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Northwestern University

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ACS Nano, Aug 22 2024, | https://doi.org/10.1021/acsnano.4c05809 Cryo-Nanocatalyst Enhances Therapeutic Efficacy of Cryo-Immunotherapy through Necroptosis and Local Delivery of Programmed Death-Ligand 1 Inhibitors

Sanghee Lee ¹, Min Jun Ko ¹, Rony Avritscher ², Robert J Lewandowski ¹, Dong-Hyun Kim ^1,3,4,5

¹Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago 60611, United States.

²Department of Interventional Radiology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.

³Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, United States.

⁴Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, Illinois 60208, United States.

⁵Department of Biomedical Engineering, University of Illinois, Chicago, Illinois 60607, United States.

S.L. and M.J.K. contributed equally to this work.

Corresponding Author : Dong-Hyun Kim

Abstract

Combining cryoablation and immunotherapy presents a promising approach to revert immunosuppressive responses to solid tumors. However, challenges such as postablated residual tumors and insufficient immune activity contribute to recurrence after cryo-immunotherapy. Herein, we investigated metallic supra-structured cryo-nanocatalyst (MSCN), which features numerous ice nucleation sites and interspace loading of therapeutic agents. MSCN elevates the freezing point and enhances ice nucleation, facilitating effective ice formation during cryotreatment. MSCN-loaded tumor cells showed a 2-fold increase in cryo-cytotoxicity and undergo osmotic-related cell damage, primarily necroptosis rather than other regulated cell death mechanisms. In prostate cancer models, RNA sequencing reveals that MSCN-cryoablation promoted antitumor inflammatory pathways, including necroptosis, compared to cryoablation alone. Additionally, following programmed death-ligand 1 (PD-L1) upregulation postcryoablation, synergistic effects with PD-L1 blockade were confirmed. Given the interspace of MSCN for aPD-L1 loading, we compared the intratumoral delivery of PD-L1 blockade against systemic injection. Enhanced necrosis and necroptosis from MSCN-cryoablation and PD-L1 blockade effectively eradicated tumors and triggered antitumor and memory immune responses locally and systemically. Lastly, a spatial landscape of tumor-infiltrating immune cells was analyzed to gain insight into heterogeneous tumor responses, leading to the limitations of conventional focal ablation techniques. Our findings highlight the potential of advanced cryo-immunotherapy using cryo-nanocatalysis to promote ice formation and necroptosis, stimulating antitumor immunogenic responses.

논문정보

형식Research article
게재일2024년 08월 (BRIC 등록일 2024-08-30)
연구진국외 연구진
분야 바이오·의료융합 > 바이오센싱 및 나노바이오물질

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