Research Progress of mRNA Vaccines for Cancer Treatment
Yingying Chen
Hubei University of Chinese Medicine, Wuhan, Hubei, China
Keywords: mRNA Vaccines, Cancer Immunotherapy, Delivery Systems.
Abstract: Cancer has a high mortality rate and a high recurrence and metastasis rate, making it one of the most
threatening diseases to humans at present. Traditional cancer treatment methods all have limitations, so it is
very necessary to explore new treatment strategies. mRNA vaccines have unique advantages in cancer
treatment and have shown excellent therapeutic effects in previous experimental studies. According to the
type of RNA used, mRNA vaccines can be divided into four categories. After the cancer mRNA vaccine
enters the human body and reaches the target cells, the antigen proteins are translated through ribosomes in
the cytoplasm, thereby stimulating the body's anti-cancer immune response. There are many delivery systems
for mRNA vaccines, mainly including lipid-based mRNA delivery tools, polymeric nanoparticles, peptide-
based nanoparticles, inorganic nanoparticles, and biogenic nanoparticles. Cancer mRNA vaccines can encode
tumor-associated antigens (TAAs), tumor-specific antigens (TSAs), CRISPR-Cas9, tumor suppressor factors,
cytokines, therapeutic antibodies, etc., each with different advantages and functions. In addition, there are
significant differences among mRNA vaccines used for different cancer treatments. mRNA vaccines for
cancer treatment still face many pain points, such as the difficulty in determining universal and effective target
antigens. In the future, we can continuously optimize cancer mRNA vaccines for these pain points to make
them better applied in cancer treatment.
1 INTRODUCTION
Cancer is currently one of the most threatening
diseases to humans. Despite ongoing medical
advancements, many types of cancer still have
extremely low cure rates in advanced stages. For
instance, pancreatic cancer, due to its non-specific
early symptoms and the current lack of reliable
biomarkers for accurate diagnosis, often results in
patients being diagnosed at an advanced stage.
According to statistics, patients with advanced
pancreatic cancer only have a five-year survival rate
of the single digits (Rawla et al., 2019). Cancer
patients may still experience recurrence after local
treatments such as surgery. Additionally, cancer cells
can spread through blood circulation, the lymphatic
system, and other pathways to other parts of the body.
Once the tumor spreads, it significantly increases the
difficulty of treatment and causes damage to multiple
organs and systems throughout the body.
Traditional cancer treatment methods primarily
include surgery, chemotherapy, and radiotherapy, all
of which have limitations. Surgery cannot eradicate
cancer cells that have already metastasized or spread,
has limited applicability for tumors in special
locations (such as brain tumors), and carries risks and
potential postoperative complications.
Chemotherapy, which involves using cytotoxic drugs
to kill cancer cells, lacks selectivity, damages normal
cells simultaneously, and can cause severe side
effects. Furthermore, cancer cells can easily develop
drug resistance. Radiotherapy utilizes high-energy
rays to destroy cancer cells locally, targeting only the
local lesion and causing radiation damage to normal
tissues. Therefore, the exploration and research of
novel cancer treatment strategies are highly
necessary.
In preclinical studies and early clinical trials,
mRNA-based cancer vaccine therapy has
demonstrated equivalent or better efficacy compared
to DNA or peptide platform-delivered cancer
vaccines (Huff et al., 2022). mRNA vaccines, as a
novel cancer treatment method, are safe and effective.
They can be delivered to target areas within the
human body through various methods, rapidly
translating into antigen proteins upon reaching target
cells, stimulating the body's immune response, and
effectively killing cancer cells. Moreover, since
212
Chen, Y.
Research Progress of mRNA Vaccines for Cancer Treatment.
DOI: 10.5220/0014464800004933
Paper published under CC license (CC BY-NC-ND 4.0)
In Proceedings of the 1st International Conference on Biomedical Engineering and Food Science (BEFS 2025), pages 212-217
ISBN: 978-989-758-789-4
Proceedings Copyright © 2026 by SCITEPRESS – Science and Technology Publications, Lda.

mRNA can encode complete cancer cell antigens, it
has the ability to overcome the limitations of human
leukocyte antigens (HLA), leading to a wider immune
response. Additionally, because mRNA cannot
integrate into chromosomes, it does not cause genetic
mutations and is relatively safe. Thus, mRNA
vaccines represent an excellent cancer treatment
method. In the following sections, I will provide a
detailed introduction to cancer mRNA vaccines.
2 BACKGROUND
INTRODUCTION OF CANCER
MRNA VACCINES
2.1 Classification
mRNA vaccines can be divided into four categories:
non-replicating mRNA (nrmRNA) vaccines, self-
amplifying RNA (saRNA) vaccines, trans-amplifying
RNA (taRNA) vaccines, and circular RNA
(circRNA) vaccines (Szabó et al., 2022).
NrmRNA only encodes the gene of interest (GOI),
along with 5' and 3' untranslated regions. NrmRNA
can only replicate the target antigen and cannot self-
amplify within cells.
SaRNA vaccines mimic the replication
characteristics of alphaviruses. The sequence
encoding the GOI and the sequence encoding the
RNA polymerase are placed on the same linear RNA.
Specifically, saRNA vaccines are modified from
alphaviruses. The sequence encoding non-structural
proteins is retained, while the region encoding
structural proteins is replaced by the sequence
encoding the GOI. The non-structural proteins are
translated from the sequence encoding non-structural
proteins and assembled into an RNA replicase
complex. After entering the cell, saRNA can replicate
the full-length positive-strand RNA (containing the
sequences encoding the GOI and RNA polymerase)
and also the RNA encoding only the GOI. Therefore,
a small amount of saRNA can self-amplify in the cell
to generate a large amount of RNA, thus producing a
large amount of target antigen (Beissert et al., 2020).
TaRNA vaccines separate the sequence encoding
the trans-replicons (TRs) of the GOI and the sequence
encoding the RNA polymerase onto two linear RNAs,
avoiding the problems caused by the large and
complex molecular sequences in saRNA and greatly
improving the translation efficiency.
CircRNA vaccines are more stable than linear
RNA because they feature a covalently closed
circular structure without the 5' cap and 3' Poly(A)
structure.
2.2 Principle of mRNA Vaccines for
Cancer Treatment
The mRNA vaccine encoding relevant antigens is
delivered into the human body by a selected delivery
system. After entering the cell, the target antigen is
translated in the cytoplasm through ribosomes and
undergoes post-translational modification. The
antigen is degraded by the proteasome complex.
Some small peptides are transported to the rough
endoplasmic reticulum of the cell and are presented
by major histocompatibility complex (MHC) class I
molecules on the cell surface. After CD8+ T cells
recognize the relevant antigens, they are activated and
exert a cytotoxic effect, leading to the apoptosis of
tumor cells (Kong et al., 2023). At the same time,
some antigens are taken up and degraded by cells.
The degraded antigens are presented to CD4+ T cells
by MHC class II molecules. CD4+ T cells activate B
cells to form plasma cells, which produce neutralizing
antibodies. Phagocytes are activated through
inflammatory factors, thus playing a role in clearing
tumor cells (Chaudhary et al., 2021).
3 CLASSIFICATION OF
DELIVERY SYSTEMS
3.1 Lipid-Based mRNA Delivery Tools
Lipid-based mRNA delivery tools are currently the
most advanced platforms for delivering mRNA in
clinical settings. They mainly include lipoplexes and
lipid nanoparticles (LNPs), which were previously
used to deliver deoxyribonucleic acid (DNA) and
small interfering RNA (siRNA), respectively (Estapé
Senti et al., 2024).
A lipid-based mRNA delivery system typically
consists of the following components: 1. Cationic
lipids (lipoplexes) or ionizable lipids; 2. Non-cationic
(phospho)lipids; 3. Cholesterol derivatives; 4. Lipids
that prevent aggregation (stabilizers, such as
polyethylene glycol-lipid conjugates). During the
encapsulation process, the aqueous phase containing
mRNA and the organic phase containing cationic or
ionizable lipids are rapidly mixed to enable the
efficient complexation of mRNA with lipid
compounds, thus achieving high-efficiency
encapsulation of mRNA (Estapé Senti et al., 2024).
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Toxicity and liver accumulation are limitations of
lipid-based mRNA delivery tools.
3.2 Polymeric Nanoparticles
Currently, poly (β-amino esters) (PBAEs),
poly(lactic-co-glycolic acid) (PLGAs), etc., have been
studied and can form good delivery systems
(Piotrowski-Daspit et al., 2020). For example, Zhang
et al. designed a polymeric nanoparticle composed of
poly (β-amino esters), polyglutamic acid (PGA), and
di-mannose moieties to deliver mRNA encoding
transcription factors. The therapeutic efficacy of this
polymeric nanoparticle was demonstrated in models
of melanoma, glioblastoma, and ovarian cancer
(Zhang et al., 2019). In related studies, cationic
chemical groups were added to PLGAs, or they were
coated with lipids to solve the problem that they
cannot complex with nucleic acids under neutral pH
conditions (Paunovska et al., 2022; Hasan et al.,
2012). Polymeric nanoparticles can be incorporated
into lipid delivery systems to deliver mRNA,
enhancing their delivery efficiency and stability in
serum.
3.3 Peptide-Based Nanoparticles
Currently, peptide-based nanoparticles mainly
include cell-penetrating peptides (CPPs) and
protamines. The sequences of cell-penetrating
peptides are generally very short and have
amphipathic regions or cationic regions, enabling
them to cross the cell membrane. Amphipathic cell-
penetrating peptides are capable of smoothly passing
through the cell membrane because of their lipophilic
and hydrophilic amino acids. Arginine, histidine, and
lysine are found in cationic cell-penetrating peptides.
They can interact with and pass through the
negatively charged cell membrane because of their
positive charges (Shoari et al., 2021). Protamine is an
arginine-rich polypeptide that has the ability to
condense mRNA into nanoparticles. Protamine has
immunogenicity and can stimulate the immune
system. For general drug delivery systems, this is a
drawback, but for cancer mRNA vaccines, this may
be a favorable factor (Kauffman et al., 2016).
Similarly, peptide-based nanoparticles can also be
used in combination with other existing delivery
systems.
3.4 Inorganic Nanoparticles
Inorganic nanoparticles include gold nanoparticles,
mesoporous silica nanoparticles, calcium phosphate
nanoparticles, iron oxide nanoparticles, etc. They can
be designed into the desired shapes and sizes, and
their surfaces are easily chemically modified.
The Ca2+ in calcium phosphate nanoparticles
easily binds to negatively charged nucleic acid
molecules, and calcium phosphate can easily pass
through the lipid bilayer of the cell membrane and be
dissolved by the acidic environment of the endosome,
making it a very good delivery system (Levingstone
et al., 2020). At the same time, since calcium
phosphate is an inorganic mineral present in the
human body, it has high biocompatibility,
biodegradability, and no immunogenicity.
It should be noted that some inorganic
nanoparticles cannot be degraded or cleared by the
human body, so their toxicological evaluation should
be carried out in advance.
3.5 Biogenic Nanoparticles
Biogenic nanoparticles include exosomes, cell
membrane nanoparticles, bacterial vesicles, etc. They
have good biocompatibility and are non-toxic.
Because there are cell receptors on their surfaces, they
can avoid being rapidly degraded by the human body,
ensuring the effective delivery of mRNA.
4 DIFFERENT MRNA VACCINES
FOR CANCER TREATMENT
There is a wide variety of cancer mRNA vaccines,
including mRNA encoding tumor-associated antigens
(TAAs), mRNA encoding tumor-specific antigens
(TSAs), mRNA encoding chimeric antigen receptors
(CARs) or T-cell receptors (TCRs), mRNA encoding
CRISPR-Cas9, mRNA encoding tumor suppressor
factors, mRNA encoding cytokines, and mRNA
encoding therapeutic antibodies.
TAAs are overexpressed in tumor cells and have
low or no expression in normal tissues. They are non-
mutated proteins with poor tumor specificity and
immunogenicity. Generally, mammals have a high
degree of immune tolerance to a single TAA.
Therefore, multiple TAAs are usually selected for
cancer treatment with mRNA vaccines (He et al.,
2022). However, TAA vaccines also have their
drawbacks. For example, TAAs may mutate and
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develop vaccine resistance, which limits their
application. TSAs are neo-antigens resulting from
tumor cell mutations and are not expressed in normal
tissues. They have strong tumor specificity and
immunogenicity and high affinity for MHC
molecules. Since TSAs do not exist in normal cells,
they do not cause immune tolerance in the body. They
can be well recognized as "non-self" substances by
the host immune system, making them very important
targets for cancer vaccines with weak "off-target
effects". Personalized tumor mRNA vaccines can be
designed according to the unique mutation
characteristics of tumor cells in cancer patients for
personalized treatment. Currently, there are
individualized mRNA vaccines encoding multiple
TSAs under pre-clinical and clinical research, and
good progress has been made. However, this method
currently has the disadvantage of high cost.
Both Chimeric Antigen Receptor T-Cell
Immunotherapy (CAR-T) and T-cell receptor
engineered T cell therapy (TCR-T) belong to adoptive
cell transfer therapy (ACT). ACT refers to obtaining
T cells from tumor patients or healthy donors,
modifying them specifically in vitro to enhance their
targeting and killing effects on tumors, and then
infusing them into patients for tumor treatment (Rataj
et al., 2019). CAR-T uses genetic engineering
techniques to equip T cells with chimeric antigen
receptors (CARs) that can specifically recognize
antigens on the surface of tumor cells in vitro. The
gene encoding CAR is mainly introduced into T cells
through viral vectors. The modified T cells can
recognize tumor cell antigens, does not rely on MHC
molecules (Schepisi et al., 2019), activate more
efficiently, and thus kill tumor cells more effectively.
TCR-T first screens out TCR sequences that can
specifically recognize tumor antigens through genetic
engineering techniques and then introduces the
screened TCR genes into the patient's own T cells,
enabling them to express T-cell receptors (TCRs) that
can specifically recognize endogenous antigens of
tumor cells. The modified T cells are activated by
recognizing the antigen peptides of tumor cells
presented by human leukocyte antigen (HLA) to
better kill tumor cells. Delivering mRNA
nanoparticles encoding CARs or TCRs into the
human body to reach T cells and genetically
reprogramming circulating T cells in the body to
directly generate CAR-T cells or TCR-T cells in vivo
is a cost-effective treatment method.
CRISPR-Cas9 is a system composed of clustered
regularly interspaced short palindromic repeats
(CRISPR) and CRISPR-associated proteins (Cas). It
consists of the Cas9 endonuclease and single-guide
RNA (sgRNA) (Li et al., 2018). After the mRNA
encoding CRISPR-Cas9 enters the human body and
reaches the target cells, the Cas9 endonuclease can be
synthesized in the cytoplasm. It forms a Cas9-sgRNA
ribonucleoprotein complex (RNPs) with specific
sgRNA. The CRISPR-Cas9 system can perform gene
editing. First, the sgRNA is used for guiding and
positioning. The sgRNA has a specific nucleotide
sequence that can base-pair with the target DNA
sequence, thus guiding the Cas9 protein to the target
site (Liao et al., 2024). Subsequently, the Cas9
protein uses its nuclease activity to cut the DNA
double-strand at the specific location. When the DNA
double-strand is broken, the cell initiates its own
repair mechanism, including non-homologous end-
joining (NHEJ) and homologous recombination
repair (HR). The NHEJ method is error-prone and
may cause the target gene to lose its function. The HR
method can accurately repair the broken DNA
according to the homologous template. By
introducing the required repair template, precise gene
editing can be achieved (Liao et al., 2024). Therefore,
the mRNA encoding CRISPR-Cas9 can generate
RNPs in vivo to complete specific gene editing,
thereby achieving the goal of tumor treatment.
The types of mRNA vaccines for cancer treatment
are very diverse, and there are significant differences
among mRNA vaccines for different cancers. The
following briefly introduces two recently studied
cancer mRNA vaccines:
4.1 Pancreatic Cancer mRNA Vaccine
Based on the S100 Protein Family
Pancreatic cancer is a common digestive tract
malignant tumor, known as the "king of cancers".
Patients with advanced pancreatic cancer only have a
five-year survival rate of the single digits (Rawla et
al., 2019), making it one of the malignant tumors with
the worst prognosis.
The S100 protein family is one of the ligands of
the receptor for advanced glycation end-products
(RAGE). It can activate RAGE and downstream
signaling pathways, thereby affecting the
proliferation, survival, and metastasis of cancer cells
(Leclerc and Vetter, 2015). The S100 protein not only
plays a role in tumor cells but also affects the tumor
microenvironment by regulating the inflammatory
response, thus promoting tumor growth and
metastasis. Obviously, it is a good starting point for
the development of new pancreatic cancer mRNA
vaccines. In vaccine development, it is crucial to
Research Progress of mRNA Vaccines for Cancer Treatment
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select target antigens with high immunogenicity and
appropriate receptors. In this study, the vaccine was
constructed by linking all selected (CTL, HTL, and
B-cell) epitopes of S100A4, S100A6, S100A8,
S100A9, and S100A11. A specific delivery system
delivers the vaccine to the target cells. And the
vaccine binds to toll-like receptors TLR-2 and TLR-
4, triggering a series of powerful immune responses
(Masum et al., 2024). According to the test results, B
cell and T cell expression is increased, dendritic cells
(DC) exhibit long-lasting immunity, INF-γ levels rise
noticeably, and tumor growth factor-β (TGF-β)
expression is suppressed, proving that the vaccine can
produce a good immune response. This is a valuable
research direction (Masum et al., 2024).
4.2 MRNA Vaccine for Malignant
Tumors Caused by HPV Infection
Persistent human papillomavirus (HPV) infection can
cause various malignant tumors such as cervical
cancer. Therefore, it is very necessary to develop
targeted mRNA vaccines.
A related study introduced an mRNA vaccine
encapsulated in lipid nanoparticles (LNP) expressing
tHA-mE7-mE6. This mRNA vaccine aims to
introduce mutations into the E6 and E7 of HPV to
eliminate their oncogenicity (Li et al., 2024). tHA is
a truncated influenza hemagglutinin protein that can
bind to the CD209 receptor on the surface of dendritic
cells (DC). tHA is also encoded into the mRNA
because the fusion of tHA with mE7-mE6 can help
antigen-presenting cells (APC) more effectively take
up antigens, thereby better stimulating the immune
response. The study shows that in the E6 and E7+
tumor model, the mRNA vaccine expressing tHA-
mE7-mE6 has a better therapeutic effect than the
mRNA vaccine expressing only mE7-mE6 (Li et al.,
2024). After treatment with the mRNA vaccine
expressing tHA-mE7-mE6, a strong CD8+ T-cell
immune response can be stimulated. At the same
time, the tumor infiltration of DC and NK cells
increases after treatment, proving that it can induce
strong anti-tumor immunity in the peripheral and
tumor microenvironments, which is very helpful for
the prevention and treatment of E6 and E7+ tumors
and has broad development prospects (Li et al., 2024).
5 CHALLENGES AND OUTLOOK
5.1 MRNA Vaccines for Cancer
Treatment Still Face Many Pain
Points
Firstly, due to the high heterogeneity of tumor cells,
it is difficult to determine universal and effective
target antigens. TAAs have the problem of self-
immune tolerance. Although TSAs have strong
specificity, the cost and difficulty of personalized
treatment are very high (He et al., 2022).
Besides, after mRNA enters the human body, it
may over-activate the innate immune system, inhibit
antigen expression, and fail to activate the adaptive
immune response well, affecting the killing effect on
tumor cells. Moreover, tumor cells can evade the
recognition and attack of the body's immune system
through immune escape, making it difficult for the
vaccine to work effectively.
Last but not least, mRNA molecules are very
unstable, requiring a high-performance delivery
system. Currently, the delivery efficiency of existing
delivery systems is low.
5.2 Suggestions for Future Research on
Cancer mRNA Vaccines Based on
the above Pain Points
Firstly, we can use precise detection technologies
such as gene sequencing and proteomics to better
analyze the antigen expression profiles of tumor cells
and combine cutting-edge analysis methods to screen
the optimal antigen targets (He et al., 2022).
Moreover, multiple tumor antigens can be combined
to design vaccines.
What’s more, we can combine cancer mRNA
vaccines with other treatment methods such as
immune checkpoint inhibitors for combined
immunotherapy (He et al., 2022).
In the research on delivery systems, new carriers
such as polymer nanoparticles and exosomes can be
developed to improve the stability of mRNA. The
LNP technology can also be optimized to improve the
delivery efficiency.
5.3 Outlook for Cancer mRNA
Vaccines
mRNA vaccines for cancer treatment are a very
valuable research field. In the future, it is very
promising to achieve breakthroughs in cancer
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treatment, which is worthy of our unremitting efforts
and investment.
6 CONCLUSION
There are many studies and clinical trials on cancer
mRNA vaccines, which is a very valuable and
promising research area, but the research on it is also
facing some difficulties, such as difficulty in
determining universal and effective target antigens,
immune escape of tumor cells, difficulty in ensuring
effective delivery of mRNA, and low delivery
efficiency of existing delivery systems. In future
research, we need to overcome these difficulties in a
targeted manner, use precision detection technology
to better analyze the antigen expression profile of
tumor cells, and screen out the optimal antigen
targets, we can combine a variety of tumor antigens
to design vaccines, we can develop new delivery
vectors and optimize LNP technology to improve
delivery efficiency, and continuously optimize and
improve cancer mRNA vaccines, so that they can be
better used to treat or even cure cancer.
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