Xiaoyu Pan,1,2,* Yang-Wen-Qing Zhang,1,2,* Caixia Dai,1,2,* Junyu Zhang,1,2 Minghe Zhang,1,2 Xi Chen1,2 

1Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Xi Chen, Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430071, People’s Republic of China, Email chenxi2022@whu.edu.cn Minghe Zhang, Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430071, People’s Republic of China, Email minghezhang@whu.edu.cn

Abstract: Cancer treatment is continually advancing, with immunotherapy gaining prominence as a standard modality that has markedly improved the management of various malignancies. Despite these advancements, the efficacy of immunotherapy remains variable, with certain cancers exhibiting limited response and patient outcomes differing considerably. Thus, enhancing the effectiveness of immunotherapy is imperative. A promising avenue is mRNA delivery, employing carriers such as liposomes, peptide nanoparticles, inorganic nanoparticles, and exosomes to introduce mRNA cargos encoding tumor antigens, immune-stimulatory, or immune-modulatory molecules into the tumor immune microenvironment (TIME). This method aims to activate the immune system to target and eradicate tumor cells. In this review, we introduce the characteristics and limitations of these carriers and summarize the application and mechanisms of currently prevalent cargos in mRNA-based tumor treatment. Additionally, given the significant clinical application of immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR)-based cell therapies in solid tumors (including melanoma, non-small-cell lung cancer, head and neck squamous cell carcinoma, triple-negative breast cancer, gastric cancer) and leukemia, which have become first-line treatments, we highlight and discuss recent progress in combining mRNA delivery with ICIs, CAR-T, CAR-NK, and CAR-macrophage therapies. This combination enhances the targeting capabilities and efficacy of ICIs and CAR-cell-based therapies, while also mitigating the long-term off-target toxicities associated with conventional methods. Finally, we analyze the limitations of current mRNA delivery systems, such as nuclease-induced mRNA instability, immunogenicity risks, complex carrier production, and knowledge gaps concerning dosing and safety. Addressing these challenges is crucial for unlocking the potential of mRNA in cancer immunotherapy. Overall, exploring mRNA delivery enriches our comprehension of cancer immunotherapy and holds promise for developing personalized and effective treatment strategies, potentially enhancing the immune responses of cancer patients and extending their survival time.

Keywords: mRNA immunotherapy, LNP-mRNA, CAR, ICI, tumor microenvironment modulation, personalized medicine