1 Introduction
2 What happened at tumor site receiving n-HT treatment modality from the immunological perspective?
Tab.1 Representative examples of NP-mediated HT effect on immunotherapy |
HT type | Design of NP | Animal model | Administration route | Major immunological endpoints | Ref. |
---|---|---|---|---|---|
NIR PTT | Chitosan-coated hollow CuS NPs with immunoadjuvants oligodeoxynucleotides containing the cytosine-guanine (CpG) motifs | EMT6 breast cancer | i.t. (intratumorally injection) | The HCuSNPs-CpG-mediated photothermal immunotherapy elicits more effective systemic immune responses than immunotherapy or PTT alone, resulting in combined anticancer effects against primary treated as well as distant untreated tumors | [29] |
NIR PTT | PEGylated SWNTs | 4T1 breast cancer | i.t. | The PEGylated SWNTs mediated photothermal tumor destruction could release tumor-associated antigens and act as an immunological adjuvant to greatly promote maturation of DCs and production of anti-tumor cytokines. The combination of SWNT-based PTT with antiCTLA-4 therapy could modulate the adaptive immune responses especially cellular immunity for the treatment of metastatic cancer | [30] |
NIR PTT | PEG and polyethylenimine (PEI) dual-polymer-functionalized GO (GO-PEG-PEI) carrying CpG | CT26 colon cancer | i.t. | The GO-PEG-PEI mediated photothermal effect enhanced immunostimulation responses of CpG, owing to the photothermally induced local heating that accelerated intracellular trafficking of nanovectors | [31] |
NIR PTT | Poly(lactic-co-glycolic) acid (PLGA) NPs encapsulating NIR photothermal agent indocyanine green (ICG) and toll-like-receptor-7 agonist imiquimod (R837) | 4T1 breast cancer CT26 colon cancer | s.c. (subcutaneously injection), i.v. (intravenously injection) | The photothermal ablation of primary tumours using PLGA-ICG-R837 NPs, generated tumour-associated antigens, which in the presence of R837-containing NPs as the adjuvant showed vaccine-like functions. In combination with anti-CTLA4, the generated immunological responses was able to attack remaining tumour cells in mice to inhibit metastasis. This strategy offered a strong immunological memory effect, which provided protection against tumour rechallenging post elimination of their initial tumours | [32] |
NIR PTT | PEG coated plasmonic gold nanostar (GNS) | MB49 bladder cancer | i.t., i.v. | The GNS-mediated PTT combined with anti-PD-L1 were able to achieve complete eradication of primary treated tumors and distant untreated tumors in some mice with effective long-lasting immunity against MB49 cancer cells rechallenge | [33] |
NIR PTT | Polydopamine-coated spiky AuNPs (SGNP@PDA) | CT26 colorectal cancer; TC-1 head and neck squamous cell carcinoma | i.t. | SGNP@PDA PTT combined with a sub-therapeutic chemo dose of doxorubicin (DOX), elicits robust anti-tumor responses in both cellular (CD8+ T and NK cells) and humoral compartments. Chemo-PTT eliminates residual tumor cells from locally treated tumors and exerts an abscopal effect against untreated, distant tumors, and also exhibits long-term resistance against tumor rechallenge due to the establishment of immunological memory | [34] |
NIR PTT | MDSC membrane-coated iron oxide MNP (MNP@MDSC) | B16-F10 melanoma | i.v. | MNPs@MDSC mediated PTT effects enhanced antitumor response by inducing ICD, reprogramming the tumor infiltrating macrophages, and reducing the tumor’s metabolic activity | [35] |
NIR PTT | CpG self-crosslinked NPs-loaded IR820-conjugated hydrogel | B16 melanoma | i.t. | IR820-hydrogel mediated PTT induced tumor antigens release for enhancing the immunotherapy effect. CpG NPs serve as adjuvant to improve the immune stimulation. The combined specific antitumor immunity achieved more effective systemic therapeutic effect than PTT or immunotherapy alone | [36] |
NIR PTT | Intracellularly generated AuNPs | B16F10 Melanoma 4T1 breast cancer | s.c. | The AuNPs were generated intracellularly and then exocytosed as nanoparticle trapped vesicles with retained original bioinformation. After further introduction to DCs, DCs-derived immunological AuNPs induced HT under NIR irradiation and provoked strong antitumor immune responses, promoting DCs maturation, multiple cytokines secretion, and T cells activation | [37] |
Magnetic HT | PEGylated iron NPs (FeNPs) | 4T1 breast cancer CT26 colon cancer | i.t. | The combination of FeNP-based MHT with local injection of nanoadjuvant and systemic injection of anti-CTLA4 checkpoint blockade would result in systemic therapeutic responses to inhibit tumor metastasis and a robust immune memory effect to prevent tumor recurrence | [38] |
NIR PTT | Mesoporous silica NPs decorated with AuNPs (Au@XL-MSNs) loaded with CpG-ODNs | 4T1 breast cancer | i.t. | The photothermal effect of AuNPs enhanced cancer immunotherapy by generating a cancer antigen at the tumor site, which can be processed by tumor-infiltrated DCs and induce antigen-specific adaptive immune response | [39] |
NIR(II) PTT | Self-assembly complex of liposome with AuNPs; two-dimensional polypyrrole nanosheets | 4T1 breast cancer | i.v. | PTT effect induced by NIR(II) light could trigger ICD more homogeneously and deeper than NIR(I) and red light, and more effective than oxaliplatin in solid tumors. The NIR(II) PTT provoked innate and adaptive immunity led to efficient antitumor and anti-metastasis effects when combined with checkpoint blockade therapy | [40] |
NIR PTT | c-RGD-functionalized conjugated polymer NPs (CP NPs) | 4T1 breast cancer | i.t. | The CP NPs mediated photothermal effect demonstrated effective activation of proinflammatory immune response, induced antitumor immunity activation and ultimately inhibited tumor growth | [41] |
NIR PTT | M NPs coated with cancer cell membrane (M@C NPs) | 4T1 breast cancer | i.v. | M@C NPs mediated PTT effects enhanced antitumor immune response by inducing ICD, which led to good therapeutic effect for primary and abscopal tumor when combined with immunoblocking inhibitor | [42] |
![](https://academic.hep.com.cn//article\2022\2095-0179/2095-0179-16-3-333/thumbnail/fce-20114-lx-fig1.jpg)
Fig.1 n-HT induced immunological genetic cell death (Schematic to illustrate the action of an inducer of ICD, achieved by n-HT. n-HT reagents induce an ICD response in which CRT expression on the dying cancer cell surface provides an “eat-me” signal for antigen presenting cells (APC). ICD response is also associated with the release of adjuvant stimuli (C), which promote APC maturation. This can further trigger the activation and recruitment of CD8+ T cells capable of mediating cytotoxic cancer cell death by the release of perforin and granzyme. DAMPs, damage-associated molecular patterns). |
![](https://academic.hep.com.cn//article\2022\2095-0179/2095-0179-16-3-333/thumbnail/fce-20114-lx-fig2.jpg)
Fig.2 Schematic illustration of (a) the synthesis of MNP@MDSC by coating magnetic Fe3O4 nanoparticle with MDSC membrane and (b) PTT inducing ICD. (c) In vivo ICD induced by PTT of MNP@MDSC characterized by the elevated expression of HMGB1 and CRT, representative images of mouse tumor slices stained for HMGB1 (top) and CRT (bottom) after the indicated treatments in B16/F10 melanoma model. Reprinted with permission from ref. [35], copyright 2018, Wiley. |
![](https://academic.hep.com.cn//article\2022\2095-0179/2095-0179-16-3-333/thumbnail/fce-20114-lx-fig3.jpg)
Fig.3 (a) Schematic showing controllable aggregation of AuNPs on fluidic liposomes; (b) localized SPRs of different sized Au15C, Au30C, and Au40C incubated with 100 nm DOPC liposomes at varied molar ratios; (c) NIR(II) PTT induced cell apoptosis and the subsequent release of DAMPs; (d) immunofluorescence staining and quantifications of CRT (upper panel) and HMGB1 release (bottom panel) in 4T1 tumors post-PTT; (e) upper panel: schematic diagram of the in vivo CRT exposure at different depths inside the tumor under the NIR(I) or NIR(II) laser irradiation; bottom panel: percentage of CRT positive areas of dissected tumor tissues at different depths (0, 3, 6, and 9 mm). Reprinted with permission from Ref. [40], copyright 2019 American Chemical Society. |
![](https://academic.hep.com.cn//article\2022\2095-0179/2095-0179-16-3-333/thumbnail/fce-20114-lx-fig4.jpg)
Fig.4 (a) In vitro ICD induced by PTT of M@C NPs characterized by the elevated expression of CRT on cell surface; (b) changes of tumor growth of 4T1 tumor-bearing mice with different treatment. p values were calculated using the t-test (***p<0.001, **p<0.01, *p<0.05). M: natural M NPs; M@C: cancer cell membrane coated M NPs; L: laser; IDOi: indoleamine IDO inhibitor. Reprinted with permission from ref. [42], copyright 2020, The Royal Society of Chemistry. |
![](https://academic.hep.com.cn//article\2022\2095-0179/2095-0179-16-3-333/thumbnail/fce-20114-lx-fig5.jpg)
Fig.5 Immunological characteristics for n-HT mediated treatment for tumor treatment. (a) Use of 3-zone model to conceptualize the temperature-gradient effect and resulting spatially-structured immunological landscape at tumor site receiving n-HT. The picture obtained from literature with minor modification. Reprinted with permission from ref. [1], copyright 2014, Springer Nature. (b) B16 tumor bearing mice received IT injection of copper sulfide nanocrystals (transmission electron microscopy). (c) Body temperature was captured post the injection of copper sulfide nanocrystals w/wo NIR light. (d) In vitro evidence of ROS production and (e) HSP70 over-expression in response to the copper sulfide nanocrystal treatment in the presence of NIR irradiation. Reprinted with permission from ref. [46], copyright 2015, American Chemical Society. |
![](https://academic.hep.com.cn//article\2022\2095-0179/2095-0179-16-3-333/thumbnail/fce-20114-lx-fig6.jpg)
Fig.6 Type I vs. type II ICD. (a) Type I ICD inducers are modalities that induce cell death via non-ER associated targets (primary) and danger signaling via ER stress (secondary). Type II ICD inducers selectively target the ER to induce both cell death as well as danger signaling thereby causing ICD-associated immunogenicity in an ER-focused manner. Reprinted with permission from ref. [48], copyright 2013, Annual Reviews, Inc. (b) Simplified schematic to show the unfolded protein stress response in the ER during a type II ICD. The basis of the HT-induced effect on the ER has been shown to involve ROS production that leads to ER-associated proteotoxicity (i.e., an unfolded protein response). This includes the phosphorylation of the eukaryotic initiation factor (eIF2α) that, in turn, is responsible for transcriptional activation of the CHOP protein. CHOP induces apoptotic cell death through the generation of immunological danger signals that promote antitumor immunity. Panel B was obtained from our previous publication with minor modification. Reprinted with permission from ref. [49], copyright 2021, Wiley. |