mRNA vaccine in cancer therapy: Current advance and future outlook

The paper frames cancer immunotherapy as a transformative approach that has evolved from early historical attempts (e.g., Coley’s toxin) to modern breakthroughs recognized in 2013. It outlines the discovery and use of tumor antigens (TAAs and TSAs) that catalyzed vaccine development and the emergence of multiple vaccine platforms (whole-cell, DNA, mRNA, antigen, and dendritic cell vaccines). Therapeutic cancer vaccines aim to specifically activate the immune system against tumor cells, offering potential for higher response rates and improved quality of life versus surgery, chemotherapy, or radiotherapy. Owing to low toxicity, rapid production, and the ability to encode diverse antigens, mRNA vaccines have rapidly advanced as a key modality in tumor biotherapy. The review aims to summarize advantages, limitations, mechanisms, technological innovations, clinical progress, and future directions of mRNA cancer vaccines.

The review synthesizes foundational and contemporary literature on cancer vaccines and mRNA platforms. It covers: (1) Basics of tumor immunology and the role of vaccines in inducing durable immune responses via recognition of tumor antigens. (2) Preventive cancer vaccines targeting oncogenic viruses, notably HBV and HPV, with global implementation and public health impact. (3) Therapeutic cancer vaccines requiring TAAs or TSAs, with challenges of immune tolerance for TAAs and cost/complexity for personalized TSA/neoantigen vaccines. (4) Historical milestones in mRNA therapeutics: discovery of mRNA (1961), in vitro translation (1969), liposome delivery (1978), early tumor immunotherapy applications (1995), nucleoside-modified RNA reducing innate immunogenicity (2005), and the approval of COVID-19 mRNA vaccines in 2020–2021. (5) Comparative advantages of mRNA versus DNA/protein vaccines, including non-integration, tunable stability, rapid scalable manufacturing, and suitability for personalization via neoepitope selection. (6) Classification by mRNA type (non-replicating mRNA, self-amplifying mRNA, trans-amplifying mRNA), administration routes (s.c., i.d., intranodal, i.m., i.v., intratumoral, intrathecal), and delivery systems (lipid-based, polymer-based, polypeptidic, hybrid, virus-based, exosomes, microneedles). (7) Recent innovations: structural element optimization (cap, UTRs, codon optimization, poly(A) tail), manufacturing platform advances (co-transcriptional capping, purification to remove dsRNA, TFF), and delivery technologies (LNPs, CARTs, CPPs, VLPs). (8) Safety, biosafety, and population considerations; and (9) future opportunities in personalized neoantigen vaccines and combination therapies.

- mRNA cancer vaccines offer distinct advantages: rapid and cost-effective manufacturing via in vitro transcription; non-infectious and non-integrating mechanism with tunable half-life; and strong, reliable immune responses with potential for both cellular (CD8+/CD4+) and humoral immunity. - Personalization: Tumor-specific neoepitopes can be identified by next-generation sequencing and encoded into individualized mRNA vaccines, improving specificity and minimizing off-target effects. - mRNA vaccine classes: non-replicating mRNA (simpler but less durable expression), self-amplifying mRNA (higher expression and longevity at lower doses), and trans-amplifying mRNA (shorter RNAs amplified in trans; effective in mice at doses as low as 50 ng, even unformulated). - Administration routes: intradermal, subcutaneous, intranodal (elicits potent T cell responses), intramuscular, intravenous (systemic, often liver-targeted), intratumoral (can reprogram TME), intrathecal (for CNS lesions). Route affects immunogenicity and efficacy. - Structural and manufacturing innovations: enhanced caps and UTR engineering (e.g., NASAR UTR) boost translation; optimal poly(A) tail length around ~100 nt supports stability and translation; co-transcriptional capping (e.g., CleanCap) lowers cost/complexity; improved purification removes dsRNA contaminants (>90% removal with cellulose-based methods) and enables scale-up (IEC, TFF). - Delivery systems: LNPs are the most clinically advanced; polymers (e.g., PEI derivatives, CARTs) enable co-delivery of adjuvants (e.g., CpG); peptide-based carriers (protamine, CPPs) protect mRNA and activate APCs; virus-like particles, exosomes, and microneedles broaden delivery options. - Immunomodulation: mRNA can encode antigens and immunomodulators (e.g., IL-12, OX40L) to remodel the tumor microenvironment toward Th1 responses and enhance antitumor immunity. - Clinical momentum: mRNA-4157 (Moderna) combined with PD-1 blockade (KEYTRUDA) under evaluation; BioNTech’s BNT111 (FixVac) and BNT122 (individualized) advancing in melanoma and colorectal cancer. - Logistics and stability: Lyophilization can extend LNP-mRNA stability for distribution; spray-drying offers alternative drying with lower cost/energy. - Limitations and risks: innate RNA sensing (PKR, OAS/RNase L, MDA-5, TLR3) may inhibit translation; special populations (elderly, children, pregnant women, immunosuppressed) require tailored considerations; supply chain and cold chain constraints, and vaccine hesitancy, can limit effectiveness.

The review argues that mRNA vaccines address core challenges in cancer vaccination by enabling rapid, scalable, and precise antigen delivery without genomic integration risks. Advances in structural optimization, purification, and delivery substantially improve translation efficiency, immunogenicity, and safety profiles. Personalized neoantigen vaccines leverage tumor genomics to overcome central tolerance and improve T cell specificity, while combinations with checkpoint inhibitors and cytokine/adjuvant-encoding mRNAs can amplify antitumor responses and remodel immunosuppressive tumor microenvironments. Remaining hurdles include mitigating detrimental innate immune activation that restricts antigen expression, ensuring efficacy and safety across diverse patient populations, and overcoming real-world implementation barriers (stability, distribution, and public acceptance). Collectively, the field is moving toward clinically practical, potent, and tailored mRNA cancer vaccines.

mRNA-based cancer vaccines, accelerated by successes against COVID-19, are emerging as potent therapeutic tools distinct from the few approved prophylactic cancer vaccines (HBV, HPV). Their ability to encode multiple antigens and immunomodulators, together with maturing manufacturing and formulation platforms, supports rapid, scalable deployment and personalization via neoantigens. The overarching goal is to maximize efficacy while minimizing adverse effects. Continued improvements in mRNA design, purification, delivery, stability, and mechanistic understanding, along with rigorous clinical evaluation and combination strategies, are essential to realize the full potential of mRNA cancer vaccines.

- Innate immune sensing can suppress antigen expression: dsRNA byproducts activate PKR (eIF2α phosphorylation), OAS/RNase L-mediated degradation, and receptors such as MDA-5 and TLR3, reducing translation and vaccine efficacy if mRNA is not properly designed/purified. - Population-specific considerations: elderly may need tailored formulations/boosting; children often exhibit higher reactogenicity and may require lower doses; data in pregnancy are limited; immunosuppressed patients show attenuated responses. - Scope limitations: few efforts against bacterial/parasite-associated cancers due to antigen identification challenges, immune evasion, and availability of effective drugs; cost–benefit may be unfavorable. - Effectiveness dependencies: packaging, storage, preparation, and administration quality; cold-chain vulnerabilities; supply chain risks; vaccine hesitancy and potential political pressures affecting development timelines. - Long-term safety/efficacy data and head-to-head comparisons of platforms are limited; extensive preclinical and post-approval surveillance are required.