Advances in the development of therapeutic mRNA vaccines for cancer therapy

<p indent="0mm">In recent years, therapeutic mRNA vaccines for tumors have emerged as a pivotal component of cancer immunotherapy. These vaccines stimulate specific immune responses against tumor-associated or tumor-specific antigens, leveraging the immune system in the body to target and eliminate cancer cells. Composed of mRNA-encoding tumor antigens and delivery vehicles, mRNA vaccines undergo structural modifications to enhance stability and transfection efficiency. Compared to other types of cancer vaccines, mRNA vaccines offer unique advantages. The mRNA vaccines exhibit excellent tolerability <italic>in vivo</italic>, with adverse reactions typically manageable and short-lived. Compared with DNA vaccines, mRNA vaccines do not pose risks of genomic integration and mutations. Moreover, mRNA vaccines avoid the use of pathogenic bacteria or viruses as carriers, ensuring non-infectious profiles. Furthermore, mRNA vaccines can induce sustained and robust humoral and cellular immune responses more effectively than direct antigen injection. The production process of mRNA vaccines is straightforward and cost-effective due to <italic>in vitro</italic> transcription technology. Herein, this review outlines the mechanism of action of therapeutic mRNA vaccines for cancer therapy. Upon administration, mRNA vaccines are internalized by antigen-presenting cells near the injection site. The internalized mRNA is transported to the cytoplasm and ribosomes for translation. This work discusses the commonly targeted antigens in mRNA vaccines, including tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs). TAAs are often overexpressed in tumor cells but possess weaker immunogenicity, which are commonly used in combination to overcome immune tolerance in mammals. TSAs, derived from tumor cell mutations, are highly tumor-specific and immunogenic but elicit weaker tolerance in body. Personalized vaccines targeting unique mutations in cancer patients have been developed clinically, although their cost remains a significant limitation. The review also covers various administration routes for mRNA vaccines, including intravenous, intramuscular, subcutaneous, nasal, and epicutaneous injections. Importantly, delivery systems play a crucial role in mRNA vaccine efficacy due to the molecule’s large size and negative charge, which hinder cellular uptake, including lipid-based, polymer-based, dendritic cell-based, and other common carriers, each tailored for specific applications and scenarios. Additionally, lipid nanoparticles (LNP) are currently the most advanced delivery system, employed in approved COVID-19 mRNA vaccines. Finally, this review summarizes current limitations and future challenges facing therapeutic mRNA vaccines for cancer. Addressing these challenges is essential for advancing the development and application of mRNA vaccines in oncology. This comprehensive review not only provides insights into the evolving landscape of therapeutic mRNA vaccines for cancer therapy, but also highlights the mechanisms, advantages, challenges, and potential for cancer combination therapy.