Bisphosphonate-mineralized Nano-IFNγ Suppresses Residual Tumor Growth Caused by Incomplete Radiofrequency Ablation Through Metabolically Remodeling Tumor-associated Macrophages

Overview

Journal Theranostics

Date 2025 Jan 8

PMID 39776793

Authors

Zhicheng Yan

Bing Wang

Yuhan Shen

Junji Ren

Meifang Chen

Yunhui Jiang

Hao Wu

Wenbing Dai

Hua Zhang

Xueqing Wang

Qiang Zhang

Wei Yang

Bing He

Affiliations

Soon will be listed here.

Abstract

Radiofrequency ablation (RFA), as a minimally invasive surgery strategy based on local thermal-killing effect, is widely used in the clinical treatment of multiple solid tumors. Nevertheless, RFA cannot achieve the complete elimination of tumor lesions with larger burden or proximity to blood vessels. Incomplete RFA (iRFA) has even been validated to promote residual tumor growth due to the suppressive tumor immune microenvironment (TIME). Therefore, exploring strategies to remodel TIME is a key issue for the development of RFA therapy. The negative effect of iRFA on colorectal cancer therapy was firstly investigated. Then a zoledronate-mineralized nanoparticle loaded with IFNγ (Nano-IFNγ/Zole) was designed and its tumor suppressive efficacy was evaluated. Finally, the metabolic reprogramming mechanism of Nano-IFNγ/Zole on tumor-associated macrophages (TAMs) was studied in detail. We found iRFA dynamically altered TIME and promoted TAM differentiation from M1 to M2. Nano-IFNγ/Zole was fabricated to metabolically remodel TAMs. IFNγ in Nano-IFNγ/Zole concentrated in the ablation site to play a long-term remodeling role. Acting on mevalonate pathway, Nano-IFNγ/Zole was discovered to reduce lysosomal acidification and activate transcription factor TFEB by inhibiting isoprene modification of the Rab protein family. These mechanisms, in conjunction with IFNγ-activated JAK/STAT1 signaling, accelerated the reprogramming of TAMs from M2 to M1, and suppressed tumor recurrence after iRFA. This study elaborates the synergistic mechanism of zoledronate and IFNγ in Nano-IFNγ/Zole to reshape suppressive TIME caused by iRFA by remodeling TAMs, and highlights the important value of metabolically induced cellular reprogramming. Since both zoledronate and IFNγ have already been approved in clinics, this integrative nano-drug delivery system establishes an effective strategy with great translational promise to overcome the poor prognosis after clinically incomplete RFA.

References

Puijk R, Ruarus A, Scheffer H, Vroomen L, van Tilborg A, De Vries J . Percutaneous Liver Tumour Ablation: Image Guidance, Endpoint Assessment, and Quality Control. Can Assoc Radiol J. 2018; 69(1):51-62. DOI: 10.1016/j.carj.2017.11.001. View

Yang L, Yang Y, Zhang J, Li M, Yang L, Wang X . Sequential responsive nano-PROTACs for precise intracellular delivery and enhanced degradation efficacy in colorectal cancer therapy. Signal Transduct Target Ther. 2024; 9(1):275. PMC: 11486899. DOI: 10.1038/s41392-024-01983-1. View

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

Cui Z, Napolitano G, de Araujo M, Esposito A, Monfregola J, Huber L . Structure of the lysosomal mTORC1-TFEB-Rag-Ragulator megacomplex. Nature. 2023; 614(7948):572-579. PMC: 9931586. DOI: 10.1038/s41586-022-05652-7. View

Zhao W, Jin L, Chen P, Li D, Gao W, Dong G . Colorectal cancer immunotherapy-Recent progress and future directions. Cancer Lett. 2022; 545:215816. DOI: 10.1016/j.canlet.2022.215816. View

Medina D, Di Paola S, Peluso I, Armani A, De Stefani D, Venditti R . Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB. Nat Cell Biol. 2015; 17(3):288-99. PMC: 4801004. DOI: 10.1038/ncb3114. View

Chu K, Dupuy D . Thermal ablation of tumours: biological mechanisms and advances in therapy. Nat Rev Cancer. 2014; 14(3):199-208. DOI: 10.1038/nrc3672. View

Chen M, Peng Z, Xu L, Zhang Y, Liang H, Li J . Role of radiofrequency ablation in the treatment of hepatocellular carcinoma: experience of a cancer center in China. Oncology. 2012; 81 Suppl 1:100-4. DOI: 10.1159/000333268. View

Pauwels A, Trost M, Beyaert R, Hoffmann E . Patterns, Receptors, and Signals: Regulation of Phagosome Maturation. Trends Immunol. 2017; 38(6):407-422. PMC: 5455985. DOI: 10.1016/j.it.2017.03.006. View

10.

Stroupe C, Hickey C, Mima J, Burfeind A, Wickner W . Minimal membrane docking requirements revealed by reconstitution of Rab GTPase-dependent membrane fusion from purified components. Proc Natl Acad Sci U S A. 2009; 106(42):17626-33. PMC: 2764952. DOI: 10.1073/pnas.0903801106. View

11.

Crocetti L, De Baere T, Lencioni R . Quality improvement guidelines for radiofrequency ablation of liver tumours. Cardiovasc Intervent Radiol. 2009; 33(1):11-7. PMC: 2816824. DOI: 10.1007/s00270-009-9736-y. View

12.

Juarez D, Fruman D . Targeting the Mevalonate Pathway in Cancer. Trends Cancer. 2020; 7(6):525-540. PMC: 8137523. DOI: 10.1016/j.trecan.2020.11.008. View

13.

Yamaguchi H, Hsu J, Yang W, Hung M . Mechanisms regulating PD-L1 expression in cancers and associated opportunities for novel small-molecule therapeutics. Nat Rev Clin Oncol. 2022; 19(5):287-305. DOI: 10.1038/s41571-022-00601-9. View

14.

Ma Z, Wang Y, Zheng W, Ma J, Bai X, Zhang Y . Prognostic factors and therapeutic effects of different treatment modalities for colorectal cancer liver metastases. World J Gastrointest Oncol. 2020; 12(10):1177-1194. PMC: 7579728. DOI: 10.4251/wjgo.v12.i10.1177. View

15.

Cui C, Chakraborty K, Tang X, Schoenfelt K, Hoffman A, Blank A . A lysosome-targeted DNA nanodevice selectively targets macrophages to attenuate tumours. Nat Nanotechnol. 2021; 16(12):1394-1402. DOI: 10.1038/s41565-021-00988-z. View

16.

Muntjewerff E, Meesters L, van den Bogaart G . Antigen Cross-Presentation by Macrophages. Front Immunol. 2020; 11:1276. PMC: 7360722. DOI: 10.3389/fimmu.2020.01276. View

17.

Komohara Y, Fujiwara Y, Ohnishi K, Takeya M . Tumor-associated macrophages: Potential therapeutic targets for anti-cancer therapy. Adv Drug Deliv Rev. 2015; 99(Pt B):180-185. DOI: 10.1016/j.addr.2015.11.009. View

18.

Subramani D, Alahari S . Integrin-mediated function of Rab GTPases in cancer progression. Mol Cancer. 2010; 9:312. PMC: 3003658. DOI: 10.1186/1476-4598-9-312. View

19.

Shi L, Wang J, Ding N, Zhang Y, Zhu Y, Dong S . Inflammation induced by incomplete radiofrequency ablation accelerates tumor progression and hinders PD-1 immunotherapy. Nat Commun. 2019; 10(1):5421. PMC: 6883042. DOI: 10.1038/s41467-019-13204-3. View

20.

Xia Y, Xie Y, Yu Z, Xiao H, Jiang G, Zhou X . The Mevalonate Pathway Is a Druggable Target for Vaccine Adjuvant Discovery. Cell. 2018; 175(4):1059-1073.e21. DOI: 10.1016/j.cell.2018.08.070. View