Kim, Eun Hye Choi, Jiwoong Jang, Hochung Kim, Yelee Lee, Jong Won Ryu, Youngri Choi, Jiwon Choi, Yeonho Chi, Sung-Gil Kwon, Ick Chan Yang, Yoosoo Kim, Sun Hwa 2024-07-26T04:30:40Z 2024-07-26T04:30:40Z 2024-07-25 2024-06 1838-7640 https://pubs.kist.re.kr/handle/201004/150293 Rationale: Growing evidence has demonstrated that miRNA-21 (miR-21) upregulation is closely associated with tumor pathogenesis. However, the mechanisms by which miR-21 inhibition modulates the immunosuppressive tumor microenvironment (TME) and improves tumor sensitivity to immune checkpoint blockade therapies remain largely unexplored. In this study, we demonstrate the precise delivery of anti-miR-21 using a PD-L1-targeting peptide conjugate (P21) to the PD-L1 high TME. Methods: Investigating miR-21 inhibition mechanisms involved conducting quantitative real-time PCR, western blot, flow cytometry, and confocal microscopy analyses. The antitumor efficacy and immune profile of P21 monotherapy, or combined with anti-PD-L1 immune checkpoint inhibitors, were assessed in mouse models bearing CT26.CL25 tumors and 4T1 breast cancer. Results Inhibition of oncogenic miR-21 in cancer cells by P21 efficiently activates tumor suppressor genes, inducing autophagy and endoplasmic reticulum stress. Subsequent cell-death-associated immune activation (immunogenic cell death) is initiated via the release of damage-associated molecular patterns. The in vivo results also illustrated that the immunogenic cell death triggered by P21 could effectively sensitize the immunosuppressive TME. That is, P21 enhances CD8 + T cell infiltration in tumor tissues by conferring immunogenicity to dying cancer cells and promoting dendritic cell maturation. Meanwhile, combining P21 with an anti-PD-L1 immune checkpoint inhibitor elicits a highly potent antitumor effect in a CT26.CL25 tumor-bearing mouse model and 4T1 metastatic tumor model. Conclusions: Collectively, we have clarified a miR-21-related immunogenic cell death mechanism through the precise delivery of anti-miR-21 to the PD-L1 high TME. These findings highlight the potential of miR-21 as a target for immunotherapeutic interventions. English Ivyspring International Publisher Targeted delivery of anti-miRNA21 sensitizes PD-L1high tumor to immunotherapy by promoting immunogenic cell death Article 10.7150/thno.97755 1 Theranostics, v.14, no.10, pp.3777 - 3792 Theranostics 14 10 3777 3792 Y scie scopus 001266358900001 2-s2.0-85197216029 Medicine, Research & Experimental Research & Experimental Medicine Article ENDOPLASMIC-RETICULUM STRESS MIR-21 MICRORNA-21 INVASION CANCER EXPRESSION GROWTH PDCD4 Anti-miRNA delivery PD-L1 miR-21 Tumor microenvironment Immunogenic cell death