Vaccine adjuvants for immunotherapy: type, mechanisms and clinical applications

Abstract

Immunotherapy has emerged as a powerful approach in treating various diseases, yet its success often hinges on the efficacy of adjuvants, agents that boost immune responses to therapeutic targets. Traditional adjuvants have offered foundational support but may fall short in achieving the specificity and potency required for advanced therapies. This review highlights a new generation of adjuvants poised to address these limitations. We explore a range of innovative agents, including non-inflammatory nucleic acid adjuvants, bacterial derivatives, and synthetic molecules, which are redefining the role of adjuvants in immunotherapy. These emerging agents hold promise for enhancing immune responses while tailoring therapies to specific disease contexts, from cancer to infectious diseases. By examining the applications and potential of these adjuvants, this review aims to provide a comprehensive understanding of how they can advance immunotherapy to new levels of efficacy and precision. Through the development of these novel adjuvants, immunotherapy stands to achieve more targeted and sustained impacts, paving the way for improved outcomes in patient care.

1 Introduction

Immunotherapy represents a paradigm shift in modern medicine, harnessing the intricacies of the immune system to combat diseases such as cancer, infectious diseases, and autoimmune disorders. Distinguished by its precision and potential for durable responses, immunotherapy has ushered in transformative advancements, including immune checkpoint inhibitors, CAR-T cell therapies, and therapeutic cancer vaccines (Dagher et al., 2023; Wallis et al., 2023; Chasov et al., 2024). Despite these milestones, the efficacy of these strategies frequently relies on the integration of adjuvants, which are agents that enhance immune responses by potentiating antigen recognition, activation of immune cells, and the downstream orchestration of adaptive immunity (Facciolà et al., 2022). Traditional adjuvants, such as alum, MF59, and Freund’s adjuvant, have laid the foundation for vaccine development and immunostimulation for decades. However, their utility in advanced immunotherapy is limited by their narrow spectrum of immune activation. For instance, most traditional adjuvants fail to effectively polarize Th1 or Th17 immune responses, which are essential for combating intracellular pathogens and tumours. Furthermore, their inability to induce robust cross-presentation of antigens hinders the generation of cytotoxic T lymphocyte (CTL)-mediated immunity (Wang and Xu, 2020; Facciolà et al., 2022). These constraints necessitate the development of novel adjuvants designed to complement the sophisticated demands of modern immunotherapy.

Several emerging adjuvants have been developed to address these shortcomings, leveraging advances in molecular immunology and material science (O’Hagan et al., 2020; Pulendran et al., 2021). These adjuvants, including ARNAX, CpG oligodeoxynucleotides (ODNs), STING agonists, beta-glucan derivatives, and synthetic molecules such as poly(I:C), possess unique mechanisms of action that modulate immune responses with greater specificity and efficacy. These emerging agents not only enhance immune responses but also provide tailored solutions for specific therapeutic contexts, from tumour immunotherapy to prophylactic and therapeutic vaccines targeting infectious diseases (Desai et al., 2024a). The rapid evolution of these adjuvants underscores their potential to redefine immunotherapeutic strategies. This review aims to provide a comprehensive analysis of these novel agents, focusing on their mechanisms of action, the immunological pathways they engage, and their potential applications in enhancing the efficacy of immunotherapy.

2 Role and need of adjuvants

Adjuvants play an indispensable role in immunotherapy and vaccine development, acting as critical enhancers of the immune system’s ability to mount effective and durable responses. By amplifying the immune recognition of antigens and directing immune polarization, adjuvants bridge the gap between innate and adaptive immunity (Schijns et al., 2020). Their primary function is to compensate for the weak immunogenicity of modern antigen formulations, such as recombinant proteins and synthetic peptides, which often fail to elicit robust immune responses without additional stimulation (Correa et al., 2022b). Moreover, adjuvants significantly enhance the efficiency of antigen presentation, facilitating the activation of APCs like dendritic cells and macrophages, which process antigens and present them to T cells to initiate adaptive immunity (Awate et al., 2013).

Adjuvants not only enhance the magnitude of immune responses but also modulate their quality and duration. By polarizing the immune response, adjuvants can promote Th1 pathways, favouring cellular immunity for intracellular pathogens and cancer, or Th2 responses for extracellular pathogens (Sarkar et al., 2019). In addition, some adjuvants can stimulate Th17 responses, which are crucial for mucosal immunity. Furthermore, adjuvants reduce the required antigen dose in vaccines (a phenomenon known as antigen sparing) and ensure the generation of immunological memory, which is vital for long-term protection and therapeutic efficacy (Lavelle and McEntee, 2024). Figure 1 shows a schematic representation illustrating the mechanism by which adjuvants enhance vaccine immunogenicity.

FIGURE 1

Despite their utility, traditional adjuvants are constrained by significant limitations. Alum, one of the most extensively used adjuvants, predominantly induces humoral immunity with a Th2 bias, making it suboptimal for applications requiring cellular immunity, such as cancer immunotherapy. Oil-based adjuvants, such as Freund’s Complete Adjuvant, though effective, are associated with severe local and systemic toxicities, rendering them unsuitable for human use (McKee and Marrack, 2017; Moni et al., 2023). Modern adjuvants like MF59 and AS03 have improved the delivery of antigens to APCs, but their ability to induce specific immune polarization, particularly robust Th1 and CTL responses, remains inadequate in many therapeutic contexts (Ko and Kang, 2018; Roman et al., 2024).

The need for novel adjuvants has become increasingly apparent as immunotherapy advances toward more sophisticated applications, including personalized medicine, cancer vaccines, and combination therapies. These emerging immunotherapeutic strategies demand adjuvants that can precisely modulate immune pathways, overcome immune evasion mechanisms, and ensure broad efficacy across diverse patient populations (Verma et al., 2023). The global health landscape has also highlighted additional challenges that must be addressed by next-generation adjuvants. These include the need for thermostable and cost-effective formulations suitable for use in resource-limited settings and adjuvants that demonstrate safety and tolerability across different age groups and immunological profiles (Qi and Fox, 2021). Additionally, the increasing integration of adjuvants into combination therapies requires compatibility with other immunotherapeutic agents, such as immune checkpoint inhibitors and monoclonal antibodies, while minimizing systemic toxicity and off-target effects (Lykins and Fox, 2023).

As the field of immunotherapy continues to evolve, the demand for adjuvants that can meet the diverse requirements of these therapies is only increasing. The development of next-generation adjuvants represents a critical step toward achieving the full potential of immunotherapy by enhancing efficacy, improving safety, and expanding the scope of therapeutic and preventive strategies.

3 Emerging adjuvants in immunotherapy

The development of novel adjuvants signifies a pivotal advancement in immunotherapy, introducing innovative mechanisms to enhance and precisely modulate immune responses. Traditional adjuvants have well-established safety profiles but are limited in their ability to induce cellular immunity, primarily favouring humoral responses with a Th2 bias. They also lack the precision required for advanced therapeutic applications. In contrast, emerging adjuvants like ARNAX, CpG ODNs, and STING agonists offer targeted immune activation by engaging specific pathways such as TLR3, TLR9, and the STING pathway. These adjuvants enhance antigen presentation, promote robust Th1 and Th17 responses, and support long-term immunological memory, making them more effective for applications like cancer immunotherapy and vaccines targeting intracellular pathogens. However, their heightened immunostimulatory capacity may lead to risks such as systemic inflammation or cytokine storms, necessitating careful formulation and delivery strategies. This distinction underscores the potential of emerging adjuvants to overcome the limitations of traditional ones while highlighting the need for continued optimization to balance efficacy and safety. Table 1 provides a detailed summary of the mechanisms, target pathways, advantages, and limitations of each of the eight emerging adjuvants discussed in this manuscript, offering a comparative overview of their unique attributes.

3.1 ARNAX

ARNAX is a synthetic double-stranded RNA (dsRNA) adjuvant engineered for non-inflammatory immune enhancement. It features a dsRNA core capped with DNA, which enhances its stability and resistance to nuclease degradation (Seya et al., 2022). ARNAX specifically targets TLR3, a receptor predominantly found on certain dendritic cell subsets, including CD141+ dendritic cells in humans. Upon binding TLR3, ARNAX triggers immune signalling through TICAM-1 (also known as TRIF), bypassing the MyD88 pathway commonly associated with inflammation (Matsumoto et al., 2015; Seya et al., 2019). This distinct activation pathway recruits TICAM-1, which in turn activates transcription factors like NF-κB, IRF-3, and AP-1. This cascade enhances antigen presentation without the cytokine storm often triggered by other TLR ligands. By favouring TICAM-1 signalling, ARNAX promotes antigen presentation and Th1 polarization, enhancing cellular immunity while minimizing inflammatory responses (Seya et al., 2023). It facilitates cross-presentation, where dendritic cells present extracellular antigens on MHC class I molecules, activating CTLs. This capability is crucial for strong immune responses against intracellular pathogens and cancer cells, both of which require potent CTL activation (Jelinek et al., 2011). ARNAX’s ability to support Th1-biased responses further aids CTL and natural killer (NK) cell activation, strengthening the immune system’s response against infected or malignant cells. This profile makes ARNAX especially suited for cancer immunotherapy and vaccines targeting intracellular pathogens, where cellular immunity is critical (Matsumoto et al., 2020; Miyazaki et al., 2025).

3.2 CpG oligodeoxynucleotides

CpG ODN are synthetic DNA sequences with unmethylated CpG motifs that mimic microbial DNA, acting as pathogen-associated molecular patterns (PAMPs) to stimulate Toll-like receptor 9 (TLR9) in plasmacytoid dendritic cells (pDCs) and B cells (Kayraklioglu et al., 2021). Upon endosomal TLR9 recognition, they initiate a MyD88-dependent signalling cascade, activating transcription factors like NF-κB, IRF-7, and AP-1. This produces Th1 cytokines such as IL-12, TNF-α, and IFN-α, driving antiviral and antitumor immunity (Yu et al., 2017). CpG ODN enhance innate immunity through pro-inflammatory cytokine and type I interferon production, recruiting monocytes, NK cells, and neutrophils. They strengthen adaptive immunity by promoting antigen presentation, T-cell activation, and antibody production, fostering Th1 responses against intracellular pathogens and tumours (Tu et al., 2020). Additionally, they enhance dendritic cell maturation, B-cell proliferation, and humoral immunity (Matsuda and Mochizuki, 2023). CpG ODNs are classified into K-, D-, C-, and P-types, each with unique properties. K-types promote TNF-α and B-cell activation, while D-types strongly induce IFN-α via pDCs. C-types combine IFN-α and IL-6 induction, and P-types form ordered structures, eliciting robust IFN-α responses (Shirota and Klinman, 2017; Hartmann, 2023).

CpG ODN have diverse clinical applications. As vaccine adjuvants, they boost antibody titters, cellular, and mucosal immunity, exemplified by HEPLISAV-B^®, a CpG-adjuvanted hepatitis B vaccine offering faster, stronger protection (Lee and Lim, 2021). They enhance responses to influenza and anthrax and improve mucosal immunity via oral or intranasal delivery (Givens et al., 2018; Muranishi et al., 2023; Wang et al., 2024c). In cancer immunotherapy, they activate tumour-infiltrating dendritic cells and reduce myeloid-derived suppressor cells, reprogramming the tumour microenvironment (Zhang et al., 2021). CpG ODN also shows promise in treating allergies and autoimmune diseases by shifting immune profiles from Th2 to Th1, benefiting asthma and similar conditions (Montamat et al., 2021).

3.3 Enterotoxin adjuvants

Enterotoxin adjuvants, derived from bacterial toxins like cholera toxin (CT) from Vibrio cholerae and heat-labile toxin (LT) from Escherichia coli, enhance mucosal immunity for oral, nasal, and intradermal vaccines. These adjuvants amplify systemic and mucosal immune responses, crucial for defending against infections in mucosal surfaces like the gastrointestinal and respiratory tracts (Crothers and Norton, 2023). Structurally, these adjuvants have an AB₅ configuration: the A-subunit activates intracellular signalling, while the B-subunit binds ganglioside receptors like GM1, enabling antigen-presenting cell (APC) uptake (Valli et al., 2020). Within APCs, they stimulate cAMP pathways, promoting T-helper cell (Th1 and Th17) activation and antigen presentation. They also enhance germinal centre reactions, boosting high-affinity antibody production (Ma et al., 2024). Delivery route influences efficacy, with oral routes targeting gastrointestinal pathogens and nasal routes excelling for respiratory pathogens (Liang and Hajishengallis, 2010).

CT potently stimulates mucosal immunity, especially IgA, but its toxicity limits clinical use. Modified CT variants reduce toxicity while retaining efficacy. LT, structurally like CT, includes derivatives like double-mutant LT (dmLT), featuring mutations (R192G/L211A) that reduce toxicity while enhancing mucosal and systemic immunity (Toprani et al., 2017). dmLT supports vaccine development against E. coli, polio, and influenza. Innovative derivatives like LTA1 and CTA1 mitigate toxicity further (Stone et al., 2023). LTA1 enhances antigen uptake in nasal vaccines, while CTA1, conjugated to targeting motifs (e.g., CTA1-DD), promotes B-cell activation and antibody production (Lavelle and Ward, 2022). Detoxified variants like LTh(αK), which completely inhibit enzymatic activity, show promise in nasal influenza vaccines (Pan et al., 2019). Enterotoxin adjuvants are valuable for vaccines targeting mucosal pathogens (E. coli, Helicobacter pylori, V. cholerae), systemic infections, and emerging applications like HIV, influenza, and substance abuse prevention (Salvador-Erro et al., 2024; Yin et al., 2024).

3.4 β-glucans

β-Glucans are naturally occurring polysaccharides found in the cell walls of fungi, yeasts, bacteria, algae, and cereals like oats and barley. They are glucose polymers linked by β-(1→3) and β-(1→6) glycosidic bonds, with structural variations depending on their source (Liang et al., 2024). These variations significantly influence their biological functions, particularly their immunomodulatory properties, making them effective biological response modifiers (BRMs) and promising vaccine adjuvants (Abbasi et al., 2022). As adjuvants, β-glucans activate immune responses through interaction with pattern recognition receptors (PRRs) such as Dectin-1, complement receptor 3 (CR3), and scavenger receptors on immune cells, including dendritic cells, macrophages, and neutrophils. Binding to these receptors triggers key signalling pathways, such as NF-κB and MAPK, leading to immune activation, cytokine release, and enhanced phagocytosis (Jin et al., 2018). They also induce “trained immunity” by epigenetically reprogramming innate immune cells, enabling a stronger and more rapid response to infections and vaccinations. Moreover, β-glucans promote dendritic cell maturation, upregulating co-stimulatory molecules and MHC class II expression to improve T cell activation (Guo et al., 2024; Wang et al., 2024b). They activate the complement system, enhancing pathogen clearance and supporting immune cell phagocytosis. By fostering Th1 and Th17 immune responses through cytokines like IL-12 and IL-6, β-glucans are crucial for combating intracellular pathogens and tumours (Cognigni et al., 2021; Córdova-Martínez et al., 2021).

The source and structural diversity of β-glucans define their specific activities. Fungal β-glucans, such as those from Lentinula edodes and Ganoderma lucidum, feature β-(1→3) backbones with β-(1→6) branches, excelling as immunomodulators in cancer and infectious disease therapies (Steimbach et al., 2021). Yeast β-glucans (e.g., Saccharomyces cerevisiae) are highly branched, activating Dectin-1 and CR3 to boost macrophage and neutrophil activity, with FDA-approved uses as dietary supplements and adjuvants (Azevedo-Silva et al., 2024). Cereal β-glucans (oats, barley), composed of β-(1→3) and β-(1→4) linkages, are effective in metabolic regulation and show potential as oral vaccine adjuvants. Algal β-glucans, primarily β-(1→3)-linked, have emerging roles in marine immunity and food science (Barsanti and Gualtieri, 2023).

3.5 Dimethyldioctadecylammonium bromide with saponin

The combination of Dimethyldioctadecylammonium bromide (DDA) and saponin enhances humoral and cellular immune responses in advanced vaccine formulations. DDA, a synthetic cationic lipid often delivered as liposomes, and saponin, a natural surfactant from Quillaja saponaria, possess complementary properties for mucosal and systemic vaccine delivery. Together, they underpin cationic adjuvant formulations (CAF) and immunostimulating complexes (ISCOMs), critical in next-generation vaccine development (Correa et al., 2022a). DDA binds negatively charged antigens via charge-based interactions, improving antigen stability and delivery to APCs. Its particle size (∼40–200 nm) promotes lymphatic uptake, while stimulating Th1-biased cytokines like interferon-gamma (IFN-γ) and interleukin-12 (IL-12), essential for intracellular pathogen defence and tumour immunity (Qu et al., 2018).

Saponin enhances immunogenicity by disrupting membranes, facilitating antigen entry into APCs and inflammasome activation. It boosts Th2 and Th17 cytokines like IL-4 and IL-17, vital for extracellular pathogen and mucosal immunity. By promoting antigen presentation via MHC class II, it strengthens T-helper and B-cell activation, increasing antibody titters and avidity (den Brok et al., 2016; Marciani, 2018). The DDA-saponin combination delivers a balanced Th1/Th2 response, enhancing IgG titters, antigen recognition, and long-term memory. It supports diverse applications, including meningococcal vaccines, where it raises bactericidal antibody levels against Neisseria meningitidis. In cancer immunotherapy, DDA’s Th1 polarization drives cytotoxic T-cell responses, making this adjuvant pair a promising strategy for therapeutic cancer vaccines (Yu et al., 2010; Vishwakarma et al., 2024).

3.6 Polyinosinic-polycytidylic acid

Poly(I:C), a synthetic double-stranded RNA analogue, mimics viral replication intermediates and acts as a potent immunostimulant. It enhances both innate and adaptive immunity, making it a promising adjuvant for cancer immunotherapy and vaccine development. Poly(I:C) activates pattern recognition receptors like Toll-like receptor 3 (TLR3) and melanoma differentiation-associated protein 5 (MDA-5) (Martins et al., 2015).

In dendritic cells and macrophages, Poly(I:C) binds TLR3 in endosomes, triggering the TRIF pathway. This induces type I interferons (IFN-α/β) and pro-inflammatory cytokines like TNF-α. In the cytoplasm, it engages MDA-5 and RIG-I, activating transcription factors such as IRF3 and NF-κB. These pathways promote dendritic cell maturation, enhancing MHC expression, co-stimulatory markers, and T-cell activation (Kester and Bortz, 2018). Poly(I:C) indirectly boosts NK cell cytotoxicity via IL-12 and IFN-γ, fostering a Th1-biased response critical for CTL activation and tumour elimination (Ball et al., 2024). Additionally, Poly(I:C) directly induces tumour cell apoptosis by activating TLR3, triggering caspase-dependent mechanisms and reducing anti-apoptotic molecules like survivin. This apoptosis releases tumour antigens, enhancing APC uptake and cross-presentation, leading to robust CD8⁺ T-cell priming (Zhu et al., 2015; Ko et al., 2023).

Poly(I:C) is versatile, functioning in peptide-, protein-, and cell-based vaccines. It synergizes with adjuvants like CpG ODNs and anti-CD40 antibodies, enhancing immune responses (Gupta et al., 2016). In cancer immunotherapy, it amplifies antigen-specific CTL and NK cell responses, showing potential in combination with tumour-associated antigens and immune checkpoint inhibitors (Aznar et al., 2019; Akache et al., 2021). For infectious diseases, it bolsters vaccine immunogenicity against viral and intracellular pathogens, making it valuable in both prophylactic and therapeutic vaccine strategies (Bardel et al., 2016; Bruun et al., 2024; Yao et al., 2024).

3.7 STING agonists

STING (Stimulator of Interferon Genes) agonists are agents that activate the STING pathway, a key element of the innate immune system. This pathway responds to cytosolic DNA by producing cyclic dinucleotides (CDNs), which stimulate robust production of type I interferons and pro-inflammatory cytokines (Gajewski and Higgs, 2020). STING agonists, either small molecules or biologically derived, are integral to enhancing cancer immunotherapy and vaccine efficacy (Le Naour et al., 2020). Located in the endoplasmic reticulum, STING is activated when CDNs like cGAMP bind to it. These CDNs are either endogenously synthesized by cGAS (cyclic GMP-AMP synthase) or delivered exogenously through STING agonists. Activation prompts STING to translocate to the Golgi, where it initiates IRF3 and NF-κB signalling pathways. This induces the expression of type I interferons (e.g., IFN-β) and inflammatory cytokines (e.g., TNF-α, IL-6), amplifying immune responses (Ohkuri et al., 2018; Van Herck et al., 2021).

STING agonists enhance antigen presentation by maturing APCs like dendritic cells, boosting their ability to activate T cells. This primes adaptive immune responses, especially against tumour-associated antigens (TAAs). They also modulate the tumour microenvironment, shifting it from immunosuppressive to immunostimulatory, promoting cytotoxic T-cell infiltration and activity (Xuan and Hu, 2023). These effects are critical for overcoming tumour-induced immune evasion. Two primary types of STING agonists exist. Cyclic dinucleotides (CDNs) include natural molecules like cGAMP and synthetic versions such as 2′3′-cGAMP, which are optimized for stability and bioavailability (Dubensky et al., 2013). Non-nucleotide agonists, small molecules that activate STING without mimicking CDNs, offer advantages in synthesis, stability, and delivery (Wang et al., 2021). Applications include cancer immunotherapy, where STING agonists synergize with immune checkpoint inhibitors (e.g., anti-PD-1, anti-CTLA-4) to enhance T-cell activation and counter tumour immunosuppression (Nicolai et al., 2020; Da et al., 2022). Intratumoral delivery can trigger systemic antitumor responses, including the abscopal effect. In vaccines, STING agonists enhance immune responses by promoting dendritic cell maturation and activation of B and T cells (Wang et al., 2024a). Combination therapies, integrating STING agonists with adjuvants like CpG ODNs or treatments such as chemotherapy and radiation, further amplify their immunostimulatory effects (Vasiyani et al., 2023; Eiro et al., 2024; Khalifa et al., 2024).

3.8 Microtubule-targeting agents

Microtubule-targeting agents (MTAs) are compounds that disrupt microtubule dynamics, essential for intracellular transport, mitosis, and cellular signalling. Traditionally utilized in chemotherapy for their ability to inhibit tumour cell division, recent research highlights their immunomodulatory potential, making them promising adjuvants for cancer immunotherapy and vaccines (Wordeman and Vicente, 2021). MTAs, including 4H-chromene-3-carbonitrile derivatives, inhibit tubulin polymerization, disrupting mitosis and intracellular trafficking. This disruption induces mitochondrial depolarization, activating pathways such as the mitogen-activated protein kinase (MAPK) cascade, which drives immune activation (Steinmetz and Prota, 2018). Furthermore, MTAs prolong NF-κB pathway activation, enhancing APC function and pro-inflammatory cytokine production. These effects amplify immune responses, with MAPK signalling fostering cytokine and chemokine production to recruit and activate immune cells. MTAs also promote dendritic cell maturation and cytokine secretion (e.g., IL-12, IL-6, TNF-α), which are crucial for effective antigen presentation and T-cell priming (Serpico et al., 2020).

MTAs’ dual antitumor and immune activation properties make them valuable in cancer immunotherapy, combining cytotoxicity with stimulation of innate and adaptive immunity. By sustaining NF-κB signalling, MTAs ensure prolonged immune activation and synergize with immune checkpoint inhibitors, such as anti-PD-1 antibodies, to enhance antitumor responses. This combination induces systemic effects, including the abscopal effect, where tumours at untreated sites regress. Additionally, MTAs selectively modulate cytokine production (e.g., IL-12, IL-6, IL-1β), driving Th1-biased responses critical for antitumor immunity and intracellular pathogen defence (Sato-Kaneko et al., 2018). Clinically, MTAs are used with immune checkpoint inhibitors to boost antitumor immunity, as seen with intratumoral 4H-chromene-3-carbonitrile derivatives in murine cancer models, which slow tumour growth and activate systemic immunity (Wang et al., 2023). MTAs also enhance cancer vaccines by improving antigen presentation and T-cell activation, making them strong candidates for next-generation vaccines. In combination therapies, MTAs are paired with chemotherapeutics or other adjuvants to enhance treatment efficacy while leveraging their immunostimulatory effects (Liang et al., 2022).

4 Challenges and future directions

Emerging adjuvants discussed herein offer immense potential to transform immunotherapy and vaccine development, but their advancement is constrained by several challenges that require careful consideration. Among the foremost concerns is the issue of safety and tolerability. Many next-generation adjuvants, such as STING agonists and poly(I:C), are designed to induce potent immune responses, yet their high immunostimulatory capacity can lead to unintended side effects (De Waele et al., 2021; Sun et al., 2023). Excessive activation of the immune system can result in systemic inflammation, cytokine storms, or localized reactogenicity, including significant pain, swelling, or erythema at the injection site (Karki and Kanneganti, 2021). These adverse effects limit their clinical applicability and necessitate the development of strategies to balance efficacy with safety. Future efforts must focus on refining the formulations of adjuvants to modulate their activity and targeting. Delivery platforms such as nanoparticles, liposomes, or hydrogels are promising approaches to localize the action of adjuvants, reduce systemic exposure, and minimize off-target effects while maintaining their immunostimulatory potential (Desai et al., 2023).

Another major hurdle is the instability and scalability of many emerging adjuvants. Complex molecules like ARNAX or synthetic cyclic dinucleotides used in STING agonists often exhibit poor stability in physiological conditions, with short half-lives that limit their therapeutic efficacy (Boehm et al., 2021; Wu et al., 2023). Furthermore, the intricate manufacturing processes required to produce these agents contribute to high production costs and hinder their scalability for widespread clinical use (Kis et al., 2019). Stabilization techniques, such as encapsulating adjuvants in biodegradable polymers or using modified molecular analogues, are critical for addressing these issues (Yenkoidiok-Douti and Jewell, 2020; Freire Haddad et al., 2023). Simplifying production workflows and developing cost-effective methodologies will also be necessary to ensure the large-scale deployment of these advanced adjuvants, particularly in resource-limited settings where affordability and accessibility are paramount.

Population-specific variability in immune responses presents an additional challenge in the clinical implementation of emerging adjuvants. Differences in genetic backgrounds, age, sex, and environmental factors significantly influence how individuals respond to adjuvants (Sanz et al., 2018). For instance, polymorphisms in genes encoding receptors such as Toll-like receptors (TLRs) or the STING protein can alter the efficacy and safety profiles of these agents. This variability complicates the design of adjuvants capable of eliciting consistent immune responses across diverse populations (Medvedev, 2013). Addressing this challenge requires a personalized approach to adjuvant development, incorporating insights from genomics, proteomics, and immunoprofiling (Bravi, 2024; Kumar et al., 2024). Future research should aim to identify biomarkers that predict individual responsiveness to specific adjuvants, enabling the design of tailored formulations optimized for distinct patient groups or populations.

The integration of adjuvants into combination therapies, particularly in cancer immunotherapy, introduces additional complexities. While combining adjuvants with immune checkpoint inhibitors or monoclonal antibodies holds promise for synergistic effects, it also increases the risk of adverse interactions and unpredictable immune dynamics (Seliger, 2019). These interactions can result in overactivation of the immune system or heightened toxicity. To address this, preclinical studies and clinical trials must rigorously evaluate the compatibility of adjuvants with other therapeutic agents. Developing standardized protocols for co-administration and optimizing the timing and dosing of combined treatments will be essential to harness their full therapeutic potential while minimizing risks (Desai et al., 2024b). Regulatory and ethical challenges further complicate the translation of novel adjuvants from research to clinical application. The stringent safety requirements imposed by regulatory agencies, while necessary, often result in lengthy and costly approval processes (Sun et al., 2012). Additionally, ethical concerns surrounding the testing of potent adjuvants in vulnerable populations, such as children, the elderly, or immunocompromised individuals, add layers of complexity (Rajani et al., 2022; Salave et al., 2023). Collaborative efforts between regulatory bodies, researchers, and industry stakeholders will be essential to streamline these pathways while maintaining rigorous safety and efficacy standards. The development of advanced preclinical models, including organ-on-chip systems and computational simulations, can provide more accurate predictions of clinical outcomes, reducing the risks associated with early-stage testing (Sunita et al., 2020; Rajpoot et al., 2022; Cook et al., 2025).

Despite these challenges, the future of adjuvant technology is promising. Continued investment in fundamental research to elucidate the molecular mechanisms underlying adjuvant activity will be critical for designing safer and more effective agents. Technologies such as single-cell sequencing, proteomics, and artificial intelligence can accelerate the discovery and optimization of novel adjuvants by providing deeper insights into immune modulation at the cellular and molecular levels (Noé et al., 2020; Shenoy et al., 2021; Kim et al., 2023; Li et al., 2023). Additionally, expanding the scope of adjuvant applications beyond traditional immunotherapy to areas such as neuroinflammation, autoimmune diseases, and metabolic disorders could unlock new therapeutic opportunities.

Global accessibility remains an overarching challenge that must be addressed to ensure the equitable distribution of next-generation adjuvants. The high costs and technical complexities associated with their production and distribution disproportionately affect low- and middle-income countries, where the need for affordable vaccines and immunotherapies is greatest (Mahoney et al., 2023). Addressing this requires the development of cost-effective formulations, scalable production techniques, and international collaborations to ensure these advances benefit all populations, regardless of geographic or economic constraints (Kozak and Hu, 2023; Yemeke et al., 2023).

5 Discussion

The integration of adjuvants into immunotherapy and vaccine development has long been recognized as a critical factor in overcoming the inherent limitations of antigens in eliciting robust immune responses. This review has highlighted the transformative potential of emerging adjuvants, including ARNAX, CpG ODNs, STING agonists, synthetic double-stranded RNA like poly(I:C), beta-glucan derivatives, and microtubule-targeting agents. Unlike traditional adjuvants, which are often limited by poor specificity, safety concerns, and suboptimal immune polarization, these next-generation agents leverage precise molecular mechanisms to enhance immune activation. By targeting specific pathways such as TLR3, TLR9, and the STING pathway, these adjuvants have demonstrated their ability to amplify antigen presentation, promote Th1 and Th17 responses, and induce long-lasting immunological memory. Their ability to complement and synergize with other immunotherapeutic agents, such as immune checkpoint inhibitors, further underscores their importance in modern medical strategies.

The adjuvants discussed in this review represent a significant leap forward, but their full potential remains untapped. Advances in molecular and cellular biology, nanotechnology, and computational modelling offer exciting opportunities to refine these agents further. For example, personalized adjuvant designs tailored to individual genetic or immunological profiles could revolutionize the way we approach precision medicine. Furthermore, the development of adjuvants that are compatible with non-traditional delivery platforms, such as intranasal, oral, or transdermal routes, could open new doors for vaccine and immunotherapy applications. Adjuvants designed for targeted delivery using nanoparticles or ligand-conjugated systems can enhance specificity while reducing systemic toxicity. Beyond their established roles in cancer and infectious disease vaccines, future applications may include conditions such as neuroinflammation, autoimmune diseases, and even metabolic disorders, where modulation of immune activity is increasingly recognized as a therapeutic strategy. The role of artificial intelligence and machine learning in accelerating adjuvant discovery and optimization is another frontier that holds great promise.

Next-generation adjuvants signify a pivotal advancement in the evolution of immunotherapy and vaccine development. Their capacity to precisely modulate immune responses, enhance therapeutic efficacy, and overcome the limitations of traditional approaches positions them as indispensable tools in modern medicine. Despite the challenges of safety, scalability, and regulatory approval, the continuous refinement of these agents through interdisciplinary efforts is expected to address these hurdles. The future of immunotherapy lies in the seamless integration of these adjuvants into therapeutic strategies, creating more effective, accessible, and patient-centric solutions.

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