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Metal-ion-chelating phenylalanine nanostructures reverse immune dysfunction and sensitize breast tumour to immune checkpoint blockade

Nature Nanotechnology (2024)Cite this article

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Abstract

An immunosuppressive tumour microenvironment strongly influences response rates in patients receiving immune checkpoint blockade-based cancer immunotherapies, such as programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1). Here we demonstrate that metal-ion-chelating l-phenylalanine nanostructures synergize with short-term starvation (STS) to remodel the immunosuppressive microenvironment of breast and colorectal tumours. These nanostructures modulate the electrophysiological behaviour of dendritic cells and activate them through the NLRP3 inflammasome and calcium-mediated nuclear factor-κB pathway. STS promotes the cellular uptake of nanostructures through amino acid transporters and plays a key role in dendritic cell maturation and tumour-specific cytotoxic T lymphocyte responses. This study demonstrates the potential role of metal-ion-chelating l-phenylalanine nanostructures in activating immune responses and the effect of STS treatment in improving nanomaterial-mediated cancer immunotherapy.

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Fig. 1: Schematic illustration of the activation of DCs by metal-ion-chelating l-Phe nanostructures.
Fig. 2: Coordination-driven self-assembly of metal-ion-chelating l-Phe nanostructures.
Fig. 3: Genomic analysis of metal-ion-chelating l-Phe nanostructure-treated BMDCs.
Fig. 4: Nanostructures induce the NLRP3 inflammasome and NF-κB pathway activation.
Fig. 5: Simulations of the interaction between metal-ion-chelating l-Phe dimers and Kv1.3.
Fig. 6: Augmenting ICB therapy with nanostructures.

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Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. There are no data from third-party or publicly available datasets. The accession number for the raw data files for the transcriptome sequencing reported in this paper is NCBI PRJNA1122081. Due to the very large file sizes and volume of data, the remaining raw data supporting the findings of this study are available from the corresponding authors on reasonable request. Source data are available in separate source data files for Figs. 2b–d, 3d–f, 4b,d,j and 6b,c,g and Extended Data Figs. 1a–e,g–j,l–o, 2a,b,d–o, 3a–f and 4b,e,g–i. Source data of uncropped gels are available in separate files for Figs. 4c,h–i and 6h and Extended Data Fig. 4f. Source data for Supplementary Figures are available in separate supplementary files for Supplementary Figs. 2a,b, 3a–d, 4, 5, 6c,d, 8d, 9b,d, 10a,b, 11a,b, 14a–c, 15a–c, 16, 17, 18a–k, 19a,b, 20, 21a, 22, 23a–d, 24b,c,e, 25a–g, 26a,b, 27b, 28a,b, 29b,c, 30a,b, 31a–h,32,33a,d, 34a–e,g–h, 35a–l, 36a–h, 37, 38a,b, 39b, 40 and 41.

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Acknowledgements

The results described in this paper (partially) were obtained on the ‘Era’ petascale supercomputer of the Computer Network Information Center of Chinese Academy of Sciences. We thank Qiantang Biotechnology and Qingbei Biotechnology for their help in the bioinformatics analysis and dynamic simulations, respectively. This work was financially supported by NSFC (31971307 to H.W., 32000950 to Y.Y., 82071926 to H.R., 81630047 to H.R. and 82302210 to M.T.), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB36000000 to G.N.), and the Start-up Foundation of NCNST to H.W.

Author information

Author notes

  1. These authors contributed equally: Mixiao Tan, Guoliang Cao.

Authors and Affiliations

  1. CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, People’s Republic of China

    Mixiao Tan, Guoliang Cao, Wenping Huang, Yue Yin, Haixia Ma, Motao Zhu, Guangjun Nie & Hai Wang

  2. The Second Affiliated Hospital of Chongqing Medical University & Chongqing Key Laboratory of Ultrasound Molecular Imaging, Chongqing, People’s Republic of China

    Mixiao Tan, Long Cheng, Zhigang Wang & Haitao Ran

  3. State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, People’s Republic of China

    Guoliang Cao, Rupeng Wang & Shih-Hsin Ho

  4. University of Chinese Academy of Sciences, Beijing, People’s Republic of China

    Guangjun Nie & Hai Wang

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Contributions

H.W. conceived the project. H.W., H.R., G.N., M.T. and G.C. analysed the data and wrote the manuscript. M.T. and G.C. conducted all the experiments with help from R.W., L.C., W.H., Y.Y., H.M., S.-H.H., M.Z. and Z.W. All authors approved the manuscript.

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Correspondence to Haitao Ran, Guangjun Nie or Hai Wang.

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Extended data

Extended Data Fig. 1 Nanostructures reshape the immunosuppressive tumour microenvironment.

a, Percentage of nanostructure-positive DCs, B cells, macrophages, T cells, and CD45− cells in tumours (n = 3 biologically independent mice per group). Black: normal treatment; Red: STS treatment. b–e, Percentage of g-MDSC (b), m-MDSC (c), TAMs (d) and M2-like macrophages (e) in tumours after the indicated treatments (n = 4 biologically independent mice per group in b–e). f, g, Representative flow cytometric analysis (f) and quantification (g; n = 4 biologically independent mice per group) of Tregs in tumours after the indicated treatments. h, i, Quantification of MHC-II positive DCs (h) and TANs (i) in tumours (n = 4 biologically independent mice per group in h, i). j, k, Quantification of (j; n = 4 biologically independent mice per group) and immunofluorescence images of (k) the CD8+ T cells in tumours after the indicated treatments. Scale bar, 100 μm and 10 μm for the inset. l, m, TNF-producing CD8+ T cells (l) and IFNγ-producing CD8+ T cells (m) in tumours after the indicated treatment for 14 days (n = 4 biologically independent mice per group in l, m). n, o, Secreted TNF (n) and IL-6 (o) in tumours (n = 4 biologically independent mice per group in n, o). The data in a–e, g–j and l–o were presented as the mean ± s.d. The P values in a–e, g–j and l–o were calculated by two-tailed one-way ANOVA (Tukey’s post-hoc test).

Source data

Extended Data Fig. 2 In vivo immune responses after treatment with nanostructures.

a, Quantification of MHC-II+ DCs (n = 3 biologically independent mice per group), TANs (n = 4 biologically independent mice per group), TAMs (n = 3 biologically independent mice per group), and M2-like macrophages (n = 3 biologically independent mice per group) in tumours with various treatments Black: normal treatment; Red: STS treatment. b, Quantification of CD8+ T cells infiltrated in the tumours (n = 6 biologically independent mice per group) c, Immunofluorescence images of CD8+ T cells in tumours. Scale bar, 100 μm and 10 μm for the inset. d–f, Flow cytometry analysis of TNF-producing CD8+ T cells (d), IFNγ-producing CD8+ T cells (e) and IL-10-producing CD4+ T cells (f) in tumours after the indicated treatments (n = 3 biologically independent mice per group in d–f). g–j, Detection of TNF (g), IFNγ (h), IL-12p70 (i) and IL-6 (j) in tumours collected at day 25 (n = 3 biologically independent mice per group in g–j). k–o, Detection of TNF (k), IFNγ (l), IL-6 (m), IL-12p70 (n) and IL-10 (o) in serum from mice after the indicated treatments (n = 3 biologically independent mice per group in k–o). The data in a, b and d–o were presented as the mean ± s.d. The P values in a, b and d–o were calculated by two-tailed one-way ANOVA (Tukey’s post-hoc test).

Source data

Extended Data Fig. 3 Antitumor ability of DC- or macrophage-depleted mice after nanostructure treatment.

a, b, E0771 tumour growth curves (a) and volume (b; day 25) of CD11c-DTR mice after receiving the indicated treatments (n = 5 biologically independent mice per group in a, b). c, Weights of tumours obtained on day 25 of CD11c-DTR mice after the indicated treatments (n = 5 biologically independent mice per group). d, e, Growth curves (d) and volumes (e) of 4T1 tumours in macrophage-depleted mice after receiving the indicated treatments (n = 5 biologically independent mice per group in d, e). f, Weights of 4T1 tumours obtained on day 25 of macrophage-depleted mice after the indicated treatments (n = 5 biologically independent mice per group). The data in a–f were presented as the mean ± s.d. The P values in b, c and e, f were calculated by two-tailed one-way ANOVA (Tukey’s post-hoc test).

Source data

Extended Data Fig. 4 Prevention of tumour metastasis by nanostructure treatment.

a, Scheme of in vivo treatments. CT26 tumour-bearing BALB/c mice (n = 6 biologically independent mice per group) were reinjected with CT26 cells on day 19. b, Tumour growth curves of primary and reinjected CT26 tumours (n = 6 biologically independent mice per group). c, Photographs of primary and reinjected CT26 tumours. d, TUNEL immunostaining and H&E images of CT26 primary tumours after the indicated treatments. e, Secretion of IL-1β in primary tumours after the indicated treatments (n = 3 biologically independent mice per group). f, Western blot analysis of CaM, pIkBα, total IkBα, pp65 and p65 in CT26 primary tumours after the indicated treatments. g, Quantification of CD8+ T cells in CT26 primary tumours (n = 6 biologically independent mice per group). h, i, Percentage of TNF-producing CD8+ T cells (h) and IFNγ-producing CD8+ T cells (i) in CT26 primary tumours (n = 3 biologically independent mice per group in h, i). j, Immunofluorescence images of CD8+ T cells in tumours. Scale bar, 100 μm and 10 μm for the inset. The data in b, e and g–i were presented as the mean ± s.d. The P values in e and g–i were calculated by two-tailed one-way ANOVA (Tukey’s post-hoc test).

Source data

Supplementary information

Supplementary Information

Supplementary Discussion, Experimental procedures, Figs. 1–42, Tables 1 and 2 and References.

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Supplementary Data

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Unprocessed western blots.

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Tan, M., Cao, G., Wang, R. et al. Metal-ion-chelating phenylalanine nanostructures reverse immune dysfunction and sensitize breast tumour to immune checkpoint blockade. Nat. Nanotechnol. (2024). https://doi.org/10.1038/s41565-024-01758-3

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