mRNA vaccines in tumor targeted therapy: mechanism, clinical application, and development trends

Abstract

Malignant tumors remain a primary cause of human mortality. Among the various treatment modalities for neoplasms, tumor vaccines have consistently shown efficacy and promising potential. These vaccines offer advantages such as specificity, safety, and tolerability, with mRNA vaccines representing promising platforms. By introducing exogenous mRNAs encoding antigens into somatic cells and subsequently synthesizing antigens through gene expression systems, mRNA vaccines can effectively induce immune responses. Katalin Karikó and Drew Weissman were awarded the 2023 Nobel Prize in Physiology or Medicine for their great contributions to mRNA vaccine research. Compared with traditional tumor vaccines, mRNA vaccines have several advantages, including rapid preparation, reduced contamination, nonintegrability, and high biodegradability. Tumor-targeted therapy is an innovative treatment modality that enables precise targeting of tumor cells, minimizes damage to normal tissues, is safe at high doses, and demonstrates great efficacy. Currently, targeted therapy has become an important treatment option for malignant tumors. The application of mRNA vaccines in tumor-targeted therapy is expanding, with numerous clinical trials underway. We systematically outline the targeted delivery mechanism of mRNA vaccines and the mechanism by which mRNA vaccines induce anti-tumor immune responses, describe the current research and clinical applications of mRNA vaccines in tumor-targeted therapy, and forecast the future development trends of mRNA vaccine application in tumor-targeted therapy.

Keywords: Clinical application; Development trends; Mechanism; Tumor-targeted therapy; mRNA vaccines.

Fig. 1

Application field of mRNA vaccines. Legend: The mRNA vaccine delivery systems primarily encompass three categories: 1) Carrier-based delivery systems, including lipid nanoparticles (LNPs), cationic nanoemulsions (CNEs), cationic peptides (e.g., protamine), viral replicating particles (VRPs), and polymers. 2) Dendritic cell mRNA delivery systems (DCs mRNA). 3) Naked mRNA. Presently, mRNA vaccines are predominantly employed in the treatment of various diseases, such as: 1) Cardiovascular diseases, including myocardial infarction and heart failure [6]. 2) Metabolic diseases, such as muscular dystrophy [7] and porphyria [8]. 3) Genetic disorders, including glycogen storage disease [9]. 4) Allergic diseases, such as food allergies [27]. 5) Infectious diseases, including human papillomavirus (HPV) [28], Corona Virus Disease 2019 (COVID-19) [29], and human immunodeficiency virus (HIV) [30], among others. 6) Tumors, such as prostate cancer [10] and glioma [31], among others. Naked mRNA vaccines are primarily utilized in the treatment of tumors [32] and infectious diseases [33]. DC-loaded mRNA vaccines are mainly applied in the treatment of tumors [10]

Fig. 2

mRNA vaccine induces innate immune mechanism. Legend: Upon stimulation of DC cells, the T cells undergo identification, whereby the MHC complex and TCR receptor on their surface serve as the initial signals for cellular immune response. Antigen-presenting cells (APCs) recognize the mRNA, activating TLR and prompting the detection of PAMP, thereby initiating the second signal. The activated second signal translocates to the nucleus as a transcription factor, recruiting various Trans-acting factors to facilitate the expression of proinflammatory cytokines and chemokines. This dual signal pathway effectively activates the initial T cells. In non-immune cells, RIG-I and MDA5 are involved in sensing exogenous mRNA and inducing cytokines/chemokines to recruit innate immune cells

Fig. 3

mRNA vaccine induces adaptive immune mechanism. Legend. After translation, the proteins encoded by mRNA are taken up by antigen-presenting cells (APCs) via mechanisms such as micropinocytosis, endocytosis, or phagocytosis. These antigens are subsequently processed into peptides and loaded onto the MHC class I pathway. The translation conducted by ribosomes produces immunogenic proteins, which are degraded into fragments within the proteasome and presented to CD8 + T cells via MHC-I. An alternative pathway allows for the direct transport of antigens from the cytoplasm to lysosomes, or the incorporation of a lysosome-targeting sequence within the mRNA structure for lysosomal degradation. The resulting MHC-II peptide complexes are then recognized by the T cell receptor (TCR) on CD4 + T cells

Fig. 4

mRNA vaccines reshape tumor immune microenvironment (TIME). Legend.mRNAvaccine possesses the potential to reshape the tumor immune microenvironment via two primary mechanisms. Firstly, it regulates the equilibrium between M1 and M2 macrophages, thus transforming M2 macrophages into M1 macrophages. Secondly, it induces the secretion of cytokines by various T cells (For example T helper cell). Additionally, the vaccine promotes the maturation of dendritic cells (DC) through Toll-like receptor (TLR) receptors, activates the transcription factor NF kB to stimulate the maturation of cytotoxic T lymphocytes (CTL), and prompts T helper cells to secrete cytokines