Harnessing dendritic cells as immunological bridges to potentiate mRNA cancer vaccines

Abstract

mRNA-based cancer vaccines have emerged as a transformative immunotherapy, with dendritic cells (DCs) serving as pivotal orchestrators of innate and adaptive antitumor immunity. This review explores how DCs function as immunological bridges to enhance mRNA vaccine efficacy by integrating antigen presentation with coordinated immune cell crosstalk. We first outline the functional diversity of DC subsets, emphasizing their maturation dynamics and intrinsic potential in mRNA vaccines. Next, we discuss key advancements in mRNA vaccine development, including optimized in vitro-transcribed (IVT) mRNA constructs and delivery platforms in vivo. A central focus is the DC-mediated immune response, detailing mechanisms by which DCs prime cytotoxic CD8⁺ T cells, engage CD4⁺ T helper cells, activate B cells for humoral responses, and recruit natural killer (NK) cells for innate killing. This review highlights the current understanding of the role of DCs in enhancing mRNA cancer vaccines and provides perspectives on future research directions, aiming to improve cancer immunotherapy outcomes.

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1. Introduction

Dendritic cells (DCs), first identified by Zanvil Cohn and Ralph Steinman in the 1970s,^1,2 were only widely recognized decades later as central orchestrators of adaptive immunity.³ Since the mid-1990s, the full scope and significance of DC diversity have been widely acknowledged for therapeutic vaccination of patients with cancer.^4,5 Steinman's 2011 Nobel Prize for Physiology or Medicine underscored their pivotal role in acquired immunity.^6–9 Currently, DCs are widely recognized as the most effective antigen-presenting cells (APCs) with the exquisite ability to prime naïve T cells, sustaining memory responses and driving antigen-specific adaptive immunity.^10–14

The key objective of vaccination is to induce tumour antigen-specific cytotoxic T lymphocytes (CTLs) that selectively eliminate tumor cells in an antigen-specific way and that are qualified to elicit immunological memory to alleviate tumour relapse.^15,16 Generally, DCs mediate this process by processing and presenting tumor antigens to T and B cells – a critical step that hinges on either exogenous antigen loading or genetic engineering to enforce sustained antigen expression, which is key to initiating an adaptive immune response.^15,17 Among emerging strategies, antigen-encoding mRNA offers a versatile platform for major histocompatibility complex (MHC) class I presentation and CTL activation. In vitro transcribed (IVT) mRNA can be efficiently delivered into APCs via carrier-mediated internalization. Following uptake, individual mRNA transcript drives sustained cytoplasmic antigen production, with subsequent proteasomal degradation of the resulting proteins and loading of processed peptides onto MHC class I molecules. To improve the therapeutic efficacy of mRNA vaccination, three frontiers demand attention: (1) the functional heterogeneity of DC subsets in antitumor immunity, (2) the impact of mRNA-delivery systems on DC activation and antigen processing, and (3) the crosstalk between DCs and other immune cells in shaping therapeutic outcomes.

In this review, we will discuss the current advances of DC lineages based on the functional heterogeneity of DC subsets in the antitumor immune response and how the different maturation states of DCs influence the mRNA vaccine efficacy. Next, the current efforts in mRNA molecular optimization and delivery materials science will be discussed, as this provides a prerequisite for mRNA vaccines. Finally, the interaction between DCs and downstream immune cells will be investigated during cancer therapy.

2. Functional diversity of DCs in the antitumor immune response

2.1. Dendritic cell lineages

Dendritic cells (DCs) comprise a heterogeneous family of bone marrow-derived leukocytes originating from CD34⁺ stem cells. Classically, DCs are classified into four major populations: (i) B220⁺ (in mouse) or CD123⁺(in human) plasmacytoid DCs (pDCs); (ii) conventional DCs (cDCs), further split into type 1 (the CD8α⁺ and/or CD103⁺ (in mouse) or CD141⁺ (in human) cDC1 subset) and type 2 (the more heterogeneous CD11b⁺ (in mouse) or CD1c⁺ (in human) cDC2 subset); (iii) monocyte-derived DCs (MoDCs); and (iv) Langerhans cells (LCs) (Fig. 1).

Fig. 1 Conventional and newly discovered DC subsets (created with https://BioRender.com). DCs have been divided into four subsets, namely, plasmacytoid DCs (pDCs), conventional DCs (cDC1 and cDC2), monocyte-derived DCs (MoDCs), and Langerhans cells (LCs), according to their functional properties and phenotype.

Each subset differs in its capacity for antigen presentation, migration, and cytokine secretion. pDCs get their name from their resemblance to plasma cells, but upon exposure to viral stimuli, pDCs produce enormous amounts of type-I interferon (IFN), such as IFN-α/β. These IFNs play dual roles – promoting cDC1 maturation to enhance antitumor activity,^18,19 while simultaneously expanding regulatory T cells (Tregs) via an inducible co-stimulatory ligand (ICOS-L) to maintain immune tolerance and potentially facilitate tumor immune evasion.^20–22 pDCs express high levels of toll-like receptor (TLR) 7 and TLR9, which are beneficial to recognizing viral and self-nucleic acids to induce immune activation.²³ Although pDCs can differentiate into immunogenic DCs capable of antigen cross-presentation under specific conditions, their efficiency remains inferior to cDCs.^24,25 cDC1s present efficient cellular immunity in cancer and exogenous pathogens owing to their incomparable antigen processing and cross-presentation via major histocompatibility complex class I (MHC-I) molecules to prime CD8⁺ T cells.^3,26–29 Cross-presentation and cytokine secretion specifically by cDC1s were considered to be essential for tumour elimination.^30–32 Through multiple mechanisms including antigen presentation, chemokine/cytokine gradient modulation, tumor-associated antigen (TAA) delivery to lymph nodes, and CD8⁺ T cell priming, cDC1s show tremendous potential for enhancing cancer vaccine efficacy.³³ In contrast, cDC2s specialize in MHC class II-mediated antigen presentation to CD4⁺ T cells, promoting efficient anti-tumour T helper 1 (Th1) or Th17 polarization.³⁴ MoDCs mostly differentiate from infiltrating monocytes in response to inflammation and also be ex vivo induced from monocytes by utilizing cytokines such as the granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4).^35,36 Although generally less immunostimulatory than cDCs, MoDC accessibility through in vitro differentiation from peripheral blood CD14⁺ monocytes has made MoDCs a popular platform for vaccine development to induce anticancer T cell responses and cytokine production.^37,38 Multiple clinical trials have leveraged MoDCs as DC vaccines to cancer therapy. Sipuleucel-T (marketed as PROVENGE, developed by Dendreon) is a representative autologous MoDC vaccine loaded with prostatic acid phosphatase (PAP), a common antigen on prostate cancer cells, and migration to the LNs presents antigens to prompt T cells to recognize and attack prostate cancer cells expressing PAP.⁵ However, the clinical performance was underwhelming, perhaps due to functional impairment of ex vivo-generated MoDCs or limited lymph node homing capacity, resulting in the suboptimal efficacy of such a vaccine constituent.^39–41 LCs, embryonic progenitor-derived macrophages with DC-like functionality, are distributed mainly in the skin epidermis where they capture antigens.⁴² They can transport to local LNs and present the antigens to T cells to elicit immune action.

Collectively, all DC subsets may contribute to anti-cancer responses in complementary ways, with the relative contribution depending on the type of malignancy. Through their specialized functions, these cells form an intricate immune network capable of recognizing and eliminating tumor cells.

2.2. The concept of DC maturation

DCs are considered to be immature without external stimulus. Upon exposure to different stimuli, DCs undergo an intricate series of phenotypical and functional changes to induce multiple states, including phenotypically mature, semi-mature (phenotypically mature or functional maturation), and fully mature.⁴³ The process is a complicated and tightly controlled differentiation closely related to antigen acquisition (Fig. 2). Notably, DCs balance immunity and tolerance and must receive an activating signal to convert from an antigen accumulation state to an antigen presentation state via initiating a terminal differentiation process of “maturation”.^11,44 Proinflammatory or inflammatory stimuli promote immunity; otherwise, they promote tolerance.⁴⁵ Therefore, DCs should receive the appropriate activation signal to prompt an effective anti-cancer response.

Fig. 2 Characteristics of different states of DCs (created using https://BioRender.com).

Immature DCs demonstrate strong phagocytic activity but express low levels of co-stimulatory molecules (CD40, CD80, and CD86) and secrete minimal inflammatory cytokines (IL-10, IL-12, IL-6, and TNF-α), thereby promoting regulatory T cell (Treg) differentiation and immune tolerance. Phenotypically mature dendritic cells (DCs) upregulate the expression of CD28 ligands B7-1 (CD80), B7-2 (CD86) and MHC class II molecules, but produce negligible amounts of inflammatory cytokines such as IL-12 and IL-6.¹¹ Therapeutic agents such as bevacizumab⁴⁶ and the tyrosine kinase inhibitor sunitinib⁴⁷ can induce this state, which has been shown to enhance the percentage of CD86⁺ cells on DCs without indeterminate cytokine secretion. Despite expressing surface markers typically associated with T cell priming capacity, phenotypically mature DCs often fail to activate effective T cell immunity and may instead induce tolerogenicity. On some level, phenotypically mature DCs are also identified as semi-mature DCs, which cause T cell anergy and immune tolerance.^48,49 Similarly, functional maturation, with a certain number of expressed cytokines while low expression of CD80 and CD86, is also a type of semi-mature DC. Thus, semi-mature DCs generally lack either the necessary phenotypic markers or adequate immunostimulatory cytokine production, resulting in impaired T cell interactions and ultimately detrimental immune effects. It has been shown that the semi-mature state is maintained only in the absence of inflammatory stimulation and continues to differentiate into fully mature DCs upon receiving appropriate inflammatory signals.⁵⁰ Both immature and semi-mature DCs elicit tolerogenicity, thereby compromising anticancer immunity, and only fully mature DCs facilitate efficient immune response.

2.3. The potential of dendritic cells in mRNA vaccines

DCs, as professional antigen-presenting cells, are crucial in immunity because of their central role in priming and activating T cells, thereby initiating robust immune responses.⁵¹ The efficacy of mRNA vaccines relies critically on DCs’ capacity for efficient antigen uptake, processing, and presentation. Upon maturation, DCs present tumor-associated antigens (TAAs) to T cells while secreting immunostimulatory cytokines, driving the expansion of neoantigen-specific T cells and eliciting coordinated innate and adaptive antitumor immunity.¹⁷ Unlike conventional therapies, DC-based neoantigen vaccines represent a promising personalized immunotherapy strategy, designed to amplify endogenous antitumor immune responses rather than directly targeting cancer cells.¹⁰ Since the published preclinical studies in the mid-1990s first introduced the concept of using autologous bone marrow derived cells as a viable vaccination option, numerous early-phase clinical trials have been performed across diverse malignancies, laying the bedrock for mRNA-transfected DC vaccines.⁵²

3. The development of mRNA-based vaccines

3.1. mRNA as an attractive source of antigen

The concept of using mRNA for antigen delivery to APCs emerged in the early 1990s.^53,54 Similar to viral infections, IVT mRNA enables endogenous protein synthesis and antigen processing in the cytoplasm, facilitating efficient MHC class I presentation.^55,56 mRNA-based antigen delivery offers several advantages: (1) it provides an easy and safe way to evoke MHC-I presentation and elicit potent cytotoxic lymphocyte (CTL) responses without the risk of insertion mutations;^57–59 (2) its flexible modular design permits rapid adaptation to new antigens, making it ideal for targeting highly mutable pathogens (such as influenza viruses, HIV, etc.);⁶⁰ and (3) it induces CD4⁺ and CD8⁺ T cell responses against the selected antigens in a first-in-human trial, suggesting the safety and feasibility of mRNA for melanoma cancers.⁶¹ In theory, mRNA presents immense potential for developing versatile vaccines against varying antigens due to their affordability, efficient production, and safety.⁶²

3.2. The construct of IVT mRNA

IVT mRNA consists of five major domains: a 5′ cap, a 5′ untranslated region (UTR), an open reading frame (ORF) encoding the protein of interest, a 3′ UTR, and a poly(A) tail,⁶³ which are structurally similar to naturally occurring mature eukaryotic mRNA (Fig. 3a). It was evident that IVT mRNA enters the cell through the endolysosomal pathway.^64,65 The unmodified IVT mRNA may contain double-stranded (ds) regions (for example, a hairpin), which can bind to the Toll-like (TLR) 3 receptor in the endosome. The unmodified single-stranded (ss) mRNA can trigger TLR7 or TLR8, resulting in an immune activation via type I interferon (IFN) and nuclear factor-κB (NF-κB) pathways and proinflammatory cytokine production.^66–68 The efficacy of vaccines depends critically on their ability to stimulate robust immune responses. While mRNA vaccines offer intrinsic adjuvant properties through innate immune activation, excessive stimulation can paradoxically suppress translation and induce cytotoxicity. As illustrated in Fig. 3b, the endosomal localization allowing for binding of IVT mRNA TLR3 and TLR7 receptors can activate antiviral defense via the type I IFN and NF-κB pathways, resulting in activation of RNA-dependent protein kinase R (PKR) and 2′–5′ oligoadenylate synthase-like (OAS-L) as well as upregulation of other pattern recognition receptor (PRR) genes and leading to the production of IFN-α, IFN-β and other proinflammatory cytokines.^69–71 The activated PKR phosphorylates the initiation factor eIF2α, a key role in the initiation of protein translation, inhibiting mRNA translation, and OAS-L degrades RNA through responding to IVT mRNA detection by activating the latent RNase-L,⁷² which ultimately inhibits protein expression (of both endogenous mRNA and IVT mRNA).^70,73

Fig. 3 IVT RNA construct and sensing. (a) A scheme of the mRNA construct and key functions and sensors of each structural region. (b) mRNA sensing and innate immunity activation (created using https://BioRender.com). (c) The negative correlation between immunogenicity and translation efficiency.

The inverse correlation between mRNA immunogenicity and translation efficiency makes it necessary to reduce mRNA immunogenicity (Fig. 3c). Several well-established approaches address this challenge:^74–76 (1) 5′ cap modification: adding a cap structure (such as the m7G cap) to the 5′ end of the mRNA mimics the structure of eukaryotic mRNA, protecting the mRNA from evading recognition by the immune system and facilitating translation.^77–79 (2) Nucleoside modification: replacing uridine with pseudouridine is capable of reducing PKR recognition and diminishing RNase-L activity, and modified nucleoside N¹-methylpseudouridine can also reduce immunogenicity and cytotoxicity, ultimately enhancing RNA translation and protein expression.^80,81 What is noteworthy is that both Moderna and Pfizer-BioNTech COVID-19 mRNA vaccines leverage nucleoside-modified mRNAs to avert non-specific immune responses.⁸² (3) mRNA purification: the phenol–chloroform extraction method, a traditional and cost-effective RNA extraction method, is usually utilized to purify IVT mRNA in most laboratories, which effectively separates nucleic acid from other cell components and obtains relatively pure nucleic acid samples. However, the phenol–chloroform extraction method may not be as efficient or convenient as commercial kits, especially when dealing with large numbers of samples. IVT mRNAs purified by high-performance liquid chromatography, free of dsRNA contaminants, demonstrate 10- to 1000-fold higher protein expression than unpurified mRNA without the production of type I IFN and inflammatory cytokines in primary cells, which represent a flexible and efficient purification method and provide an alternative for the production of highly pure IVT mRNA,^83,84 while their universality is limited by the high expense, the complexity of the operation and the dependence of the equipment. mRNA vaccines prepared by modified and purified RNA show unparalleled safety, precision, and efficiency advantages, representing an important direction of modern vaccine research and development.^85,86

3.3. mRNA delivery carriers

Despite these optimizations, mRNA vaccines face significant biological barriers: (1) rapid nuclease degradation in extracellular environments; (2) poor cellular uptake due to negative charge repulsion; and (3) inefficient endosomal escape, even when internalized by DCs. These limitations underscore the need for advanced delivery platforms that simultaneously minimize immune stimulation while ensuring efficient endo-lysosomal escape for mRNA-DC vaccine development. Recently, scientists have developed several RNA delivery strategies that employ diverse nanomaterial systems,⁸⁷ including biological nanoparticles (involving virus-like particles (VLPs),⁸⁸ exosomes,⁸⁹ and outer membrane vesicles (OMVs)),⁹⁰ lipid-based structures (involving micelles, liposomes, and lipid-based nanoparticles (LNPs)),⁹¹ lipid–polymer hybrid nanoparticles, and polymeric nanoparticles (Fig. 4). Among these, LNPs and polymeric nanoparticles are the most commonly used and potentially clinically translatable nanomaterials.

Fig. 4 Representative mRNA delivery vehicles and their composition (created using https://BioRender.com).

The classical LNPs consist of four components: a cationic or ionizable lipid, a helper lipid, cholesterol, and a poly(ethylene glycol) (PEG)-lipid.⁹² The cationic or ionizable lipids, the key components of LNP, are positively charged and combine with negatively charged nucleic acid molecules through electrostatic interactions to form lipid–nucleic acid complexes, facilitating nucleic acid encapsulation and endocytosis.^93,94 The helper lipid and cholesterol contribute to the stability of LNPs, and PEG-lipid reduces immunogenicity and cytotoxicity. Usually, LNPs present a self-adjuvant effect through TLR-mediated DC maturation^95,96 Promoting the full maturation of DCs without affecting RNA translation boosts the immune response and improves the effectiveness of vaccines.⁹⁷ However, some reports have shown that LNPs activate multiple inflammatory pathways and massive neutrophil infiltration, resulting in rapid and robust inflammatory responses and diverse inflammatory cytokine and chemokine production.^98–101 As the most intensively studied and clinically advanced vehicles for mRNA delivery,^102,103 LNPs have been continuously improved to achieve better efficacy with minimal side effects. LNPs deliver mRNA to APCs, where tumor-associated antigens (TAAs) or neoantigens are expressed, processed, and presented to T lymphocytes, activating CD4⁺ and CD8⁺ T lymphocytes and ultimately killing tumor cells.¹⁰⁴ A few tumor antigens released by tumor cells can be phagocytosed by APCs to further promote the immune response (Fig. 5). Although LNPs have excellent protein expression in vivo, the efficiency of mRNA delivery of DCs by LNP in vitro is inadequate,¹⁰⁵ which leads to insufficient protein translation and antigen presentation and poor immune response.

Fig. 5 Mechanism of action of mRNA-LNP cancer vaccines (created using https://BioRender.com).

Polymer nanocarriers are nano-scale or sub-micron drug delivery systems based on polymer materials, which can deliver mRNA to the cytoplasm through electrostatic interactions or hydrophobic interactions between cationic polymers and mRNA. They have been widely applied in nucleic acid delivery due to their favorable pharmacokinetics, good stability during lyophilization, design flexibility, and ease of functionalization.^106–108 Poly(β-amino ester) (PBAE), with good biocompatibility and biodegradability, is considered a safe carrier for mRNA delivery. Ben-Akiva et al. designed PBAEs with a quadpolymer architecture that can deliver mRNA to splenic dendritic cells, promoting antigen-specific tumor cell killing (Fig. 6a).¹⁰⁶ The PBAE structure consists of the diacrylate backbone, amine side chain, and endcap monomers via a two-step Michael addition (Fig. 6b). In addition to the biodegradable ester bonds in the backbone structure, bioreducible disulfide bonds were incorporated to create environmentally responsive degradation in the reducing environment of the cytosol, enabling the rapid release of mRNA (Fig. 6c). Tu et al. incorporated hydrophobic groups, aromatic groups, and hydroxyl groups to obtain different PBAEs with electrostatic interactions, π–π conjugate interactions, and hydrogen bond interactions for effective mRNA delivery (Fig. 6d).¹⁰⁹ Li et al. synthesized a new generation of multi-cyclic poly(β-amino ester)s (CPAEs) with a unique topology structure via step growth polymerization and the CPAEs with macrorings significantly boosted the cellular uptake and gene expression compared to their branched counterparts (Fig. 6e).¹¹⁰ Suberi et al. optimized biodegradable poly(amine-co-ester) (PACE) polyplexes for efficient mRNA delivery to the lung, achieving high transfection of mRNA throughout the lungs, particularly in epithelial cells and APCs (Fig. 6f).¹⁰⁸ Biocompatible PBAEs, as efficient polymeric carriers, demonstrated the translational potential of polyplexes for therapeutic delivery of mRNA to the APCs and other immune-related cells for in vitro or in vivo therapy. Furthermore, the immunogenicity of PBAEs can promote the maturation of DCs as a self-adjuvant, enhancing antigen processing and presentation and effectively activating the immune system. On the other hand, the early activation of DCs may inhibit antigen presentation, thus inducing immune tolerance rather than immune response. Overactivation of DCs may trigger an excessive inflammatory response, leading to tissue damage.¹¹¹

Fig. 6 Biocompatible polymer as a mRNA carrier for cancer immunotherapy. (a) Schematic of the mRNA-based vaccine using polymeric (PBAE) nanoparticles (NPs). (b) Reaction scheme for bioreducible lipophilic PBAEs. (c) Monomers used in the combinatorial library synthesis to form PBAEs.¹⁰⁶ Reprinted with permission from ref. 106. Copyright (2023) The author(s). (d) A library of PBAEs using a multiple interaction synergistic strategy.¹⁰⁹ Reprinted with permission from ref. 109. Copyright (2024) American Chemical Society. (e) CPAEs with a 3D macrocyclic structure boosted gene delivery.¹¹⁰ Reprinted with permission from ref. 110. Copyright (2023) The authors. Published by American Chemical Society. (f) Biodegradable poly(amine-co-ester) polyplexes for lung-targeting mRNA delivery using end-group modifications and polyethylene glycol.¹⁰⁸ Reprinted with permission from ref. 108. Copyright (2023) The American Association for the Advancement of Science.

Charge-altering releasable transporters (CARTs), inherently nonimmunogenic vehicles, were produced by a two-step organocatalytic oligomerization, which electrostatically encapsulated mRNA and lost their cationic charge through a charge-altering rearrangement to produce neutral diketopiperazine small molecules (Fig. 7a), facilitating the intracellular release of functional mRNA in cells.^112,113 Haabeth et al. leveraged these inherently nonimmunogenic carriers to tailor the vaccine immunogenicity in combination with specific adjuvants, eliciting strong and enduring T cell responses (Fig. 7b). Li et al. introduced a CART delivery system with a beta-amido carbonate backbone (bAC) using an amido-variant of previously reported 8-membered cyclic carbonates incorporating nitrogen as a tertiary amine or urethane (Fig. 7c). The Cre recombinase murine model (Ai14 mice) was used to measure specific cell recombination after intravenous injection of mRNA Cre complexed with different CARTs. Fig. 7d shows Cre-mediated recombination (tdTomato⁺) in most subsets of CD45⁺ leukocytes in the spleen, including T cells, DCs, macrophages, and B cells.¹¹⁴ The inherently nonimmunogenic CARTs exhibit enhanced mRNA delivery and protein expression in DCs and primary T lymphocytes in vitro, supporting their therapeutic application in cell therapy.

Fig. 7 Nonimmunogenic CART as a mRNA carrier. (a) The synthesis routes of CART and its chemical structure, degradation products, and charge-altering mechanism. (b) CART electrostatic formulation, cellular uptake, endosomal escape, and mRNA translation.¹¹² Reprinted with permission from ref. 112. Copyright (2021) The authors. Published by American Chemical Society. (c) The synthesis of CART based on their beta-amido carbonate backbone (bAC) and side chain spacing. (d) Schematic representation of mRNA delivery in vivo and the percentage of Cre-mediated recombination in CD45⁺ subsets in vivo.¹¹⁴ Reprinted with permission from ref. 114. Copyright (2023) the author(s).

4. DCs as immunological bridges for potentiating mRNA cancer vaccines

DCs serve as pivotal immunological bridges that connect innate and adaptive immunity, making them indispensable for the success of mRNA cancer vaccines.^115–117 By efficiently capturing, processing, and presenting, DCs amplify antigen-specific T cell, B cell, and NK cell activation, overcoming the immunosuppressive tumor microenvironment. Harnessing DCs’ unique ability to link vaccine-induced immunity with robust antitumor effects holds promise for next-generation mRNA vaccine design.^118,119 This synergy between DC biology and mRNA technology may unlock new paradigms in precision cancer immunotherapy.^120,121

4.1. Antigen expression and presentation

The ideal antigen should be unique and cancer-specific and elicit strong immune responses when presented to T cells by DCs, which can be a specific antigen identified by extensive screening or multiple antigens through incubation with tumor lysate or killed tumor cells.^122,123 This antigen-coded mRNA is delivered to the cytoplasm by the carrier and translated into antigen after lysosomal escape. The expression and presentation of antigen are crucial for optimizing mRNA vaccines, which determines the effectiveness of the vaccines.

The cellular uptake, lysosome escape, mRNA translation, and antigen processing are the cornerstones of antigen presentation. Deng et al. developed a sialic acid (SA)-modified mRNA vaccine that simultaneously achieved DC targeting and efficient endosomal/lysosomal escape (Fig. 8a). The addition of SA promoted quick escape from the endoplasmic reticulum and avoided the entry of lysosomes, significantly increasing the expression of proteins in DCs (Fig. 8b).¹²⁴ Tan et al. synthesized a library of stimuli-responsive bivalent ionizable lipids (srBiv iLPs) (Fig. 8c), aiming to leverage physiological cues to elicit rapid lipid degradation, promote mRNA translation, and induce robust antitumor immunity via reactive oxygen species (ROS)-mediated DC maturation (Fig. 8d).¹²⁵ It is established that activated DCs terminated phagocytosis activity and improved antigen-presenting cell and cytokine production, thereby promoting T cell priming and memory T cell activation, leading to widespread and long-lasting immunity.^125,126 Therefore, simple strategies for maturing APCs are highly appealing for prompting antigen-specific protective immunity. Lee et al. optimized to stimulate endoplasmic reticulum stress via modulating electrostatic charge, hydrophobicity, and secondary conformation of cationic helical polypeptides, provoking an innate and adaptive immune response (Fig. 8e).¹²⁷ Although the activation of some immune pathways is beneficial to antigen presentation, several signals have been found to be counterproductive. Chen et al. reported that silencing SOCS1 enhanced antigen presentation of DCs and antigen-specific anti-cancer immunity.¹²⁸ A study also showed that SOCS1^−/−DCs were hyperresponsive to lipopolysaccharide and induced autoreactive antibody production displaying a more mature phenotype, which hinted a negative role for SOCS1 in the regulation of DCs.^129,130

Fig. 8 The optimization of antigen presentation. (a) Flowchart of microfluidic hybrid synthesis of a SA-modified mRNA vaccine. (b) Diagram of the cell transfection mechanism of a SA-modified mRNA vaccine.¹²⁴ Reprinted with permission from ref. 124. Copyright (2023) Elsevier. (c) The design of srBiv iLPs. (d) Robust immune responses induced by srBiv mRNA vaccines based on enhanced antigen presentation.¹²⁵ Reprinted with permission from ref. 125. Copyright (2024), American Chemical Society. (e) The design of cationic helical polypeptides.¹²⁷ Reprinted with permission from ref. 127. Copyright (2024) Springer Nature. (f) A layer of iron oxide hydroxide nanocomposite mask of TEV promotes potent internalization. (g) Flow cytometry plots of the cellular uptake of DiD-labeled TEVs and mTEVs after incubation with DCs for 3 h.¹³¹ Reprinted with permission from ref. 131. Copyright (2024) Springer Nature.

In addition to developing various methods based on DCs themselves to enhance the antigen presentation, tumor-based countermeasures can also enhance the phagocytosis and presentation ability of DCs. Tumor cells have developed a mechanism to bypass immune surveillance and attack by presenting anti-phagocytic antigens, such as an anti-phagocytic ligand cluster of differentiation 47 (CD47), resulting in DCs unable to phagocytose tumor antigens. Wang et al. developed an iron oxide hydroxide as a mask for shielding the tumor-derived extracellular vesicle (TEV) surface to prevent the immune evasion (Fig. 8f). The mask disintegrates in the late lysosome and releases the tumor antigenic cargo after endocytosis, triggering antigen presentation and DC maturation. To investigate nano-masking-mediated phagocytosis enhancement, bone marrow-derived dendritic cells (BMDCs) were incubated with tumor cell line-derived TEVs. Flow cytometry analysis on BMDCs revealed more internalization of different masking tumor cell line-derived TEVs (Fig. 8g).¹³¹

4.2. DC-cytotoxic T cells

The DC-cytotoxic T cell axis represents a cornerstone of antitumor immunity, with CD8⁺ T lymphocytes serving as primary effectors through their ability to directly recognize and eliminate tumor cells via T cell receptor (TCR)-mediated antigen detection. Within the tumor microenvironment, activated CD8⁺ T cells secrete critical cytokines including IL-2, IL-12 and IFN-γ that amplify their cytotoxic potential. DCs orchestrate this process by processing tumor antigens into peptide fragments presented through MHC class I molecules, while simultaneously delivering essential costimulatory signals: the secondary signal through CD80/86–CD28 interactions and tertiary signals via immunostimulatory cytokines like IL-12 and IFN-γ. In mRNA vaccine contexts, DCs primarily acquire antigenic information through vaccine transfection, with the quality of subsequent immune responses being heavily dependent on DC maturation status. The efficacy of such vaccines fundamentally relies on two key parameters: the efficiency of antigen-presenting cell uptake and the subsequent antigen presentation capacity. However, current mRNA vaccine platforms face three major limitations: suboptimal transfection efficiency or impaired antigen presentation in transfected DCs, insufficient immunogenicity to adequately stimulate DC activation, and the immunosuppressive tumor microenvironment that actively suppresses both DC and T cell function – all of which ultimately compromise the downstream CD8⁺ T cell response and weaken antitumor immunity.

To address these challenges, significant research efforts have focused on developing advanced mRNA delivery systems. Li and colleagues employed high-throughput Ugi multicomponent reactions to synthesize novel ionizable lipid libraries that replaced conventional LNP components, achieving fourfold greater circRNA transfection efficiency compared to industry-standard LNPs (ALC-0315 used in Pfizer/BioNTech COVID-19 vaccines) in LLC1 lung cancer cells (Fig. 9a).¹³² Lu's team made important strides by incorporating negatively charged lipids into traditional four-component LNPs to create charge-assisted stabilized nanoparticles (CAS-LNPs) that demonstrated exceptional stability during nebulization while significantly improving mRNA delivery efficiency for metastatic lung cancer prevention and treatment.¹³³ Mitchell's innovative approach involved introducing branched alkyl chains (isopropyl, n-butyl, and isobutyl) at lipid termini, which formed cone-shaped structures that enhanced endosomal escape and dramatically improved transfection efficiency. These branched lipids also showed superior liver targeting and T cell transfection capabilities compared to their linear counterparts (Fig. 9b).¹³⁴ Collectively, these examples and preceding evidence confirm that contemporary LNP design strategies primarily focus on component substitution or addition to improve targeting specificity, stability, or endosomal escape performance. Given the central role of ionizable lipids in mRNA complexation and transfection, their structural optimization has become a major research focus.

Fig. 9 (a) Synthesis of LNPs by the Ugi reaction and screening of LNPs that efficiently deliver circular RNA (circRNA) to lung tumors. Reprinted with permission from ref. 132. Copyright (2024), Wiley-VCH GmbH. (b) A platform for synthesizing branched ionizable lipids that improve T cell transfection. Reprinted with permission from ref. 134. Copyright (2025), The author(s). (c) HER2-clustered nanovaccine (ACNVax) to achieve long-term tumor remission by promoting B/CD4⁺ T cell crosstalk. Reprinted with permission from ref. 147. Copyright (2024), American Chemical Society. (d) Tri-specific nano-antibody (Tri-NAb) effectively binds to NK and CD8⁺ T cells, triggering their activation and proliferation. Reprinted with permission from ref. 157. Copyright (2024), The author(s). (e) Calcium phosphate nanoparticles (CaP-PME) activate DCs and elicit CD8⁺ T cell and NK cell proliferation. Reprinted with permission from ref. 154. Copyright (2024) Elsevier B.V.

Beyond carrier optimization, researchers have also explored innovative mRNA engineering approaches. Ligon's group drew inspiration from the observation that highly aggregated viruses exhibit superior infectivity compared to dispersed particles, developing a vacuum-based method to prepare multilamellar lipid nanoparticles that concentrated mRNA payloads and significantly enhanced transfection efficiency, consequently improving DC antigen presentation and maturation.¹³⁵ Laoui's team achieved breakthrough results by co-delivering three functional mRNAs (IL-21, IL-7, and 4-1BB) using LNPs, which overcame treatment resistance in refractory tumors through multifaceted immunomodulation: IL-21 broadly regulates various immune subsets including T cells, B cells, NK cells, macrophages, monocytes and DCs while promoting NK and T cell proliferation; IL-7 governs naive CD8⁺ T cell development, survival and proliferation while driving memory differentiation; and 4-1BB (a TNF receptor family member) enhances CD8⁺ T cell expansion, cytotoxicity and cytokine production upon ligand engagement.¹³⁶ This work established an important paradigm where co-delivery of immunomodulatory genes with antigen-encoding mRNA can enhance DC-T cell crosstalk while ameliorating the immunosuppressive tumor microenvironment. In conclusion, the regulation of mRNA quantity and variety demonstrates significant instructive implications for enhancing anti-tumor immunity.

The critical importance of DC costimulatory signaling has become increasingly apparent. While genetically modified DCs successfully present tumor antigen peptides via MHC class I (signal 1), insufficient CD80/86–CD28 mediated costimulation (signal 2) leads T cells to misinterpret antigenic signals as themselves, resulting in anergy or apoptosis – outcomes completely contrary to vaccine objectives. Therefore, effective antitumor mRNA vaccines must simultaneously achieve high-efficiency gene transfer and adequate immune stimulation to ensure proper DC maturation. Numerous studies have addressed this challenge by incorporating innate immune agonists into delivery systems. Yu's innovative design featured cyclodextrin-modified ionizable lipids that complexed with the TLR7/8 agonist R848 through host–guest interactions. In acidic lysosomal environments, these interactions weakened to release R848, which then engaged lysosomal TLR7/8 receptors to stimulate DC maturation and CD80/86 upregulation, while the mRNA payload escaped into the cytoplasm for translation.¹³⁷ Alternative approaches have utilized metal ions like Mn²⁺ as innate immune stimulants. Wei's team employed SORT technology to develop spleen-targeting LNPs containing variable ratios of anionic lipids (18PA, DOPG, and DOPS) that co-delivered Mn²⁺ (a potent STING activator) with mRNA. Mn²⁺ directly activated cGAS and enhanced cGAMP-STING binding affinity, resulting in superior antigen presentation and immune activation in splenic DCs that robustly stimulated both CD8⁺ T cells and NK cells. To minimize formulation complexity while reducing systemic side effects from small-molecule agonists, some researchers have focused on developing intrinsically immunostimulatory ionizable lipids.¹³⁸ Anderson's group created a diverse library of ionizable lipids with varying headgroup structures using one-pot reactions, identifying cyclic amine-headed lipids that specifically activated the STING pathway and dramatically improved vaccine potency when substituted into conventional LNP formulations.¹³⁹

While adjuvants undoubtedly enhance DC maturation, growing evidence suggests that concurrent innate immune activation during mRNA translation may paradoxically reduce protein expression. Exogenous mRNA recognition by TLRs and RLRs can upregulate protein kinase R, ultimately suppressing antigen expression and limiting antigen-specific immunity. Similarly, LNP-mediated translation has been shown to increase intracellular reactive oxygen species (ROS) that induce inflammatory responses and impair translation efficiency. These findings highlight the need to carefully coordinate the timing of mRNA translation and innate immune activation while minimizing negative regulators during translation to optimize DC antigen presentation and maturation, thereby promoting robust T cell responses and preventing exhaustion. Yu's group addressed this challenge by developing poly(guanidine thioctic acid) lipids that scavenged excess ROS during mRNA translation, significantly improving antigen-specific T cell responses. More sophisticated regulation strategies involve fusing immunostimulatory genes with antigen-encoding sequences on the same construct.¹⁴⁰ Lee's team created a plasmid simultaneously expressing tumor antigen mRNA (mOVA) and STAT3-silencing siRNA connected by an RNase H-cleavable linker. Following cytoplasmic delivery, the linker was cleaved to release both RNAs separately, allowing STAT3 knockdown to restore TLR/STING receptor activity and promote DC maturation while avoiding premature innate immune activation that could compromise translation.¹⁴¹ Liu's group developed uniSTING, an innovative mRNA-encoded fusion protein that mimics cGAMP-induced STING oligomerization. Unlike endogenous STING, uniSTING spontaneously forms tetramers and higher-order aggregates independent of endosomal localization. When delivered via LNPs to tumor microenvironments, uniSTING induced TBK1 and IRF3 phosphorylation in both DCs and tumor cells, triggering robust IFN-β and ISG production.¹⁴² Additionally, extracellular vesicles from uniSTING-treated tumor cells contained elevated levels of miR-130-3p, miR-15b-5p and miR-16-3p which downregulated the immunosuppressive protein Wnt2b in DCs, further enhancing their functionality. These advanced strategies exemplify how coordinated control of antigen presentation, costimulatory signaling, and immunosuppression relief can be achieved, potentially enabling the combination of “cocktail” approaches with other immunomodulatory mRNAs for enhanced antitumor efficacy.

4.3. DC-CD4⁺ T cells and B cells

While cytotoxic T lymphocytes remain central to antitumor immunity, the limitations of exclusive focus on DC-CTL interactions have become increasingly apparent. Persistent antigen exposure in tumor microenvironments leads to CD8⁺ T cell exhaustion and diminished cytotoxicity, contributing to the generally low response rates observed with current immunotherapies. This realization has driven exploration of alternative immune axes, particularly the underappreciated roles of CD4⁺ T cells and B cells in antitumor responses. Cytotoxic CD4⁺ T cells represent a functionally distinct population that not only expresses key cytolytic molecules like granzyme and perforin but also demonstrates direct tumor-killing capacity. In preclinical models using lymphopenic (RAG-deficient or lethally irradiated) hosts bearing syngeneic melanoma, adoptive transfer of TRP-1-specific TCR-transgenic CD4⁺ T cells mediated tumor elimination through IFN-γ, granzyme B and perforin-dependent mechanisms. Clinical relevance was confirmed by identification of melanoma-specific cytotoxic CD4⁺ T cells in patients using MHC class II tetramers, with these cells demonstrating potent activity against CIITA-transduced tumor cells expressing enhanced MHC class II levels.¹⁴³ Importantly, cytotoxic CD4⁺ T cells appear to be particularly crucial for recognizing tumor-derived neoantigens, suggesting that their activity may be closely tied to DC-CD4⁺ T cell-B cell crosstalk networks.¹⁴⁴ The current paradigm proposes that while DCs present limited neoantigen epitopes through MHC class I to CD8⁺ T cells (restricting their target repertoire), B cells can capture diverse tumor antigens through surface immunoglobulins and present processed peptides to CD4⁺ follicular helper T (TFH) and peripheral helper T (TPH) cells. Activated B cells subsequently differentiate into antibody-secreting plasma cells that generate antigen–antibody complexes, which are then internalized by APCs for processing and presentation to both CD4⁺ and CD8⁺ T cells.¹⁴⁵ This creates a positive feedback loop that compensates for the inherent limitations of CD8⁺ T cell recognition, ultimately optimizing cytotoxic T lymphocyte effector function against heterogeneous tumor populations.

Given these insights, contemporary mRNA vaccine design must incorporate strategies to enhance DC interactions with both CD4⁺ T cells and B cells. Shi's work demonstrated this principle through metabolizable lipid-conjugated TLR2/6 agonists that induced IL-12/IL-17 production while activating cDC2 antigen presentation, resulting in potent CD4⁺ and CD8⁺ T cell-mediated antitumor effects in both prophylactic and therapeutic models.¹⁴⁶ Despite these advances, current mRNA vaccine research has inadequately addressed DC-CD4⁺ T cell-B cell crosstalk, representing a critical knowledge gap that must be filled to achieve comprehensive antitumor immunity. Illustrating alternative approaches, Sun's HER2 peptide-conjugated gold nanoparticles (ACNVax) successfully engaged B cell antigen presentation in lymph nodes, establishing productive B cell-CD4⁺ T cell-CD8⁺ T cell communication that synergized with the checkpoint blockade (Fig. 9c).¹⁴⁷ Similarly, Zhan's folate-modified liposomes co-loaded with ovalbumin and TLR4 agonist MPLA (FA-sLip/OVA/MPLA) exploited natural IgM opsonization to target marginal zone B cells, inducing robust humoral and cytotoxic T lymphocyte responses.¹⁴⁸ Li's innovative platform featured triple-negative breast cancer cell membranes decorated with CpG oligonucleotides and CD40 antibodies, where simultaneous CD40-BCR engagement promoted B cell internalization, maturation, and enhanced antigen presentation/antibody secretion that amplified adaptive immunity through DC-independent pathways.¹⁴⁹ These examples highlight how traditional mRNA vaccines may suffer from poor CD4⁺ T cell and B cell targeting – a significant limitation given that B cells represent the only clonally expandable professional APCs capable of presenting low-abundance antigens to T cells with superior efficiency compared to DCs. Future designs could incorporate B cell-targeting antibodies or integrate conventional vaccine adjuvants to specifically enhance B cell maturation and proliferation.

4.4. DC-NK cells

The immunological interplay between DCs and NK cells has been recognized since the late 1990s, when seminal studies first demonstrated that direct DC-NK cell contacts markedly enhance NK cytotoxicity and IFN-γ production in vitro.¹⁵⁰ Modern techniques like multiplex immunofluorescence have revealed intricate DC-NK-T cell interactions within tumor lesions, with NK cell abundance correlating positively with neuroblastoma patient outcomes. DC-based vaccines have proven to be particularly effective at promoting NK cell proliferation and IFN-γ production, although full effector maturation requires at least 72 h – similar to T cell activation kinetics.¹⁵¹ The therapeutic relevance of DC-NK interactions is underscored by the common tumor immune evasion strategy of MHC class I downregulation, which renders malignant cells resistant to CD8⁺ T cell killing but vulnerable to MHC class I-independent NK cell cytotoxicity.¹⁵² As central hubs connecting innate and adaptive immunity, DCs coordinate both arms through distinct mechanisms: the classical DC-CD8⁺ T cell axis (MHC I-restricted) and the DC-NK cell axis (mediated by cytokines like IL-12 and IL-18).¹⁵³ Recent advances in mRNA vaccine technology have begun exploiting these interactions.

Xia's calcium phosphate-stabilized Pickering multiple emulsions (CaP-PMEs) demonstrated preferential DC tropism that enhanced activation, IFN-γ production and CD8⁺ T cell responses while simultaneously promoting NK cell proliferation and tumor infiltration. The tumor suppressor p53 serves as a master regulator of cell cycle progression, apoptosis, and cellular senescence, with frequent mutations observed in hepatocellular carcinoma. Beyond its cell-intrinsic functions, p53 modulates immune responses through regulation of key cytokines (TNF-α, IL-12, and IL-15), chemokines (CCL2 and CXCL12), and pathogen recognition receptors (TLRs), thereby recruiting and activating immune cells including DCs and T cells (Fig. 9e).¹⁵⁴ Shi's team engineered a nanovaccine by complexing p53-encoding mRNA with cationic polymers and lipids using nanoprecipitation. In murine models, this nanovaccine along with the PD-1 blockade significantly increased the proportion of mature NK cells (KLRG1⁺CD11b⁺) within the tumor microenvironment while enhancing the expression of activation markers (IFN-γ and IFN-γR⁺). These findings demonstrate that p53 restoration potently augments NK cell-mediated antitumor activity.¹⁵⁵ Hiratsuka's discovery of a naturally occurring IL1β-mRNA in premetastatic lungs revealed an unconventional activation mechanism where IL1β-mRNA-ZC3H12D receptor complexes translocate to the nucleus to enhance NK cell cytotoxicity 3.2-fold.¹⁵⁶ While chemical modification improved stability for intravenous administration, targeted delivery systems could further optimize this approach by preventing mRNA degradation. Wang et al. immobilized three types of mAbs targeting PDL1 (a well-known checkpoint protein and tumor-associated antigen), NKG2A (an inhibitory member of the NKG2 family expressed in activated NK and T cells), and 4-1BB (a costimulatory glycoprotein receptor expressed in activated NK and T cells) on the albumin/polyester composite nanoparticle (Tri-Nab). This design enhanced the orchestration of NK and T cells, achieving remarkable antitumor efficacy (Fig. 9d).¹⁵⁷ While NK cells serve as pivotal effectors that complement CD8⁺ T cell-mediated tumor killing, research on their cytotoxic roles and the DC-NK cell axis remains underexplored in the context of tumor-associated DCs or mRNA vaccines. Building upon existing evidence, we propose two strategic approaches to enhance current vaccine platforms: (1) employing bispecific antibodies to spatially and functionally bridge DCs with NK cells and (2) screening mRNA payloads that potentiate NK cell activation and cytotoxicity. These synergistic strategies may substantially improve the vaccine's capacity to overcome immunosuppressive tumor microenvironments. Together, these findings underscore the importance of incorporating NK cell activation strategies into mRNA vaccine design to complement CTL-mediated antitumor immunity.

5. Conclusions and perspective

Over the past few decades, DCs have been widely acknowledged and studied for initiate immune responses. During mRNA vaccine immunization, DCs are responsible for capturing injected mRNA vaccines, translating mRNA into proteins by ribosomes after escaping the endoplasmic reticulum. The antigen peptides are presented to the cell surface to activate T cells and stimulate the immune system. These properties demonstrate that DCs play a key role in the immune system, connecting innate and acquired immunity.

Though low-risk and flexibly manipulated mRNA vaccines have showcased remarkable potential that makes them promising contenders for cancer immunotherapy, several phase I–II trials have yielded promising results and many early phase trials testing a wide range of vaccine designs are currently ongoing;^117,158 the successful clinical application still faces several challenges. One primary challenge is accurately identifying personalized neoantigens. The selection of antigens determines the efficacy and application scope of the vaccines. Besides, the innate immune response triggered by unmodified IVT mRNA resulted in unwanted inflammation, and how to optimally boost vaccine responses through the most effective dosing schedule needs to be figured out. Also, the improved targeting, enhanced stability, reduced toxicity, and ease of storage are crucial for the successful clinical translation. Conclusively, mRNA vaccines hold significant potential for improving outcomes for cancer patients. The flexibility of this platform enables the use of multiple permutations of targets and combinations that ensure usher in new therapeutic regimens for cancer patients.

Author contributions

All authors contributed to the article and approved the submitted version.

Data availability

No primary research results, software or code have been included, and no new data were generated or analyzed as part of this review.

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgements

The authors thank the National Natural Science Foundation of China (52433006, 52495010, and 51925305), the National Key Research and Development Program of China (2021YFB3800900), and the talent cultivation project Funds for the Innovation Laboratory for Sciences and Technologies of Energy Materials of Fujian Province (HRTP-[2022] 52).

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Footnote

† R. W. and H. L. contributed equally to this work.

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