Combined Effects of Anti-PD-L1 and Nanosonodynamic Therapy on HCC Immune Activation in Mice: An Investigation

Abstract

Meng Wei,1,2,* Xiaobo Wang,1,2,* Yunhai Mo,1,2,* Cunqing Kong,3 Mengqi Zhang,2,4 Guanhua Qiu,2,5 Zhihong Tang,1,2 Jie Chen,1,2 Feixiang Wu1,2 1Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, 530021, People’s Republic of China; 2Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education/Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Nanning, 530021, People’s Republic of China; 3Medical Imaging Center, Affiliated Taihe Hospital, Hubei University of Medicine, Hubei, 442000, People’s Republic of China; 4Department of Interventional Therapy, Guangxi Medical University Cancer Hospital, Nanning, 530021, People’s Republic of China; 5Department of Ultrasound, Guangxi Medical University Cancer Hospital, Nanning, 530021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie Chen; Feixiang Wu, Email [email protected]; [email protected]: Current therapeutic strategies, including immune checkpoint blockade (ICB), exhibit limited efficacy in treating hepatocellular carcinoma (HCC). Nanoparticles, particularly those that can accumulate specifically within tumors and be activated by sonodynamic therapy (SDT), can induce immunogenic cell death (ICD); however, ICD alone has not achieved satisfactory therapeutic effectiveness. This study investigates whether combining ICB with ICD induced by nanoparticle-mediated SDT could enhance anti-tumor immunity and inhibit HCC growth.Methods: We developed an iron-based micelle nanodelivery system encapsulating the Near-Infrared Dye IR-780, which was surface-modified with a cyclic tripeptide composed of arginine-glycine-aspartic acid (cRGD). This led to the synthesis of targeted IR780@FOM-cRGD nanoparticles. These nanoparticles were specifically engineered to kill tumor cells under sonication, activate immunogenic cell death (ICD), and be used in conjunction with immune checkpoint blockade (ICB) for the treatment of hepatocellular carcinoma (HCC).Results: The synthesized IR780@FOM-cRGD nanoparticles had an average diameter of 28.23± 1.750 nm and a Zeta potential of − 23.95± 1.926. Confocal microscopy demonstrated that IR780@FOM-cRGD could target HCC cells while minimizing toxicity to healthy cells. Upon sonodynamic activation, these nanoparticles consumed significant amounts of oxygen and generated substantial reactive oxygen species (ROS), effectively killing tumor cells and inhibiting the proliferation, invasion, and migration of H22 cells. Hemolysis assays confirmed the in vivo safety of the nanoparticles, and in vivo fluorescence imaging revealed significant accumulation in tumor tissues. Mouse model experiments showed that combining ICB(which induced by Anti-PD-L1) with ICD (which induced by IR780@FOM-cRGD), could effectively activated anti-tumor immunity and suppressed tumor growth.Discussion: This study highlights the potential of IR780@FOM-cRGD nanoparticles to facilitate tumor eradication and immune activation when used in conjunction with Anti-PD-L1 therapy. This combination represents a non-invasive, efficient, and targeted approach for the treatment of hepatocellular carcinoma (HCC). By integrating sonodynamic therapy with immunotherapy, this strategy promises to substantially improve the effectiveness of traditional treatments in combating HCC, offering new avenues for clinical application and therapeutic innovation.Keywords: nanomaterials, sonodynamic therapy, tumor immunity, PD-L1, immunogenic cell death

Keywords

• nanomaterials
• sonodynamic therapy
• tumor immunity
• pd-l1
• immunogenic cell death