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Immunostimulant nanomodulator boosts antitumor immune response in triple negative breast cancer by synergism of vessel normalization and photothermal therapy

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Abstract

Tumor vascular dysfunction and immune suppression predict poor outcomes of tumor therapy. Combination of photothermal therapy (PTT) and vessel normalization with tumor immunotherapy is promising to augment antitumor benefit. Herein, we develop a potential immunostimulatory nanomodulator for treatment of triple-negative breast cancer (TNBC) treatment via synergism of PTT, vessel normalization, and priming of tumoral suppressive immune microenvironment by blocking transforming growth factor-β (TGF-β) pathway. The nanomodulator, namely Vac@Apt@BPs, is developed by conjugation of TGF-β inhibitor Vactosertib (Vac) and nucleolin-recognizing aptamer (Apt) on the surface of black phosphorus nanoparticles (BPs). Vac@Apt@BPs show good accumulation in TNBC via aptamer-induced active targeting of TNBC. Via the blockade of TGF-β signaling, Vac@Apt@BPs effectively inhibit the formation of tumor neovascular, and normalize the vessels to recover vascular integrity and alleviate the hypoxia stress. Together with the tumor eradication and immunogenic cell death via PTT, robust immune response was boosted by promoted maturation of dendritic cells, suppression of regulatory T cells, and stimulation of effective T cells. This synergistic therapeutic strategy potentially suppresses the growth of TNBC in mice.

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References

  1. Bianchini, G.; Balko, J. M.; Mayer, I. A.; Sanders, M. E.; Gianni, L. Triple-negative breast cancer: Challenges and opportunities of a heterogeneous disease. Nat. Rev. Clin. Oncol. 2016, 13, 674–690.

    CAS  Google Scholar 

  2. Gruosso, T.; Gigoux, M.; Manem, V. S. K.; Bertos, N.; Zuo, D. M.; Perlitch, I.; Saleh, S. M. I.; Zhao, H.; Souleimanova, M.; Johnson, R. M. et al. Spatially distinct tumor immune microenvironments stratify triple-negative breast cancers. J. Clin. Invest. 2019, 129, 1785–1800.

    Google Scholar 

  3. Jamdade, V. S.; Sethi, N.; Mundhe, N. A.; Kumar, P.; Lahkar, M.; Sinha, N. Therapeutic targets of triple-negative breast cancer: A review. Br. J. Pharmacol. 2015, 172, 4228–4237.

    CAS  Google Scholar 

  4. Chen, D. S.; Mellman, I. Elements of cancer immunity and the cancer-immune set point. Nature 2017, 541, 321–330.

    CAS  Google Scholar 

  5. Havel, J. J.; Chowell, D.; Chan, T. A. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat. Rev. Cancer 2019, 19, 133–150.

    CAS  Google Scholar 

  6. Mediratta, K.; El-Sahli, S.; D’Costa, V.; Wang, L. S. Current progresses and challenges of immunotherapy in triple-negative breast cancer. Cancers (Basel) 2020, 12, 3529.

    CAS  Google Scholar 

  7. Hegde, P. S.; Chen, D. S. Top 10 challenges in cancer immunotherapy. Immunity 2020, 52, 17–35.

    CAS  Google Scholar 

  8. Jardim, D. L.; Goodman, A.; de Melo Gagliato, D.; Kurzrock, R. The challenges of tumor mutational burden as an immunotherapy biomarker. Cancer Cell 2021, 39, 154–173.

    CAS  Google Scholar 

  9. Overchuk, M.; Zheng, G. Overcoming obstacles in the tumor microenvironment: Recent advancements in nanoparticle delivery for cancer theranostics. Biomaterials 2018, 156, 217–237.

    CAS  Google Scholar 

  10. Kalbasi, A.; Ribas, A. Tumour-intrinsic resistance to immune checkpoint blockade. Nat. Rev. Immunol. 2020, 20, 25–39.

    CAS  Google Scholar 

  11. Nicolas-Boluda, A.; Silva, A. K. A.; Fournel, S.; Gazeau, F. Physical oncology: New targets for nanomedicine. Biomaterials 2018, 150, 87–99.

    CAS  Google Scholar 

  12. Zhou, F. Y.; Feng, B.; Yu, H. J.; Wang, D. G.; Wang, T. T.; Ma, Y. T.; Wang, S. L.; Li, Y. P. Tumor microenvironment-activatable prodrug vesicles for nanoenabled cancer chemoimmunotherapy combining immunogenic cell death induction and CD47 blockade. Adv. Mater. 2019, 31, 1805888.

    Google Scholar 

  13. McLaughlin, M.; Patin, E. C.; Pedersen, M.; Wilkins, A.; Dillon, M. T.; Melcher, A. A.; Harrington, K. J. Inflammatory microenvironment remodelling by tumour cells after radiotherapy. Nat. Rev. Cancer 2020, 20, 203–217.

    CAS  Google Scholar 

  14. Chen, Q.; Hu, Q. Y.; Dukhovlinova, E.; Chen, G. J.; Ahn, S.; Wang, C.; Ogunnaike, E. A.; Ligler, F. S.; Dotti, G.; Gu, Z. Photothermal therapy promotes tumor infiltration and antitumor activity of CAR T cells. Adv. Mater. 2019, 31, 1900192.

    Google Scholar 

  15. Dai, H. X.; Fan, Q.; Wang, C. Recent applications of immunomodulatory biomaterials for disease immunotherapy. Exploration 2022, 2, 20210157.

    Google Scholar 

  16. Shao, Y. L.; Liu, B.; Di, Z. H.; Zhang, G.; Sun, L. D.; Li, L. L.; Yan, C. H. Engineering of upconverted metal-organic frameworks for near-infrared light-triggered combinational photodynamic/chemo-/immunotherapy against hypoxic tumors. J. Am. Chem. Soc. 2020, 142, 3939–3946.

    CAS  Google Scholar 

  17. He, L. Z.; Nie, T. Q.; Xia, X. J.; Liu, T.; Huang, Y. Y.; Wang, X. J.; Chen, T. F. Designing bioinspired 2D MoSe2 nanosheet for efficient photothermal-triggered cancer immunotherapy with reprogramming tumor-associated macrophages. Adv. Funct. Mater. 2019, 29, 1901240.

    Google Scholar 

  18. Ni, W. D.; Wu, J. Y.; Fang, H. P.; Feng, Y. J.; Hu, Y. Y.; Lin, L.; Chen, J.; Chen, F. F.; Tian, H. Y. Photothermal-chemotherapy enhancing tumor immunotherapy by multifunctional metal-organic framework based drug delivery system. Nano Lett. 2021, 21, 7796–7805.

    CAS  Google Scholar 

  19. Yang, W. J.; Zhang, F. W.; Deng, H. Z.; Lin, L. S.; Wang, S.; Kang, F.; Yu, G. C.; Lau, J.; Tian, R.; Zhang, M. R. et al. Smart nanovesicle-mediated immunogenic cell death through tumor microenvironment modulation for effective photodynamic immunotherapy. ACS Nano 2020, 14, 620–631.

    CAS  Google Scholar 

  20. Cheng, H. B.; Qiao, B.; Li, H.; Cao, J.; Luo, Y.; Kotraiah Swamy, K. M.; Zhao, J.; Wang, Z. G.; Lee, J. Y.; Liang, X. J. et al. Protein-activatable diarylethene monomer as a smart trigger of noninvasive control over reversible generation of singlet oxygen: A facile, switchable, theranostic strategy for photodynamic-immunotherapy. J. Am. Chem. Soc. 2021, 143, 2413–2422.

    CAS  Google Scholar 

  21. Fei, Z. Y.; Fan, Q.; Dai, H. X.; Zhou, X. F.; Xu, J. L.; Ma, Q. L.; Maruyama, A.; Wang, C. Physiologically triggered injectable red blood cell-based gel for tumor photoablation and enhanced cancer immunotherapy. Biomaterials 2021, 271, 120724.

    CAS  Google Scholar 

  22. Ni, K. Y.; Luo, T. K.; Culbert, A.; Kaufmann, M.; Jiang, X. M.; Lin, W. B. Nanoscale metal-organic framework co-delivers TLR-7 agonists and anti-CD47 antibodies to modulate macrophages and orchestrate cancer immunotherapy. J. Am. Chem. Soc. 2020, 142, 12579–12584.

    CAS  Google Scholar 

  23. Núñez, C.; Capelo, J. L.; Igrejas, G.; Alfonso, A.; Botana, L. M.; Lodeiro, C. An overview of the effective combination therapies for the treatment of breast cancer. Biomaterials 2016, 97, 34–50.

    Google Scholar 

  24. Martin, J. D.; Seano, G.; Jain, R. K. Normalizing function of tumor vessels: Progress, opportunities, and challenges. Annu. Rev. Physiol. 2019, 81, 505–534.

    CAS  Google Scholar 

  25. Zhao, Y.; Yu, X. R.; Li, J. Manipulation of immune-vascular crosstalk: New strategies towards cancer treatment. Acta Pharm. Sin. B 2020, 10, 2018–2036.

    CAS  Google Scholar 

  26. Huang, N.; Liu, Y. Q.; Fang, Y. S.; Zheng, S. T.; Wu, J. H.; Wang, M. H.; Zhong, W.; Shi, M.; Xing, M.; Liao, W. J. Gold nanoparticles induce tumor vessel normalization and impair metastasis by inhibiting endothelial Smad2/3 signaling. ACS Nano 2020, 14, 7940–7958.

    CAS  Google Scholar 

  27. Sung, Y. C.; Jin, P. R.; Chu, L. A.; Hsu, F. F.; Wang, M. R.; Chang, C. C.; Chiou, S. J.; Qiu, J. T.; Gao, D. Y.; Lin, C. C. et al. Delivery of nitric oxide with a nanocarrier promotes tumour vessel normalization and potentiates anti-cancer therapies. Nat. Nanotechnol. 2019, 14, 1160–1169.

    CAS  Google Scholar 

  28. Jiang, Z. J.; Xiong, H.; Yang, S.; Lu, Y.; Deng, Y. D.; Yao, J. X.; Yao, J. Jet-lagged nanoparticles enhanced immunotherapy efficiency through synergistic reconstruction of tumor microenvironment and normalized tumor vasculature. Adv. Healthc. Mater. 2020, 9, 2000075.

    CAS  Google Scholar 

  29. Taleb, M.; Atabakhshi-Kashi, M.; Wang, Y. Z.; Rezvani Alanagh, H.; Farhadi Sabet, Z.; Li, F. F.; Cheng, K. M.; Li, C.; Qi, Y. Q.; Nie, G. J. et al. Bifunctional therapeutic peptide assembled nanoparticles exerting improved activities of tumor vessel normalization and immune checkpoint inhibition. Adv. Healthc. Mater. 2021, 10, 2100051.

    CAS  Google Scholar 

  30. Liu, M.; Kuo, F. S.; Capistrano, K. J.; Kang, D.; Nixon, B. G.; Shi, W.; Chou, C.; Do, M. H.; Stamatiades, E. G.; Gao, S. Y. et al. TGF-β suppresses type 2 immunity to cancer. Nature 2020, 587, 115–120.

    CAS  Google Scholar 

  31. Li, S.; Liu, M.; Do, M. H.; Chou, C.; Stamatiades, E. G.; Nixon, B. G.; Shi, W.; Zhang, X.; Li, P.; Gao, S. Y. et al. Cancer immunotherapy via targeted TGF-β signalling blockade in TH cells. Nature 2020, 587, 121–125.

    CAS  Google Scholar 

  32. Akhurst, R. J.; Hata, A. Targeting the TGFβ signalling pathway in disease. Nat. Rev. Drug Discov. 2012, 11, 790–811.

    CAS  Google Scholar 

  33. Yang, L.; Pang, Y. L.; Moses, H. L. TGF-β and immune cells: An important regulatory axis in the tumor microenvironment and progression. Trends Immunol. 2010, 31, 220–227.

    CAS  Google Scholar 

  34. Jiao, S. P.; Subudhi, S. K.; Aparicio, A.; Ge, Z. Q.; Guan, B. X.; Miura, Y.; Sharma, P. Differences in tumor microenvironment dictate T helper lineage polarization and response to immune checkpoint therapy. Cell 2019, 179, 1177–1190.e13.

    CAS  Google Scholar 

  35. Mariathasan, S.; Turley, S. J.; Nickles, D.; Castiglioni, A.; Yuen, K.; Wang, Y. L.; Kadel III, E. E.; Koeppen, H.; Astarita, J. L.; Cubas, R. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 2018, 554, 544–548.

    CAS  Google Scholar 

  36. Colak, S.; ten Dijke, P. Targeting TGF-β signaling in cancer. Trends Cancer 2017, 3, 56–71.

    CAS  Google Scholar 

  37. Ling, X.; Jiang, X. M.; Li, Y. Y.; Han, W. B.; Rodriguez, M.; Xu, Z. W.; Lin, W. B. Sequential treatment of bioresponsive nanoparticles elicits antiangiogenesis and apoptosis and synergizes with a CD40 agonist for antitumor immunity. ACS Nano 2021, 15, 765–780.

    CAS  Google Scholar 

  38. Wang, B. L.; Bai, J. Y.; Tian, B.; Chen, H.; Yang, Q. Y.; Chen, Y. T.; Xu, J. L.; Zhang, Y.; Dai, H. X.; Ma, Q. L. et al. Genetically engineered hematopoietic stem cells deliver TGF-β inhibitor to enhance bone metastases immunotherapy. Adv. Sci. 2022, 9, 2201451.

    CAS  Google Scholar 

  39. Zhu, R. R.; Zhu, X. F.; Zhu, Y. J.; Wang, Z. J.; He, X. L.; Wu, Z. R.; Xue, L.; Fan, W. Y.; Huang, R. Q.; Xu, Z. et al. Immunomodulatory layered double hydroxide nanoparticles enable neurogenesis by targeting transforming growth factor-β receptor 2. ACS Nano 2021, 15, 2812–2830.

    CAS  Google Scholar 

  40. Duan, X. P.; Chan, C.; Lin, W. B. Nanoparticle-mediated immunogenic cell death enables and potentiates cancer immunotherapy. Angew. Chem., Int. Ed. 2019, 58, 670–680.

    CAS  Google Scholar 

  41. Gao, S.; Yang, X. Y.; Xu, J. K.; Qiu, N.; Zhai, G. X. Nanotechnology for boosting cancer immunotherapy and remodeling tumor microenvironment: The horizons in cancer treatment. ACS Nano 2021, 15, 12567–12603.

    CAS  Google Scholar 

  42. Galon, J.; Bruni, D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat. Rev. Drug Discov. 2019, 18, 197–218.

    CAS  Google Scholar 

  43. Irvine, D. J.; Dane, E. L. Enhancing cancer immunotherapy with nanomedicine. Nat. Rev. Immunol. 2020, 20, 321–334.

    CAS  Google Scholar 

  44. Shi, Y.; Lammers, T. Combining nanomedicine and immunotherapy. Acc. Chem. Res. 2019, 52, 1543–1554.

    CAS  Google Scholar 

  45. Gong, N. Q.; Sheppard, N. C.; Billingsley, M. M.; June, C. H.; Mitchell, M. J. Nanomaterials for T-cell cancer immunotherapy. Nat. Nanotechnol. 2021, 16, 25–36.

    CAS  Google Scholar 

  46. Zhang, C.; Pu, K. Y. Molecular and nanoengineering approaches towards activatable cancer immunotherapy. Chem. Soc. Rev. 2020, 49, 4234–4253.

    CAS  Google Scholar 

  47. Wang, H.; Mooney, D. J. Biomaterial-assisted targeted modulation of immune cells in cancer treatment. Nat. Mater. 2018, 17, 761–772.

    CAS  Google Scholar 

  48. Cheng, Y. Y.; Chen, Q.; Guo, Z. Y.; Li, M. W.; Yang, X. Y.; Wan, G. Y.; Chen, H. L.; Zhang, Q. Q.; Wang, Y. S. An intelligent biomimetic nanoplatform for holistic treatment of metastatic triple-negative breast cancer via photothermal ablation and immune remodeling. ACS Nano 2020, 14, 15161–15181.

    CAS  Google Scholar 

  49. Revuri, V.; Rajendrakumar, S. K.; Park, M. S.; Mohapatra, A.; Uthaman, S.; Mondal, J.; Bae, W. K.; Park, I. K.; Lee, Y. K. Heat-confined tumor-docking reversible thermogel potentiates systemic antitumor immune response during near-infrared photothermal ablation in triple-negative breast cancer. Adv. Healthc. Mater. 2021, 10, 2100907.

    CAS  Google Scholar 

  50. Tian, Y.; Wang, X. F.; Zhao, S.; Liao, X.; Younis, M. R.; Wang, S. J.; Zhang, C. N.; Lu, G. M. JQ1-loaded polydopamine nanoplatform inhibits c-MYC/programmed cell death ligand 1 to enhance photothermal therapy for triple-negative breast cancer. ACS Appl. Mater. Interfaces 2019, 11, 46626–46636.

    CAS  Google Scholar 

  51. Chen, L.; Zhou, L. L.; Wang, C. H.; Han, Y.; Lu, Y. L.; Liu, J.; Hu, X. C.; Yao, T. M.; Lin, Y.; Liang, S. J. et al. Tumor-targeted drug and CpG delivery system for phototherapy and docetaxel-enhanced immunotherapy with polarization toward M1-type macrophages on triple negative breast cancers. Adv. Mater. 2019, 31, 1904997.

    CAS  Google Scholar 

  52. Chang, M. Y.; Hou, Z. Y.; Wang, M.; Li, C. X.; Lin, J. Recent advances in hyperthermia therapy-based synergistic immunotherapy. Adv. Mater. 2021, 33, 2004788.

    CAS  Google Scholar 

  53. Chen, J. Q.; Ning, C. Y.; Zhou, Z. N.; Yu, P.; Zhu, Y.; Tan, G. X.; Mao, C. B. Nanomaterials as photothermal therapeutic agents. Prog. Mater. Sci. 2019, 99, 1–26.

    Google Scholar 

  54. Shao, X. M.; Ding, Z. H.; Zhou, W. H.; Li, Y. Y.; Li, Z. B.; Cui, H. D.; Lin, X.; Cao, G. L.; Cheng, B. H.; Sun, H. Y. et al. Intrinsic bioactivity of black phosphorus nanomaterials on mitotic centrosome destabilization through suppression of PLK1 kinase. Nat. Nanotechnol. 2021, 16, 1150–1160.

    CAS  Google Scholar 

  55. Liu, S.; Pan, X. T.; Liu, H. Y. Two-dimensional nanomaterials for photothermal therapy. Angew. Chem., Int. Ed. 2020, 59, 5890–5900.

    CAS  Google Scholar 

  56. Luo, M. M.; Fan, T. J.; Zhou, Y.; Zhang, H.; Mei, L. 2D black phosphorus-based biomedical applications. Adv. Funct. Mater. 2019, 29, 1808306.

    Google Scholar 

  57. Chen, W. S.; Ouyang, J.; Liu, H.; Chen, M.; Zeng, K.; Sheng, J. P.; Liu, Z. J.; Han, Y. J.; Wang, L. Q.; Li, J. et al. Black phosphorus nanosheet-based drug delivery system for synergistic photodynamic/photothermal/chemotherapy of cancer. Adv. Mater. 2017, 29, 1603864.

    Google Scholar 

  58. Shao, J. D.; Xie, H. H.; Huang, H.; Li, Z. B.; Sun, Z. B.; Xu, Y. H.; Xiao, Q. L.; Yu, X. F.; Zhao, Y. T.; Zhang, H. et al. Author correction: Biodegradable black phosphorus-based nanospheres for in vivo photothermal cancer therapy. Nat. Commun. 2021, 12, 3923.

    CAS  Google Scholar 

  59. Zhao, Y. T.; Tong, L. P.; Li, Z. B.; Yang, N.; Fu, H. D.; Wu, L.; Cui, H. D.; Zhou, W. H.; Wang, J. H.; Wang, H. Y. et al. Stable and multifunctional dye-modified black phosphorus nanosheets for near-infrared imaging-guided photothermal therapy. Chem. Mater. 2017, 29, 7131–7139.

    CAS  Google Scholar 

  60. Qu, G. B.; Xia, T.; Zhou, W. H.; Zhang, X.; Zhang, H. Y.; Hu, L. G.; Shi, J. B.; Yu, X. F.; Jiang, G. B. Property-activity relationship of black phosphorus at the nano-bio interface: From molecules to organisms. Chem. Rev. 2020, 120, 2288–2346.

    CAS  Google Scholar 

  61. Tao, W.; Zhu, X. B.; Yu, X. H.; Zeng, X. W.; Xiao, Q. L.; Zhang, X. D.; Ji, X. Y.; Wang, X. S.; Shi, J. J.; Zhang, H. et al. Black phosphorus nanosheets as a robust delivery platform for cancer theranostics. Adv. Mater. 2017, 29, 1603276.

    Google Scholar 

  62. Zhao, Y. T.; Xie, Z. Z.; Deng, Y. Y.; Huang, A. J.; He, Y. L.; Wen, B.; Liao, X. X.; Chang, R. M.; Zhang, G. X.; Zhu, L. et al. Photothermal nanobomb blocking metabolic adenosine-A2AR potentiates infiltration and activity of T cells for robust antitumor immunotherapy. Chem. Eng. J. 2022, 450, 138139.

    CAS  Google Scholar 

  63. Zhao, Y. T.; Wang, H. Y.; Huang, H.; Xiao, Q. L.; Xu, Y. H.; Guo, Z. N.; Xie, H. H.; Shao, J. D.; Sun, Z. B.; Han, W. J. et al. Surface Coordination of black phosphorus for robust air and water stability. Angew. Chem., Int. Ed. 2016, 55, 5003–5007.

    CAS  Google Scholar 

  64. Qu, G. B.; Liu, W.; Zhao, Y. T.; Gao, J.; Xia, T.; Shi, J. B.; Hu, L. G.; Zhou, W. H.; Gao, J. J.; Wang, H. Y. et al. Improved biocompatibility of black phosphorus nanosheets by chemical modification. Angew. Chem., Int. Ed. 2017, 56, 14488–14493.

    CAS  Google Scholar 

  65. Yazdian-Robati, R.; Bayat, P.; Oroojalian, F.; Zargari, M.; Ramezani, M.; Taghdisi, S. M.; Abnous, K. Therapeutic applications of AS1411 aptamer, an update review. Int. J. Biol. Macromol. 2020, 155, 1420–1431.

    CAS  Google Scholar 

  66. Peng, T. H.; Deng, Z. Y.; He, J. X.; Li, Y. Y.; Tan, Y.; Peng, Y. B.; Wang, X. Q.; Tan, W. H. Functional nucleic acids for cancer theranostics. Coord. Chem. Rev. 2020, 403, 213080.

    CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (Nos. 32000931, 81672632, 81972312, and 82103184), the Natural Science Foundation of Hunan Province for outstanding Young Scholars (No. 2021JJ20083), Natural Science Foundation of Hunan Province of China (Nos. 2021JJ30912, 2021JJ40720 and 2021JJ30950), the science and technology innovation Program of Hunan Province (No. 2022RC1165), and the Open Sharing Fund for the Large-scale Instruments and Equipment of Central South University, Changsha, China.

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Immunostimulant nanomodulator boosts antitumor immune response in triple negative breast cancer by synergism of vessel normalization and photothermal therapy

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Jiang, H., He, Y., Zhao, J. et al. Immunostimulant nanomodulator boosts antitumor immune response in triple negative breast cancer by synergism of vessel normalization and photothermal therapy. Nano Res. 16, 11149–11163 (2023). https://doi.org/10.1007/s12274-023-5786-8

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