Sensitize Tumor Immunotherapy: Immunogenic Cell Death Inducing Nanosystems

Abstract

Low immunogenicity of tumors poses a challenge in the development of effective tumor immunotherapy. However, emerging evidence suggests that certain therapeutic approaches, such as chemotherapy, radiotherapy, and phototherapy, can induce varying degrees of immunogenic cell death (ICD). This ICD phenomenon leads to the release of tumor antigens and the maturation of dendritic cells (DCs), thereby enhancing tumor immunogenicity and promoting immune responses. However, the use of a single conventional ICD inducer often fails to achieve in situ tumor ablation and establish long-term anti-tumor immune responses. Furthermore, the induction of ICD induction varies among different approaches, and the distribution of the therapeutic agent within the body influences the level of ICD and the occurrence of toxic side effects. To address these challenges and further boost tumor immunity, researchers have explored nanosystems as inducers of ICD in combination with tumor immunotherapy. This review examines the mechanisms of ICD and different induction methods, with a specific focus on the relationship between ICD and tumor immunity. The aim is to explore the research advancements utilizing various nanomaterials to enhance the body's anti-tumor effects by inducing ICD. This paper aims to contribute to the development and clinical application of nanomaterial-based ICD inducers in the field of cancer immunotherapy by providing important theoretical guidance and practical references.

Keywords: DAMPs; ICD; immunogenicity; nanosystems; tumor immunotherapy.

Figure 1

Antitumor immunity elicited by ICD inducers and pathways involved in the endoplasmic reticulum stress response triggered. Created with BioRender.com.

Figure 2

Overview of immunogenic cell death inducers. Created with BioRender.com.

Figure 3

Nanomedicine design for restoring or enhancing the effects of immunogenic cell death. Created with BioRender.com.

Figure 4

(A) aCD47-DMSN was constructed by the loading of DOX within the mesoporous cavity while adsorbing aCD47 on the surface. (B) Mechanism of action of aCD47-DMSN. (C) Average tumor growth curves after the treatments (n = 5, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001). (D). Level of CALR exposure a) and BMDMs phagocytosis b) under basal condition or aCD47DMSN treatment. c) The correlation between the fold of CALR expression and phagocytosis enhancement after aCD47-DMSN treatment. Reprinted with the permission from Luo JQ, Liu R, Chen FM, et al. Nanoparticle-Mediated CD47-SIRPα blockade and calreticulin exposure for improved cancer chemo-immunotherapy. ACS Nano. 2023;17(10):8966–8979. Copyright © 2023 American Chemical Society.

Figure 5

(A) Schematic drawing showing the fabrication process of UCNP/ICG/RB-mal. (B) Schematic illustration of both fabrication and mechanism of near-infrared (NIR)-triggered antigen-capturing nanoplatform for synergistic photo-immunotherapy. (C) a) The zeta potential of UCNP/ICG/RB-mal or UCNP/ICG/RB-PEG before and after antigen capture (n=4, ***p < 0.001); b) Quantification of protein captured by nanoparticles (n=4, ***p < 0.001). (D) Average tumor-growth curves of different treatment groups of mice with orthotopic 4T1 tumors (n = 6, **p < 0.01 vs PBS group). Reprinted from Wang M, Song J, Zhou F, et al. NIR‐triggered phototherapy and immunotherapy via an antigen‐capturing nanoplatform for metastatic cancer treatment. Adv Sci. 2019;6(10):1802157. © 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figure 6

(A) LDHs-cGAMP adsorbed TAAs released by RFA-induced tumour cell death, which was internalised by the cells and activated through the cGAS-STING pathway. Meanwhile, the formed nanovaccine stimulates APCs and promotes an immune response. (B) Nanovaccine could enhance infiltration of immune cells into tumors (n=8, *p < 0.05; **p < 0.01; ****p < 0.0001). (C) a) Representative HE staining of lung metastases and b) the corresponding quantitative analysis results (n=4, ****p < 0.0001). (D) The results of lung metastases observed by SFM (green light represents metastases). Reprinted with the permission from Tian Z, Hu Q, Sun Z, et al. A booster for radiofrequency ablation: advanced adjuvant therapy via in situ nanovaccine synergized with anti-programmed death ligand 1 immunotherapy for systemically constraining hepatocellular carcinoma. ACS Nano. 2023;17(19):19441–19458. Copyright ©2023 American Chemical Society.

Figure 7

(A) Preparation of liposomes using a “self-assembly” mechanism in a microfluidic device with a focusing pipeline. (B). Par-ICG-Lipo colocalized almost completely with the ER (n=3, **p < 0.01). Scale bar: 20 μm. (C). a) Par-ICG-Lipo-mediated PDT significantly induces CRT exposure (ecto-CRT). b) Quantitative analysis of CRT exposure in B16 cells (n=3, ***p < 0.001). Scale bar: 100 μm. Reprinted with the permission from Liu X, Liu Y, Li X, et al. ER-Targeting PDT converts tumors into in situ therapeutic tumor vaccines. ACS Nano. 2022;16(6):9240–9253. Copyright ©2022 American Chemical Society.

Figure 8

(A) Construction of Au/Toy@G3 NGs. (B) Au/Toy@G3 NGs for UTMD-enhanced chemoimmunotherapy and CT imaging of pancreatic tumor in combination with anti-PD-L1-mediated ICB. (C) The content of ATP and HMGB-1 secreted in the culture medium of cells treated by the Au/Toy@G3 NGs + UTMD reaches the highest level among all groups, suggesting the enhanced ICD effect through UTMD-facilitated improved chemotherapy of the hybrid NGs (n=3, *p < 0.05, **p < 0.01, and ***p < 0.001). (D) Au NPs could efficiently convert TAMs from M2 to M1-type. Scale bar: 100 μm. (E) Au/Toy@G3 NGs effectively increased the proportion of tumour-infiltrating CTLs, including CD4, CD8 T cells and Tregs (n=3, *p < 0.05, **p < 0.01, and ***p < 0.001). Reprinted from Zhang G, Zhan M, Zhang C, et al. Redox-responsive dendrimer nanogels enable ultrasound-enhanced chemoimmunotherapy of pancreatic cancer via endoplasmic reticulum stress amplification and macrophage polarization. Adv. Sci. 2023;10(24):2301759. © 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.

Figure 9

(A) Schematic illustration of the HCJSP prodrug nanoparticle prepared via the host–guest interaction between HA-CD and AD-SS-JQ1 and AD-SS-PPa. (B) BRD4i JQ1 can relieve PDT-promoted glycolysis and immunosuppressive tumor microenvironment by impeding the transcription of c-Myc and the downstream genes of the c-Myc pathway, including HK-2 and LDHA. Meanwhile, JQ1 can specifically downregulate IFN-γ-inducible PD-L1 expression on the surface of the tumor cells for combating PDT-inducible adaptive immune evasion. (C) Membrane exposure of CRT and extracellular efflux of HMGB1 as well-known hallmarks of ICD were determined in Panc02 cells in vitro. Scale bar: 50 μm. (D) Biodistribution and antitumor effect of the prodrug nanoparticles in vivo (n=3, *p < 0.05, **p < 0.01, and ***p < 0.001). Reprinted from Sun F, Zhu Q, Li T, et al. Regulating glucose metabolism with prodrug nanoparticles for promoting photoimmunotherapy of pancreatic cancer. Adv Sci. 2021;8(4):2002746. © 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.

Figure 10

(A) Schematic illustration of the preparation of nanoscale coordination polymers H@Gd-NCPs. (B) The mechanism of H@Gd-NCPs for radiosensitization via amplifying intracellular oxidative stress to potentiate checkpoint blockade immunotherapies. (C) Gd in a free state or nanoparticles could enhance X-ray absorption and energy deposition to promote •OH generation (n = 3, **p = 0.0049). (D) H@Gd-NCPs could dramatically decrease the intracellular GSH/GSSG ratio in CT26 colorectal tumor cells ((n = 3, ***p = 0.0001). (E) Amplification of oxidative stress could induce potent immunogenicity (exposure of CRT, the release of HMGB1 and ATP) (n=3, *p < 0.05, **p < 0.01, and ***p < 0.001). Reprinted from Huang Z, Wang Y, Yao D, Wu J, Hu Y, Yuan A. Nanoscale coordination polymers induce immunogenic cell death by amplifying radiation therapy mediated oxidative stress. Nat Commun. 2021;12(1):145. Creative Commons.