Circular RNA vaccines: Pioneering the next-gen cancer immunotherapy

• Published in: Cancer pathogenesis and therapy Vol. 3; no. 4; pp. 309 - 321
• Main Authors: Das, Uddalak, Banerjee, Soupayan, Sarkar, Meghna, Muhammad L, Fathah, Soni, Tanveen Kaur, Saha, Madhumita, Pradhan, Gayatri, Chatterjee, Bhaskarjyaa
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2025; Elsevier
• Subjects: Cancer vaccines; Circular; Drug delivery systems; Immunology; Immunotherapy; mRNA vaccines; Neoplasms; Review; RNA; Circular; Cancer vaccines; Drug delivery systems; Immunology; RNA; Immunotherapy; mRNA vaccines; Neoplasms
• ISSN: 2949-7132; 2097-2563; 2949-7132
• DOI: 10.1016/j.cpt.2024.11.003

Circular ribonucleic acid (circRNA) vaccines have emerged as a revolutionary strategy in cancer immunotherapy, facilitating novel approaches to induce robust and durable immune responses. Unlike traditional linear messenger RNA (mRNA) vaccines, circRNAs exhibit exceptional stability, enhanced translational efficiency, and resistance to exonuclease degradation, making them ideal candidates for vaccine development. This review delved into the fundamental principles underlying circRNA biology, highlighting their unique structural advantages and translational potential. We examined recent advancements in circRNA vaccine design, focusing on their application in oncology. As the circRNA-based cancer vaccine is a relatively novel technology, findings from all the major studies describing its efficacy were discussed. We further investigated their combination with other immunotherapeutic modalities, such as immune checkpoint inhibitors and adoptive cell therapies, that ensure the maximal anticancer effects of circRNA vaccines. Large-scale manufacturing, immunogenicity optimization, delivery systems, and other challenges and future directions in this field were also discussed. This study aims to thoroughly analyze the state-of-the-art and potential future applications of circRNA vaccines in cancer immunotherapy, highlighting them as exciting possibilities for next-generation cancer therapies. Mechanism of action of circular RNA vaccines in cancer immunotherapy. In step 1, linear mRNA is transformed into covalently closed loops through ligation, thereby enhancing its stability and translational efficiency compared to linear mRNA, which possesses exonuclease-sensitive ends. This circularization not only optimizes RNA for higher expression levels but also reduces its immunogenicity, mitigating unwanted immune responses that typically degrade linear RNA. In step 2, the circRNA vaccine is administered intravenously. Delivery methods include LNPs, exosomes, or other nanocarriers; methods without carriers are also sometimes employed. The use of LNPs improves cellular uptake, shields the RNA from degradation, and promotes endosomal escape, enabling cytoplasmic release. In step 3, once internalized by the target cells, the circRNA is translated into tumor-specific antigenic proteins by ribosomes. These antigens are subsequently processed and presented on the cell surface by APCs, such as dendritic cells, thereby initiating the activation of adaptive immune pathways. Step 4 delineates the activation of the immune response, wherein these tumor antigens are identified by TCRs on cytotoxic T-cells, leading to a vigorous immune attack against cancer cells that present these antigens. Finally, step 5 underscores the potential for combination therapies, where circRNA vaccines, when combined with other cancer treatments like immune checkpoint inhibitors, radiosensitizers, or chemotherapeutic agents, amplify the overall anti-tumor immune response, thus enhancing the treatment's specificity and efficacy. The figure highlights the potential of circRNA vaccines in fostering a durable, antigen-specific immune memory, presenting a novel platform for personalized cancer therapy. APC: Antigen-presenting cell; circRNA: Circular ribonucleic acid; LNP: Lipid nanoparticle; mRNA: Messenger ribonucleic acid; TCR: T-cell receptor. [Display omitted] •Circular RNA (circRNA) cancer vaccines advance next-gen immunotherapy with enhanced stability and efficacy for precision oncology.•CircRNAs encode tumor antigens and adjuvants, enabling personalized vaccines to modulate heterogeneity and gene expression.•Novel delivery methods, like lipid nanoparticles and exosomes, improve circRNA vaccine efficacy.•Combining circRNA vaccines with therapies like T-cell receptor-engineered T-cell therapy enhances anti-cancer efficacy.