2021; 13(21): 24442–52.

[79] Zhao H, Zhao B, Wu L, Xiao H, Ding K, Zheng C, et al. Amplified Cancer Immunotherapy of a Surface-Engineered Antigenic Microparticle Vaccine by Synergistically Modulating Tumor Microenvironment. ACS Nano. 2019; 13(11): 12553–66.

[80] Qiu Q, Li C, Song Y, Shi T, Luo X, Zhang H, et al. Targeted delivery of ibrutinib to tumor-associated macrophages by sialic acid-stearic acid conjugate modified nanocomplexes for cancer immunotherapy. Acta Biomater. 2019; 92: 184–95.

[81] Chen C, Song M, Du Y, Yu Y, Li C, Han Y, et al. Tumor-Associated-Macrophage-Membrane-Coated Nanoparticles for Improved Photodynamic Immunotherapy. Nano Lett. 2021; 21(13): 5522–31.

[82] Tie Y, Zheng H, He Z, Yang J, Shao B, Liu L, et al. Targeting folate receptor β positive tumor-associated macrophages in lung cancer with a folate-modified liposomal complex. Signal Transduct Target Ther. 2020; 5(1): 6.

[83] Xu M, Hu Y, Wu J, Liu J, Pu K. Sonodynamic Nano-LYTACs Reverse Tumor Immunosuppressive Microenvironment for Cancer Immunotherapy. J Am Chem Soc. 2024; 146(50): 34669–80.

[84] Herbst RS, Soria J-C, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014; 515(7528): 563–7.

[85] Kunz-Schughart LA, Knuechel R. Tumor-associated fibroblasts (part II): Functional impact on tumor tissue. Histol Histopathol. 2002; 17(2): 623–37.

[86] Alili L, Sack M, Karakoti AS, Teuber S, Puschmann K, Hirst SM, et al. Combined cytotoxic and anti-invasive properties of redox-active nanoparticles in tumor-stroma interactions. Biomaterials. 2011; 32(11): 2918–29.

[87] Miao L, Wang Y, Lin CM, Xiong Y, Chen N, Zhang L, et al. Nanoparticle modulation of the tumor microenvironment enhances therapeutic efficacy of cisplatin. J Control Release. 2015; 217: 27–41.

[88] Chen B, Wang Z, Sun J, Song Q, He B, Zhang H, et al. A tenascin C targeted nanoliposome with navitoclax for specifically eradicating of cancer-associated fibroblasts. Nanomedicine. 2016; 12(1): 131–41.

[89] Senthebane DA, Jonker T, Rowe A, Thomford NE, Munro D, Dandara C, et al. The Role of Tumor Microenvironment in Chemoresistance: 3D Extracellular Matrices as Accomplices. Int J Mol Sci. 2018; 19(10): 2861.

[90] Klemm F, Joyce JA. Microenvironmental regulation of therapeutic response in cancer. Trends Cell Biol. 2015; 25(4): 198–213.

[91] Correia AL, Bissell MJ. The tumor microenvironment is a dominant force in multidrug resistance. Drug Resist Updat. 2012; 15(1-2): 39–49.

[92] Maeda H, Khatami M. Analyses of repeated failures in cancer therapy for solid tumors: poor tumor-selective drug delivery, low therapeutic efficacy and unsustainable costs. Clin Transl Med. 2018; 7(1): 11.

[93] Jo Y, Choi N, Kim K, Koo H-J, Choi J, Kim HN. Chemoresistance of Cancer Cells: Requirements of Tumor Microenvironment-mimicking In Vitro Models in Anti-Cancer Drug Development. Theranostics. 2018; 8(19): 5259–75.

[94] Matsunuma S, Handa S, Kamei D, Yamamoto H, Okuyama K, Kato Y. Oxaliplatin induces prostaglandin E2 release in vascular endothelial cells. Cancer Chemother Pharmacol. 2019; 84(2): 345–50.

[95] Gamradt P, De La Fouchardière C, Hennino A. Stromal Protein-Mediated Immune Regulation in Digestive Cancers. Cancers. 2021; 13(1): 146.

[96] Gordon-Weeks A, Yuzhalin AE. Cancer Extracellular Matrix Proteins Regulate Tumour Immunity. Cancers(Basel). 2020; 12(11): 3331.

[97] Wight TN, Kang I, Evanko SP, Harten IA, Chang MY, Pearce OMT, et al. Versican-A Critical Extracellular Matrix Regulator of Immunity and Inflammation. Front Immunol. 2020; 11: 512.

[98] Zhan M, Yu X, Zhao W, Peng Y, Peng S, Li J, et al. Extracellular matrix-degrading STING nanoagonists for mild NIR-II photothermal-augmented chemodynamic-immunotherapy. J Nanobiotechnology. 2022; 20(1): 23.

[99] Xiao Z, Tan Y, Cai Y, Huang J, Wang X, Li B, et al. Nanodrug removes physical barrier to promote T-cell infiltration for enhanced cancer immunotherapy. J Control Release. 2023; 356: 360–72.

[100] Xu S, Xu H, Wang W, Li S, Li H, Li T, et al. The role of collagen in cancer: from bench to bedside. J Transl Med. 2019; 17(1): 309.

[101] Wang Y, Gao Z, Du X, Chen S, Zhang W, Wang J, et al. Co-inhibition of the TGF-β pathway and the PD-L1 checkpoint by pH-responsive clustered nanoparticles for pancreatic cancer microenvironment regulation and anti-tumor immunotherapy. Biomater Sci. 2020; 8(18): 5121–32.

[102] Galmarini FC, Galmarini CM, Sarchi MI, Abulafia J, Galmarini D. Heterogeneous distribution of tumor blood supply affects the response to chemotherapy in patients with head and neck cancer. Microcirculation (New York, NY: 1994). 2000; 7(6 Pt 1): 405–10.

[103] Benjamin LE, Golijanin D, Itin A, Pode D, Keshet E. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Invest. 1999; 103(2): 159–65.

[104] Trédan O, Galmarini CM, Patel K, Tannock IF. Drug resistance and the solid tumor microenvironment. J Nat Cancer Inst. 2007; 99(19): 1441–54.

[105] Heldin C-H, Rubin K, Pietras K, Ostman A. High interstitial fluid pressure - an obstacle in cancer therapy. Nat Rev Cancer. 2004; 4(10): 806–13.

[106] Padera TP, Stoll BR, Tooredman JB, Capen D, di Tomaso E, Jain RK. Pathology: cancer cells compress intratumour vessels. Nature. 2004; 427(6976): 695.

[107] Tatum JL, Kelloff GJ, Gillies RJ, Arbeit JM, Brown JM, Chao KSC, et al. Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy. Int J Radiat Biol. 2006; 82(10): 699–757.

[108] Du S, Xiong H, Xu C, Lu Y, Yao J. Attempts to strengthen and simplify the tumor vascular normalization strategy using tumor vessel normalization promoting nanomedicines. Biomater Sci. 2019; 7(3): 1147–60.

[109] Li W, Zhao X, Du B, Li X, Liu S, Yang X-Y, et al. Gold Nanoparticle-Mediated Targeted Delivery of Recombinant Human Endostatin Normalizes Tumour Vasculature and Improves Cancer Therapy. Sci Rep. 2016; 6: 30619.

[110] Gao W, Li S, Liu Z, Sun Y, Cao W, Tong L, et al. Targeting and destroying tumor vasculature with a near-infrared laser-activated “nanobomb” for efficient tumor ablation. Biomaterials. 2017; 139: 1–11.

[111] Satterlee AB, Rojas JD, Dayton PA, Huang L. Enhancing Nanoparticle Accumulation and Retention in Desmoplastic Tumors via Vascular Disruption for Internal Radiation Therapy. Theranostics. 2017; 7(2): 253–69.

[112] Zhou P, Qin J, Zhou C, Wan G, Liu Y, Zhang M, et al. Multifunctional nanoparticles based on a polymeric copper chelator for combination treatment of metastatic breast cancer. Biomaterials. 2019; 195: 86–99.

[113] Shen R, Peng L, Zhou W, Wang D, Jiang Q, Ji J, et al. Anti-angiogenic nano-delivery system promotes tumor vascular normalizing and micro-environment reprogramming in solid tumor. J Control Release. 2022; 349: 550–64.

[114] Kim S-S, Harford JB, Moghe M, Rait A, Chang EH. Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor. Oncoimmunology. 2018; 7(10): e1484982.

[115] Allen SD, Liu X, Jiang J, Liao Y-P, Chang CH, Nel AE, et al. Immune checkpoint inhibition in syngeneic mouse cancer models by a silicasome nanocarrier delivering a GSK3 inhibitor. Biomaterials. 2021; 269: 120635.

[116] Hsieh C-H, Hsieh H-C, Shih F-S, Wang P-W, Yang L-X, Shieh D-B, et al. An innovative NRF2 nano-modulator induces lung cancer ferroptosis and elicits an immunostimulatory tumor microenvironment. Theranostics. 2021; 11(14): 7072–91.

[117] Song Z, Wang X, Chen F, Chen Q, Liu W, Yang X, et al. LncRNA MALAT1 regulates METTL3-mediated PD-L1 expression and immune infiltrates in pancreatic cancer. Front Oncol. 2022; 12: 1004212.

[118] He W, Zhang Z, Yang W, Zheng X, You W, Yao Y, et al. Turing milk into pro-apoptotic oral nanotherapeutic: De novo bionic chiral-peptide supramolecule for cancer targeted and immunological therapy. Theranostics. 2022; 12(5): 2322–34.

[119] Meng X, Wang J, Zhou J, Tian Q, Qie B, Zhou G, et al. Tumor cell membrane-based peptide delivery system targeting the tumor microenvironment for cancer immunotherapy and diagnosis. Acta Biomater. 2021; 127: 266–75.

[120] Bonvalot S, Rutkowski PL, Thariat J, Carrère S, Ducassou A, Sunyach M-P, et al. NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): a multicentre, phase 2-3, randomised, controlled trial. Lancet Oncol. 2019; 20(8): 1148–59.

[121] Hu Y, Paris S, Barsoumian H, Abana CO, He K, Sezen D, et al. A radioenhancing nanoparticle mediated immunoradiation improves survival and generates long-term antitumor immune memory in an anti-PD1-resistant murine lung cancer model. J Nanobiotechnology. 2021; 19(1): 416.

[122] Xu H-Z, Li T-F, Wang C, Ma Y, Liu Y, Zheng M-Y, et al. Synergy of nanodiamond-doxorubicin conjugates and PD-L1 blockade effectively turns tumor-associated macrophages against tumor cells. J Nanobiotechnology. 2021; 19(1): 268.

[123] Cai S, Chen Z, Wang Y, Wang M, Wu J, Tong Y, et al. Reducing PD-L1 expression with a self-assembled nanodrug: an alternative to PD-L1 antibody for enhanced chemo-immunotherapy. Theranostics. 2021; 11(4): 1970–81.

[124] Su W-P, Chang L-C, Song W-H, Yang L-X, Wang L-C, Chia Z-C, et al. Polyaniline-Based Glyco-Condensation on Au Nanoparticles Enhances Immunotherapy in Lung Cancer. ACS Appl Mater Interfaces. 2022; 14(21): 24144–59.

[125] Nakamura T, Sato T, Endo R, Sasaki S, Takahashi N, Sato Y, 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.

[126] Tourneau CL, Calugaru V, Takacsi-Nagy Z, Liem X, Papai Z, Fijuth J, et al. Phase I study of functionalized hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy in cisplatin-ineligible locally advanced HNSCC patients. J Clin Oncol. 2021; 39(15_suppl): 6051.

[127] Beg MS, Brenner AJ, Sachdev J, Borad M, Kang Y-K, Stoudemire J, et al. Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors. Invest New Drugs. 2017; 35(2): 180–8.

[128] Burris HA, Patel MR, Cho DC, Clarke JM, Gutierrez M, Zaks TZ, et al. A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors. J Clin Oncol. 2019; 37(15_suppl): 2523.

[129] Kranz LM, Diken M, Haas H, Kreiter S, Loquai C, Reuter KC, et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature. 2016; 534(7607): 396–401.

RIGHTS & PERMISSIONS

2025 The Author(s). Cancer Communications published by John Wiley & Sons Australia, Ltd on behalf of Sun Yat-sen University Cancer Center.