Advancing cancer immunotherapy through siRNA-based gene silencing for immune checkpoint blockade

Youngjin Choi; Su Hyun Seok; Hong Yeol Yoon; Ju Hee Ryu; Ick Chan Kwon

doi:10.1016/j.addr.2024.115306

Advancing cancer immunotherapy through siRNA-based gene silencing for immune checkpoint blockade

Adv Drug Deliv Rev. 2024 Apr 16:209:115306. doi: 10.1016/j.addr.2024.115306. Online ahead of print.

Authors

Youngjin Choi¹, Su Hyun Seok¹, Hong Yeol Yoon², Ju Hee Ryu³, Ick Chan Kwon⁴

Affiliations

¹ Medicinal Materials Research Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
² Medicinal Materials Research Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Division of Bio-Medical Science &Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea.
³ Medicinal Materials Research Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea. Electronic address: jhryu@kist.re.kr.
⁴ Medicinal Materials Research Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea. Electronic address: ikwon@kist.re.kr.

PMID: 38626859
DOI: 10.1016/j.addr.2024.115306

Abstract

Cancer immunotherapy represents a revolutionary strategy, leveraging the patient's immune system to inhibit tumor growth and alleviate the immunosuppressive effects of the tumor microenvironment (TME). The recent emergence of immune checkpoint blockade (ICB) therapies, particularly following the first approval of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors like ipilimumab, has led to significant growth in cancer immunotherapy. The extensive explorations on diverse immune checkpoint antibodies have broadened the therapeutic scope for various malignancies. However, the clinical response to these antibody-based ICB therapies remains limited, with less than 15% responsiveness and notable adverse effects in some patients. This review introduces the emerging strategies to overcome current limitations of antibody-based ICB therapies, mainly focusing on the development of small interfering ribonucleic acid (siRNA)-based ICB therapies and innovative delivery systems. We firstly highlight the diverse target immune checkpoint genes for siRNA-based ICB therapies, incorporating silencing of multiple genes to boost anti-tumor immune responses. Subsequently, we discuss improvements in siRNA delivery systems, enhanced by various nanocarriers, aimed at overcoming siRNA's clinical challenges such as vulnerability to enzymatic degradation, inadequate pharmacokinetics, and possible unintended target interactions. Additionally, the review presents various combination therapies that integrate chemotherapy, phototherapy, stimulatory checkpoints, ICB antibodies, and cancer vaccines. The important point is that when used in combination with siRNA-based ICB therapy, the synergistic effect of traditional therapies is strengthened, improving host immune surveillance and therapeutic outcomes. Conclusively, we discuss the insights into innovative and effective cancer immunotherapeutic strategies based on RNA interference (RNAi) technology utilizing siRNA and nanocarriers as a novel approach in ICB cancer immunotherapy.

Keywords: Cancer Immunotherapy; Combination therapy; Gene silencing; Immune checkpoint blockade; Nanoparticle; siRNA.

Publication types

Review