Hydrogel-Based Vaccines: A Promising Approach for Cancer Immunotherapy

Introduction

Neoplastic diseases persist as a predominant contributor to global health deterioration and premature mortality,¹ underscoring the critical demand for innovative therapeutic modalities. Conventional oncological interventions such as surgical resection, radiation therapy, and cytotoxic agents,^2,3 have significant limitations, promoting the rise of immunotherapy as a promising approach for combating various cancers.⁴ Currently, cancer immunotherapy mainly comprises immune checkpoint (eg, programmed cell death ligand-1/PD-L1, cytotoxic T-lymphocyte-associated antigen-4/CTLA-4) blockades (ICBs), adoptive cell transfer (eg, T cell, natural killer cells, macrophages) and vaccines therapy.⁵ These therapeutic approaches leverage endogenous immune defenses against malignancies to target neoplastic cells, suppressing oncogenesis while reducing relapse and metastatic dissemination.⁶ The year 1986 marked the inaugural regulatory authorization by the US Food and Drug Administration (FDA) of synthetic interferon-α, a pioneering immunomodulatory agent, for deployment in tumor-targeting therapeutic regimens.^7,8 Immunotherapeutic approaches have achieved remarkable progress in the clinical management of diverse malignancies, including non-small cell lung carcinoma, gastric adenocarcinoma, and cutaneous melanoma.^9,10 However, several challenges persist in the practical application of immunotherapy, including insufficient immune response and the risk of adverse effects. Continued efforts to explore personalized treatment strategies and optimize combination therapies are also essential for improving patient outcomes.

Among these above-mentioned approaches of cancer immunotherapy, cancer vaccines have become important weapons to fight against tumors. Traditional vaccines, which include whole inactivated organisms or attenuated pathogens, have limitations in term of safety and efficacy when applied to cancer. Recent advancements have introduced novel vaccine candidates, including DNA, RNA, peptides and tumor cell lysates, which are under extensive research.¹¹ Vaccines can recognize and eradicate tumor cells by eliciting specific immune response and establishing immunological memory through targeting tumor antigens.¹² For example, Sipuleucel-T, a pioneering immunotherapeutic agent sanctioned by the FDA in 2010, demonstrated significant survival benefit in castration-resistant prostate carcinoma cohorts during Phase III investigations.¹³ However, its broad clinical application has been hindered by high costs, limited treatment efficacy, and the need for multiple injections. In addition, several other cancer vaccines are currently in the preclinically or clinically stage, but have not yet been approved by the FDA.^14,15 The clinical effectiveness of anticancer vaccines is frequently compromised by immunosuppressive TME characteristics and neoplastic immune evasion strategies. Additionally, vaccines are prone to rapid clearance at the injection site, and certain tumor antigens with low immunogenicity may only evoke a weak immune response. Without repeated injections into the cancer host, there is also a lack of sufficient vaccines to stimulate a continuous and robust immune response.^16,17 Consequently, a critical imperative exists to develop innovative approaches that overcome current barriers and optimize the therapeutic performance of vaccine-based immunotherapies within clinical oncology practice.¹⁸

To overcome existing barriers in application of cancer vaccines, the development of optimal vaccine delivery platforms has garnered significant attention. Among these novel delivery strategies, hydrogel-based systems have gained prominence as versatile biomaterial matrices for therapeutic immunization agents, demonstrating potential to optimize immunotherapeutic outcomes. Hydrogel is a biomaterial composed of a network of hydrophilic polymers, emulating the architectural and functional attributes of native extracellular matrices (ECM).¹⁹ As a delivery carrier, hydrogels can encapsulate substances such as water, proteins and drugs, effectively preserving their structure and function.^20,21 Hydrogel-based systems have garnered considerable interest as delivery matrices owing to their favorable safety profiles, superior biocompatibility, controlled biodegradation kinetics, and high payload encapsulation efficiency.²² In cancer therapy, hydrogels are expected to maximize the efficacy of cancer vaccines. On one hand, hydrogels protect vaccines from in vivo degradation, owing to their extracellular matrix (ECM)-like structure, which is composed of a highly porous network. On the other hand, therapeutic immune activation of anticancer immunization agents can be amplified via multimodal adjuvant interactions engineered into hydrogel-based delivery matrices.^23,24 Additionally, hydrogels not only allow for minimally invasive injection near tumor sites but also enable the controlled, spatiotemporal release of vaccine agents.²⁵ This approach yields reduced systemic toxicity while promoting durable tumor-specific immunoreactivity within biological systems. Therefore, understanding the current application status of hydrogel-based vaccines and optimizing their properties is crucial for advancing cancer immunotherapy.

This analysis methodically synthesizes current advances in hydrogel-based cancer vaccines and their role in optimizing therapeutic performance across solid tumor management paradigms. Specifically, we begin by presenting a detailed analysis of the general application and mechanisms of vaccines involved in cancer treatment. Next, we delve into the distinctive characteristic of hydrogels, highlighting their potential in vaccine delivery. We then classify hydrogel-based vaccines and critically evaluate their current status and application in cancer therapy. Subsequently, we summarize the underlying mechanisms by which hydrogel-based cancer vaccines modulate host immune response. Finally, we conclude with a prognostic analysis of emerging opportunities and translational barriers inherent to associated with hydrogel-based cancer vaccines.

Cancer Vaccines: A New Era in Treatment

Vaccines have long been employed for decades as prophylactic countermeasures against a diverse spectrum of infectious and clinically significant pathologies. With continuous advancements in vaccine technology, they are increasingly being explored for the prophylactic and therapeutic paradigms for diverse oncological indications. Currently, cancer vaccines are categorized into two main categories: preventive and therapeutic vaccines, differentiated by their target demographics and clinical implementation objectives. Prophylactic vaccines are designed to protect healthy individuals by preventing viral infections that can lead to virus-associated cancers. For example, HPV and HBV vaccines have been sanctioned for clinical use by the FDA to prevent virus-associated malignancies, specifically cervical carcinoma (HPV) and HBV-related hepatocarcinogenesis.²⁶ However, prophylactic vaccines have a relatively limited scope of protection, as they are ineffective against cancers that have already happened. Conversely, therapeutic cancer vaccines are engineered for individuals with established malignancies, inducing tumor-specific immune activation that facilitates targeted recognition and elimination of neoplastic cells. These therapeutic cancer vaccines provide a potent defense mechanism to prevent tumor progression, metastasis carcinoma and recurrence. Therefore, the development of novel therapeutic vaccines targeting existing cancers remains an active and ongoing area of research. Several promising therapeutic cancer vaccines are currently under clinical trials, as outlined in Table 1.

Table 1 Emerging Cancer Vaccine Candidates Under Active Clinical Investigation

Exogenous vaccines are primarily delivered to the host through various methods, including polymeric microspheres, scaffolds, hydrogels or microneedles.^34–37 Once introduced into the body, cancer vaccines leverage endogenous immune pathways to selectively eradicate malignant cells through antigenic recognition, initiating a tailored immunological cascade. Notably, tumor-specific immunity involves both humoral and cellular immunity induced by cancer vaccines.^38,39 Mechanistically, vaccines containing antigens are internalized and processed by professional antigen-presenting cells (APCs), with dendritic cells (DCs) serving as the principal mediators of this uptake mechanism. During immune activation, cytokines initiate a signaling cascade that enhances DC recruitment and functional maturation, thereby optimizing antigen presentation. Mature DCs subsequently traffic to lymphoid tissues, where processed antigens are displayed through MHC molecules for recognition by T cell receptors (TCRs) on naïve T lymphocytes. Critical to this process, full T cell activation necessitates dual signaling: primary antigen-specific recognition through MHC-TCR engagement and secondary co-stimulatory signals mediated by molecules like CD28/B7-1,2 complexes. Post-activation, naïve T cells undergo differentiation into effector subtypes – CD4⁺ T helper (Th) cells, CD8⁺ cytotoxic T lymphocytes (CTLs), and memory T cells – each executing distinct immunological roles. In antitumor immunity, vaccine-derived antigens are preferentially loaded onto MHC-I complexes by antigen-presenting cells, enabling CD8⁺ T cell priming. These activated cytotoxic lymphocytes subsequently infiltrate tumor microenvironments to mediate direct neoplastic cell destruction. Parallel MHC-II-mediated antigen presentation to CD4⁺ T cells induces helper cell differentiation, with resultant interferon-γ and interleukin-2 secretion augmenting CTL-mediated cytotoxicity. The humoral response involves B cell antigen capture via surface immunoglobulins followed by MHC-II-restricted presentation to helper T cells. This cognate interaction induces CD40 ligand upregulation on T cells, which engages CD40 receptors on B lymphocytes to drive plasma cells differentiation and memory cell formation. Mature plasma cells secrete tumor-targeting antibodies that mediate complement activation, antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) through Fc receptor engagement on innate immune cells, establishing systemic immunosurveillance against malignant cells (Figure 1).

Figure 1 General function mechanism of cancer vaccine. Created in BioRender. Wenqin, Z. (2025) https://BioRender.com/ d9hih0q. Abbreviations: DCs, dendritic cells; Th cell, T helper cell; CTL, cytotoxic T lymphocyte; BCR, B cell receptor; ADCP, antibody-dependent cellular phagocytosis; ADCC,: antibody dependent cellular cytotoxicity; IFN-γ, interferon-γ; IL-2, interleukin-2.

Although cancer vaccines have made notable progress in clinical studies, challenges such as low immunogenicity and inefficient delivery system continue to limit their widespread application in cancer treatment. Additionally, the immunosuppressive TME and immune evasion mechanism produced by tumor cells further impede the efficacy of cancer vaccines. To overcome these obstacles, hydrogels have risen as innovative delivery vehicles (as depicted in Figure 2). Research demonstrates their ability to preserve cancer vaccines from enzymatic breakdown in vivo, while orchestrating spatiotemporally programmed payload distribution within biological systems. Moreover, the incorporation of immune adjuvants within hydrogels can also enhance the immunogenicity of cancer vaccines, thereby initiating a robust immune response in host. The systematic comparative analysis between traditional cancer vaccines and hydrogel cancer vaccines is depicted in Table 2. Given these advantages, hydrogel-based cancer vaccines warrant further investigation and attention as a potential breakthrough in cancer therapy.

Table 2 Traditional Cancer Vaccines vs Hydrogel Cancer Vaccines: Comparison

Figure 2 Comparison of conventional cancer vaccine and hydrogel-based cancer vaccine. Their advantages and limitations are listed in corresponding dashed or solid boxes, respectively. Created in BioRender. Wenqin, Z. (2025) https://BioRender.com/ qkezscp.

Characteristics of Hydrogels

Hydrogel is designed as a three-dimensional, across-linked macromolecular network.⁴⁰ Hydrogel matrices are predominantly engineered from biopolymers such as collagen, alginate, chitosan, and hyaluronic acid (HA), or synthetic counterparts including polyacrylamide, polyethylene glycol (PEG), and polyvinyl alcohol (PVA). These hydrogels also incorporate crosslinking agents, such as chemical materials (eg, glutaraldehyde, ethylene glycol dimethacrylate) or physical forces (eg, hydrogen bonds, ionic interactions). The three-dimensional crosslinked networks of hydrogels endow them with exceptional swelling capacity in aqueous media without structural destruction, together with tunable mechanical characteristics, such as adjustable stiffness, elasticity, and tensile strength. Notably, hydrogel incorporates a significant amount of water or biological fluids. Hydrogel materials derive their functional properties from their aqueous composition-water constituting approximately 99% of their mass. This inherent hydration confers exceptional biocompatibility and facilitates enzymatic or hydrolytic biodegradation in physiological settings, particularly within aqueous biological systems like human tissues.^22,41 The hydrophilic structure of hydrogel contributes to its reduced off-target toxicity and side-effects in the host.

Emerging innovations in nanomedicine are revolutionizing the engineering of nanocomposite hydrogel systems functionalized with precisely size-tuned nanoparticles (NPs, 1–100 nm). These nanoscale additives not only strengthen the hydrogel’s mechanical integrity by interfacial interactions but also confer stimuli-sensitive behavior to microenvironmental cues, including pH gradients, thermal fluctuations, photonic inputs, and electromagnetic fields. For instance, gold nanoparticles transduce near-infrared light into thermal energy, which selectively activates temperature-sensitive hydrogel phase transitions to achieve spatiotemporally precise payload release. In intravesical bladder cancer therapy, superparamagnetic Fe₃O₄ nanoparticles enable remote manipulation of hydrogels via magnetic fields, useful in targeted delivery or dynamic tissue scaffolds.⁴² Besides, nanoparticles serve as precision therapeutic vectors, through transporting anti-cancer drugs as nanocarriers. The incorporation of nanoparticles in hydrogels contributes to controlled spatiotemporal release of chemotherapy drugs and reduces their systemic toxicity. For example, hydrogel matrices incorporating curcumin-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles⁴³ establish a tandem delivery system for hydrophobic chemotherapeutics like 5-fluorouracil⁴⁴ or paclitaxel,⁴⁵ keeping their sustained release and prevent them from degradation in vivo. Notably, PLGA-NPs⁴⁶ have been approved by FDA as a kind of biodegradable material in clinical studies, and are considered as a promising vaccines carrier.⁴⁷ Currently, nanotechnology combination with cancer vaccines has also made some progress in development of immunotherapy, that enable effective load and transportation and maintain stability of tumor antigens. Hence, emerging nanotechnology results in the production of nanovaccines constructed by nanoparticles.⁴⁸ A nanoparticle-based immunotherapeutic vaccine may be inhaled or taken orally into the host. Upon absorption by APCs, nanoparticles can facilitate the generation of pro-inflammatory cytokines (eg, IL-1β, IL-12p70) while concurrently upregulating chemokine ligands (CXCL9, CCL5). This dual action facilitates the CXCR3/CCR5-guided infiltration of cytotoxic CD8⁺ T cells and NK cells into immunologically “cold” tumor microenvironments, thereby converting localized immune activation into systemic antitumor immunity.⁴⁹ Modifying the properties of nanoparticles can enhance the tissue targeting of nanovaccines, thus improving their absorption efficiency. Taking advantage of these properties, hydrogels are used to encapsulate nanovaccines to optimize their delivery system in some researches. Recent studies have reported that nanocomposite hydrogel vaccines engineered with PLGA-NPs⁴⁶ and CPMV nanoparticles,⁵⁰ when incorporated into vaccines encapsulated in hydrogels, effectively suppress tumor growth, locoregional recurrence, and metastatic outgrowth. An injectable polymer-nanoparticle (PNP) hydrogel technology delivers lipid nanoparticle (LNP)-encapsulated messenger RNA (mRNA) to APCs using a modular targeting strategy. This approach enhances both the magnitude and quality of the germinal center reaction, establishing an immunological niche in vivo.⁵¹ In addition, TSA-based nanovaccines synergized with PD-1 checkpoint blockade antibodies effectively suppress the locoregional tumor recurrence and metastatic dissemination, while simultaneously triggering specific and durable immune memory in the host.⁵² This paradigm underscores the potential of converging patient-derived nanovaccines, hydrogel-enabled spatiotemporal delivery, and ICIs rewiring to overcome resistance mechanisms in advanced malignancies.

Hydrogels can be injected, implanted, or sprayed onto subjects.²² These versatile delivery methods make hydrogel-based systems minimally invasive, improving operational feasibility and patient compliance. In current cancer therapies, injectable hydrogels carrying vaccines can be administered to nearly any part of the host, including tumor sites, via a syringe.⁵³ Hydrogels are broadly categorized by physiological stimulus responsiveness into thermo-sensitive and non-sensitive types. At room temperature, hydrogel is in a flowable fluid state, allowing for easy administration. Once administered into warmer physiological environment (~37°C), thermosensitive hydrogels undergo temperature-driven conformational reorganization, transitioning from a liquid-phase “sol” state to a semi-solid “gel” matrix in situ.⁵⁴ This temperature-triggered sol-gel transition enables minimally invasive delivery. The injectable sol facilitates administration, while subsequent gelation ensures localized confinement and sustained release of payloads (eg, antigens/drugs), exploiting intrinsic body heat. This responsiveness further allows dynamic modulation of release kinetics during local temperature fluctuations, such as inflammation. Unlike thermo-sensitive variants, non-sensitive hydrogels form stable networks via mechanisms independent of physiological temperature. Gelation occurs through: ionic crosslinking (eg, alginate/Ca²⁺), covalent bonding (photo-/enzyme-initiated in PEG/HA systems), physical interactions (H bonding, hydrophobic forces), or enzymatic reactions (eg, fibrin/thrombin). These hydrogels are either injectable (solidifying post-injection via specific triggers) or pre-formed (surgically implanted). Examples include alginate, fibrin, collagen, and crosslinked synthetics (eg, PEG-DA). Their primary strengths include broader material selection with proven biocompatibility predictable, and stable release profiles achieved through controlled polymer chemistry, crosslink density, and porosity. Though lacking thermo-sensitive gels’ environmental responsiveness, their release kinetics exhibit superior stability against physiological fluctuations. Both thermo-sensitive and non-sensitive hydrogels serve as powerful platforms for advanced biomedical applications, particularly sustained delivery of vaccines. Thermo-sensitive variants enable injectable, temperature-triggered depot formation with potential for intelligent release. Non-sensitive types leverage broader material diversity to achieve precisely tunable stability, though requiring distinct gelation triggers or administration. Selection depends critically on the therapeutic agent, target release kinetics, administration route, and material constraints.

To enable in situ injection and prevent the rapid metabolism of hydrogel cargoes by liver and gut wall, injectable hydrogels with diverse properties are increasingly used in research applications (Table 3). By cross-linking different materials, a variety of hydrogels can be fabricated, including sulfated chitosan hydrogel, HA-based hydrogel, supramolecular and PEG-b-poly(L-alanine) hydrogel. Moreover, cells, such as DCs, can survive within the hydrogel matrix due to its favorable network structure. The porous nature of hydrogel serves as a platform that supports communication between DCs and tumor cells.⁵⁵ Inside the hydrogel, sustained tumor antigen internalization by DCs drives their phenotypic maturation and subsequent lymphoid trafficking to draining lymph nodes, culminating in MHC-mediated antigen presentation to naïve T lymphocytes.⁵⁶

Table 3 Examples of Hydrogel Formulation Applicated in Cancer Vaccines

As an emerging delivery carrier, hydrogels can be used to transport drugs, vaccines, bioactive molecules or cells, or participate in tissue engineering in the application of biomedicine.^62,63 In addition, hydrogels are also increasingly engineered as adjuvants to synergistically amplify vaccine potency. For example, aluminum hydroxide gel is a well-established adjuvant in vaccine formulations. It helps maintain the stability of antigenic ingredients during vaccine storage and use, thereby avoiding their degradation. Aluminum hydroxide gel is commonly incorporated into subunit vaccine formulations, including diphtheria-tetanus-pertussis (DTP) combinations and hepatitis A prophylaxis. By retaining antigenic substances at the vaccination site, it prolongs DCs/lymphocytes engagement with the antigenic payload, thereby promoting the production of antibodies and enhancing vaccine effectiveness. In addition, positively charged multidomain peptide hydrogel, K₂, is also utilized as a vaccine adjuvant to activate Th cells to participate in humoral immunity.⁶⁴ Current clinical investigations of hydrogel vaccines demonstrate promising outcomes. In a study administering a hydrogel patch delivering tetanus and diphtheria antigens to 27 healthy participants, booster immunization was subsequently provided to a subset. No severe local or systemic adverse events were observed with this system. Notably, elevated antibody titers persisted for ≥1 year post-administration, consistently exceeding pre-vaccination baselines.⁶⁵ ViscoGel, a chitosan-based hydrogel adjuvant, was co-administered via single intramuscular injection with the Haemophilus influenzae type b model vaccine Act-HIB to healthy subjects. No tolerability or safety concerns emerged. Compared to solo Act-HIB recipients, cohorts receiving ViscoGel-adjuvanted vaccination exhibited significantly elevated interferon-γ (IFN-γ) responses to Act-HIB in PBMCs. Critically, the hydrogel platform reversed vaccination-induced suppression of IFN-γ production toward both the target antigen and heterologous influenza epitopes.⁶⁶

In cancer immunotherapy, hydrogels exhibit high storage capacity for antigen-based vaccines and various immunoadjuvants additionally.⁶⁷ Cancer vaccines often work synergistically with immunoadjuvants, with hydrogel serving as a delivery medium.⁶⁸ Both immunoadjuvants and hydrogels can enhance immune stimulation in vaccine recipients. Hydrogels protect these components from degradation and enable the controlled, sustained release of vaccines in vivo, thereby reducing dosing frequency and prolonging the duration of the antitumor immune response.⁶⁹

Categories of Hydrogel-Based Cancer Vaccines

Hydrogel-formulated cancer vaccines primarily function encapsulating tumor antigens, which trigger a specific immunity targeting tumors. Tumor antigens can originate from tumor-associated proteins, DNA/RNA or tumor cells, and are then encapsulated in special hydrogels for cancer treatment. For example, the tumor-associated glycoprotein TROP2 can be effectively integrated into an oxidized dextran-based polymeric matrix for localized delivery via subcutaneous administration in preclinical studies of aggressive mammary carcinoma lacking estrogen, progesterone, and HER2 receptors. This method significantly inhibits tumor cells growth and achieves complete tumor regression in 50% of treated subjects with receptor-negative breast malignancies.⁷⁰ Yuta Yoshizaki et al have reported that DCs and ovalbumin (OVA) as the antigen are encapsulated in a temperature-responsive biodegradable hydrogel. Upon injection into a mouse lymphoma model, this approach induces dendritic cells activation, potentiating antigen processing and improving treatment efficacy.⁶¹ Similarly, Chao Gao et al have demonstrated that the engineered thermoresponsive chitosan-based delivery system co-encapsulating an immunostimulatory mRNA (LIRF5) and CXCL5-targeting siRNA promotes M1 polarization, thus inhibiting tumor growth, thereby improving the therapeutic efficacy in a pancreatic cancer model.⁷¹

Based on the source of these tumor antigens, cancer vaccine immunogens are stratified into tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs), the latter colloquially termed neoantigens.⁷² TAAs are the proteins or molecules expressed on the surface or inside of tumor cells, which can also be found in normal cells, arising from host’s genes without mutations. TAAs exhibit ubiquitous overexpression, aberrant expression or different structure modification across malignant tissues, whereas retain baseline expression in select healthy cell populations, such as carcinoembryonic antigen, alpha-fetoprotein, mucin 1. Constitutive TAA expression in normal tissues induces central/peripheral tolerance, promoting immune ignorance toward these self-antigens. Furthermore, their non-exclusive tumor expression limits immunogenicity, typically eliciting weak antitumor responses.⁷³ Clinically validated vaccine platforms have historically leveraged these antigens for therapeutic development. Conversely, non-self-antigens constitute tumor-specific antigens (TSAs), primarily generated by somatic mutations. Neoantigens—such as those derived from mutated genes like KRAS—represent a key subset. Certain viral antigens (eg, HPV E6/E7 in cervical cancer) also qualify as TSAs. These antigens exhibit exclusive tumor cell expression, absent in normal tissues.⁷⁴ Relative to TAAs, TSAs exhibit superior immunogenicity, driving robust T-cell responses. Owing to their tumor-restricted expression profiles and enhanced immune activation potential, neoantigens are regarded as ideal candidates for personalized cancer vaccines.⁷⁵ The existing studies have shown that hydrogel-based cancer vaccines come in various forms, including DNA/RNA, protein, peptides, and vaccines based on DCs or tumor cells. Additionally, cancer vaccines frequently incorporate immunoadjuvants - non-antigenic substances that potentiate immune responses against tumor antigens. Examples include mineral salts, saponins, oil-in-water emulsions, immune potentiators (eg, STING, NOD-like, or Toll-like receptor agonists), cytokines, and microbial components (viruses/bacteria). By amplifying the immune system’s reaction, these adjuvants generate significantly stronger, broader, and more durable responses than immunization with antigens alone. Accordingly, tumor antigens are often paired with diverse immunoadjuvants to enhance their immunogenicity, thereby forming hydrogel-based vaccines against cancers (as shown in Table 4). Subsequent sections systematically delineate the classification and current application status of cancer vaccines, with analytical emphasis on the components encapsulated in hydrogels.

Table 4 Summary of Immunoadjuvants Types in Hydrogel-Based Cancer Vaccines

DNA Based Vaccines

Circular plasmid DNA are primarily employed to construct DNA vaccines, which encode specific tumor antigens.³⁰ For some self-antigens that are difficult to synthesize, time-consuming and costly, plasmid DNA serves as an alternative due to its tunability, thermal stability and cost-effectiveness. Once introduced into the body, plasmid DNA can be transcribed and subsequently translated into the corresponding tumor antigens, priming MHC class I-restricted CTL responses via cross-presentation mechanisms in immunocompetent hosts. Although DNA vaccines offer many advantages, there are still deficiencies that need to be addressed in practical applications. DNA vaccines encounter barriers such as nuclease-mediated catabolism within biological systems, and lower transfection efficiency, which can lead to insufficient antigen expression and weak immunogenicity, thus failing to trigger a robust immune response.

Smart hydrogel, such as poly(methacrylicacid)/poly(N-vinylpyrrolidone) multilayer hydrogel, is increasingly recognized as effective delivery platforms for DNA vaccines, enhancing their loading capacity and enabling controlled release of the vaccine contents. Such kind of hydrogel synergistically helps DNA vaccines work more effectively.⁹² For example, vaccines encapsulating plasmid DNA encoding for a tumor-associated idiotype antigen, through a thermoresponsive polysaccharide matrix, stimulate dendritic cells recruitment and activation in a B cell lymphoma mouse model. The combinatorial therapeutic platform utilizing immunosuppressive interleukin-10 (IL-10) silencing siRNA via the hydrogel, this approach amplifies the cytolytic activity of CTLs and CD4⁺ T cells, significantly increasing total survival rate versus monotherapy controls in lymphoma-bearing BALB/c murine models.⁹³ Besides, hydrogels made from special materials also enhance the therapeutic efficacy of DNA vaccines. A hydrogel constructed from HA and levodopa (DOPA), loaded with OVA-expressing plasmid promotes DCs infiltration and induces the generation of OVA-specific antibody, thus inhibiting tumor growth in human lung carcinoma. This hydrogel delivery system provides a minimally invasive approach for DNA administration. After administration in vivo, the structure of DOPA conjugated with HA maintains the stability of hydrogel and OVA- expressing plasmid. The hydrogel with such unique structure also keeps the sustaining release of DNA vaccines in vivo, extending their retention time and strengthening the specific humoral immune response.⁹⁴

These studies indicate that hydrogel-based DNA vaccines exhibit substantial therapeutic potential for tumor treatment. The smart hydrogel designed with special biodegradable and biocompatible polymers leads to their controlled degradation, subsequently regulating the release of DNA plasmid to recruit APCs such as DCs. Mass production of safe, hydrogel-based DNA vaccines for in situ tumor administration may pave the way for personalized therapeutics.

RNA Based Vaccines

Synthetic messenger RNA (mRNA)-based vaccines exploit endogenous ribosomal machinery to affect the translation of tumor antigens, thereby initiating specific immune response against tumors.⁹⁵ Compared to DNA vaccines, RNA vaccines offer advantages such as simplicity, safety and production flexibility. Through crossing cell membrane, RNA vaccines, represented by mRNA, enable ribosome-mediated biosynthesis of tumor-specific polypeptides, avoiding their potential integration into the genome of cell nucleus.⁹⁶ However, RNA vaccines still face challenges such as inherent instability, susceptibility to degradation, and low transfection efficiency.

Hydrogel delivery systems engineered for RNA encapsulation demonstrate enhanced ribonucleic acid integrity preservation and spatiotemporal biodistribution control, allowing them to effectively reach targeted cells or tissues. For example, a photopolymerizable hydrogel made with gelatin methacryloyl has been reported to significantly achieve enhancement in mRNA transfection and translation efficiency, through ROS-mediated endosomal escape mechanisms in mesenchymal stem cells of human.⁹⁷ The engineered graphene oxide-polyethylenimine hydrogel encapsulating OVA-encoding mRNA has been shown to deliver mRNA to APCs without degradation, thus eliciting clonal expansion of antigen-specific CD8⁺T lymphocytes, ultimately achieving tumor volume reduction in B16-F10 syngeneic melanoma-bearing C57BL/6 murine systems.⁹⁸ With a single subcutaneous administration, this hydrogel effectively protects mRNA from enzymatic degradation and enables its sustained release, thereby activating specific immune cells to achieve durable and effective anti-tumor immunity. Besides, hydrogel containing siRNA or miRNA can also inhibit protein translation by interacting with corresponding mRNA, thus participating in tumor immunity to fight against cancers. Ankur Singh et al reported that IL-10 siRNA delivered by hydrogel successfully silences the expression of immunosuppressive IL-10, through interacting with corresponding mRNA to induce its degradation. That further leads to increased DCs homing to tumor-draining lymph nodes, while potentiating Th1 polarization of CD4⁺ T cell precursors in A20 cell-derived B-cell lymphoma murine xenografts.⁹³ Similarly, miRNA-205 and miRNA-182 delivered by hydrogel achieves sequence-specific oncogene silencing through RNA interference (RNAi) pathways, ultimately suppressing malignant cells growth and metastatic in triple-negative breast cancer (TNBC) xenografts.⁹⁹ The application of hydrogel significantly prevents siRNA and miRNA from being decomposed in vivo, thereby achieving the intervention of relevant mRNA target to treat cancers.

Although hydrogel delivery significantly improves the stability of RNA vaccines, several issues remain to be addressed. Because of intratumoral genomic diversity, the same type of tumor can present different TSAs in individuals. Therefore, current translational efforts tend to focus on designing personalized RNA vaccines targeting specific TSAs. In addition to RNA vaccines delivery, combining chemotherapy drug, such as DOX, with other cancer treatment strategies via hydrogel delivery is expected to maximum the therapeutic efficacy of RNA vaccines.

Protein or Peptides Based Vaccines

Proteins of tumor antigen, or peptides consisting of 8–35 amino acids, presented on tumor cells, are often employed in protein or peptides-based cancer vaccines.^100–102 These vaccines are relatively simple to produce, store, transport and safe,¹⁰³ but their lower immunogenicity may lead to unsatisfied antigen processing and presenting, thereby causing limited T cells-mediated immune responses. Additionally, the short survival time of proteins and peptides in vivo reduces their ability to induce lasting immune responses. Notably, short peptides-based vaccines may cause immune tolerance of host, instead of eliciting anti-tumor immunity.¹⁰⁴ Furthermore, the proportion of people, who is most likely to benefit, may be restrained by human leukocyte antigen, when subjected to peptides-based vaccines.¹⁰⁵

Beyond the use of protein OVA as a model tumor antigen, proteins extracted from surgically removed tumors can be loaded into star-shaped polyethylene glycol-oxidized dextran copolymer matrices to create a hydrogel-based vaccine (DCHVax). When administrated subcutaneously, DCHVax recruits DCs in situ, stimulating tumor-specific immunity, thus suppressing the growth of residual tumors in various murine tumor models.¹⁰⁶ Peptides constituted by dozens of amino acids are utilized as peptides-based vaccines, which are expressed on tumor cells and possess at least one antigen epitope of T or B cells.¹⁰⁷ For example, human basic fibroblast growth factor (bFGF), an oncogenic driver overexpressed across multiple malignancies, contributes to their proliferation. Consequently, peptides derived from the immunodominant regions of the heparin-binding domain of bFGF, or namely truncated bFGF (tbFGF) are used to construct peptide vaccines.^78,108 A thermosensitive hydrogel containing tbFGF peptides has been reported to elicit CTL-mediated adaptive immunity and specific antibody production, effectively suppressing primary neoplastic progression and distal metastatic colonization in lung adenocarcinoma murine systems.⁷⁸ Hyaluronic acid hydrogel containing neoantigen peptides, such as PancVax, composed of AddaVaxTM adjuvant with a STING agonist, is implanted at the tumor site in pancreatic adenocarcinoma (PDAC) mice via surgery. This approach promotes tumor-specific T cell priming and clonal proliferation, thereby preventing local tumor relapse in PDAC mice following incomplete resection surgery.¹⁰⁹ These hydrogels achieve easy-to-operate transportation of protein or peptides vaccines, and control their spatiotemporally on-going delivery to trigger a specific immune response in vivo.

Although hydrogel delivery systems for protein or peptide vaccines improve their stability, low immunogenicity of protein or peptides still hinders their widespread application. Therefore, immunoadjuvants have been added to protein/peptides vaccines and co-embedded in hydrogels to increase their immunogenicity in vivo.^43,110 Additionally, self-assembling peptides with multiple antigen epitopes, which can trigger more vigorous immune response, may may offer a valuable strategy for enhancing hydrogel-based peptide vaccine efficacy.^111,112

Dendritic Cells-Based Vaccines

DCs serve as pivotal orchestrators of adaptive immunity, distinguished by their unparalleled capacity to internalize, process, and display antigens with high efficiency.¹¹³ As specialized sentinel cells, they bridge innate and adaptive immune responses by activating naïve T lymphocytes through MHC-peptide complex presentation and co-stimulatory signaling, thereby initiating antigen-specific immune cascades critical for pathogen clearance and tumor surveillance. Especially in anti-tumor immune response, DCs can activate tumor-specific T cells, such as CTLs, to target and eliminate tumor cells. Consequently, DCs have been harnessed to fabricate DCs-based vaccines in cancer therapy.^114,115 Traditionally, exogenous DCs originate from autologous peripheral blood cells and turn to be mature by tumor antigens stimulation, and then are delivered to patients as DCs vaccines.¹¹⁶ Following in vivo lymphoid trafficking, mature dendritic cells prime naïve CD8⁺T lymphocytes through MHC class I-restricted antigen presentation coupled with co-stimulatory cues, thereby initiating antigen-specific cytotoxic T lymphocyte responses critical for adaptive immune defense. However, the clinical potential of DC-based vaccines remains constrained by biological challenges, including the transient survival kinetics of activated dendritic cells in vivo and the immunosuppressive mechanisms inherent to tumor ecosystems.

As the appealing transportation system, hydrogels are employed to deliver DCs to participate in DCs vaccines-based cancer immunotherapy. For instance, DCs and tumor antigens encapsulated in peptide nanofibrous hydrogels are subcutaneously administered to tumor-bearing mice, resulting in the enhanced lymphoid recruitment and migration of endogenous DCs, therefore driving amplified intratumoral infiltration of effector CD8⁺T cell populations. This biomaterial-mediated strategy achieves significant tumor suppression and prolongs survival duration in the mice.¹¹⁷ The usage of nanofibrous hydrogels ensures the survival and duration of DCs in vivo. Besides, such hydrogels containing tumor antigens stimulate both exogenous DCs maturation and autologous DCs accumulation to capture antigens released by hydrogels. Additionally, the use of hydrogels containing activated DCs and interleukin-15 superagonist, which are constructed by polysaccharide alginate, are peritumorally injected to murine melanoma model. This strategy facilitates cytotoxic CD8⁺ T cell sequestration within alginate-based scaffolds and neoplastic lesions, achieving robust suppression of progressive malignancies while extending survival duration in melanoma-challenged murine models.⁸⁴ Such kind of hydrogels can keep their structures and contents stable in vivo for a long time, decreasing the frequency of dosing and systemic exposure by local administration.

To maximize the therapeutic potential of DCs vaccines, hydrogel delivery systems are being studied in combination with immunotherapy strategies. For example, CaCO₃ biomineralized hydrogel containing TAAs from mouse breast cancer cells-DCs fusion cells was injected into triple-negative breast cancer mice. This biomaterial platform enhanced vaccine immunogenicity through dual mechanisms: sustaining TAAs release to promote endogenous dendritic cell maturation while maintaining lymph node trafficking capacity, ultimately driving tumor-specific CD8⁺ T cell responses that correlated with improved therapeutic outcomes. The structure of CaCO₃ biomineralized hydrogels also promotes M1 polarization to mitigate the immunosuppression of TME, where repolarized myeloid cells synergize with reinvigorated cytotoxic T lymphocytes to dismantle immunosuppressive networks.¹¹⁸ The use of DC vaccines combined with tumor antigens or coupled with cytokines or immunoadjuvants, and delivered through hydrogels with personalized structures, demonstrates significant potential for optimizing treatment outcomes in cancer immunotherapy.¹¹⁹

Tumor Cells-Based Vaccines

As a form of patient-individualized antigen, tumor cells-based vaccines are widely used in practice. These vaccines are made from whole tumor cell antigens or products derived from tumor cells, such as tumor cell membranes, tumor-derived extracellular vesicles (EVs), and tumor cell lysates. However, the inherent limitations of unmodified tumor cell-derived vaccines, characterized by rapid enzymatic degradation and systemic clearance post-administration, frequently compromise APC-mediated antigen processing efficiency, resulting in attenuated adaptive immune responses against malignancies. To address these pharmacokinetic challenges, engineered hydrogel matrices have emerged as a predominant biomaterial platform for achieving targeted co-delivery and spatiotemporal control of tumor-associated antigens while maintaining vaccine bioactivity throughout therapeutic windows.^120,121

Autologous or Allogeneic Tumor Cells-Based Vaccines

Comparable to their products, whole tumor cell-based vaccines release a full range of TSAs and TAAs. Therapeutic induction of immunogenic cell death (ICD) in neoplastic cells represents a strategic approach to generate tumor-associated antigens exhibiting enhanced immunostimulatory properties.¹²² This modality of programmed cellular demise can be elicited through radiation-based interventions, photoactivated therapies, virolytic agents, and specific chemotherapeutic compounds including oxaliplatin, taxanes, and cyclophosphamide.¹²³ Mechanistically, the ICD process generates critical immunostimulatory signals through liberation of key damage-associated molecular patterns (DAMPs), including high mobility group box 1 (HMGB1)¹²⁴ and extracellular ATP,¹²⁵ which orchestrate dendritic cell activation through dual mechanisms: facilitating phenotypic maturation via pattern recognition receptor engagement while simultaneously establishing chemotactic gradients for immune cell trafficking.¹²⁶ Dying tumor cells also expose calreticulin protein on their surface, allowing APCs to capture and present tumor antigens, thus inducing CTL-mediated adaptive immunity.⁵⁷ In short, ICD serves to reprogram immunosuppressive tumor milieus into immune-responsive neoplastic ecosystems through initiation of regulated cell death cascades, thereby priming a robust immune response to attack tumor cells. Consequently, ICD induction is often employed to initiate potent antitumor immunity in vaccines therapy containing tumor cells.

In the development of whole-cell vaccine platforms for oncological applications, tumor cells can originate from autologous or allogeneic sources. Regardless of their origin, the proliferative capacity of these tumor cells is abrogated, while their immunogenicity is preserved. Autologous tumor cell vaccines are developed using tumor cells derived from patients or tumor models, triggering the endogenous tumor-targeting immunity via synchronized liberation of clonotypic tumor-associated epitopes. For example, autologous tumor cells obtained through surgery undergo ICD to form a tumor cell-based vaccine, which is delivered to a tumor mouse model using a hydrogel constructed from mannan and polyethyleneimine. This hydrogel offers a simple and feasible method of delivering the autologous tumor cell-based vaccine. The vaccine effectively triggers CTLs-mediated immune response to suppress tumor recurrence.¹²⁷ In addition, hydrogel containing neoplasm-derived vaccine platforms enable remotely triggered antigen liberation spatiotemporally through near-infrared (NIR) laser irradiation, eliciting specific tumor immunity to prevent metastasis and recurrence after tumor surgery.¹²⁸ NIR laser irradiation, in combination with a photosensitizer, also induces ICD of autologous tumor cells loaded in Fmoc-KCRGDK-functionalized phenylboronic acid hydrogel matrices. The hydrogel achieves biomolecular recognition of malignant cells with overexpressed sialic acid, undergoing thermoresponsive sol-gel phase transition precisely within post-resection tumor niches, thus providing a sustained immune stimulus. This approach further inhibits the relapse of postoperative melanoma and colorectal tumors by generating reactive oxygen species (ROS), optimizing DCs immunocompetence, further expanding tumor-specific CD8⁺ cytotoxic T lymphocytes.¹²⁹

Notably, autologous cancer cells undergoing oncolysis (ACCO) can also result in oncolysis immunization against cancer.¹³⁰ A hydrogel is injected into cavity created by tumor resection, establishing a scaffold, and degrades to release the contained autologous tumor cells. ROS from adjacent trauma sites induces ACCO, enhancing immunogenicity and achieving antitumor immunization, ultimately restraining metastasis and recurrence of tumors.¹³¹ Additionally, ACCO vaccines can function as a prophylactic vaccine when delivered to mice in advance using a generalized framework hydrogel. This approach builds enduring and specific immune memory targeting TSAs. When tumors are orthotopically transplanted in the vaccinated mice, the immune status improves, coupled with CD8⁺ cytotoxic T cells homing to tumor beds increasingly.¹³²

Personalized tumor cells-based vaccines not only utilize autologous tumor cells encapsulated directly by hydrogel in vitro but also apply hydrogel contents to induce tumor cells death in situ in tumor mice, thus facilitating synchronized liberation of intact tumor antigenic payloads. Such in situ tumor vaccines (ITV) are derived from ICD of the primary tumor using hydrogel loaded with DOX. Upon injection in vivo, the hydrogel exhibits ROS-responsive release of DOX, which induces ICD to liberate whole tumor antigens, forming ITV that suppresses malignant cells development through triggering effective anti-tumor immunity.^133,134

For allogenic tumor cell-based cancer vaccines, both tumor cells carrying antigens,¹³⁵ NIR laser irradiation-induced ICD of live mouse breast cancer cells,¹³⁶ and immunogenically dying tumor cells¹¹⁹ are encapsulated in hydrogel and delivered to the host via a minimally invasive method. The hydrogel’s engineered architecture establishes a protective immunogenic niche for the allogenic tumor cells vaccines and controls the spatiotemporal and sustained release of tumor antigens. These hydrogel-based allogenic tumor cell vaccines have been shown to enhance DCs accumulation, then initiating a vigorous effector T immune response against various cancers.

Tumor Cell Membranes-Based Vaccines

Regarding tumor cells products, tumor cell membranes can be obtained in various ways to construct membranes-based vaccines. Hydrogel decorated with tumor cell membranes, constructed from oxidized sodium alginate (OSA), is subcutaneously injected into breast tumor mice. The decomposition of OSA orchestrates spatiotemporally controlled liberation of tumor-associated antigenic payloads derived from the tumor cell membrane. This effectively promotes DCs maturation, thereby stimulating T-cell-mediated immunity to inhibit tumor relapse.⁵⁹ Additionally, autologous tumor cell membranes encapsulated in polysaccharide hydrogels, which provide a repertoire of tumor antigens, effectively suppress tumor relapse in the postoperative B16F10 murine model.¹³⁷ Postoperative tumoral specimens are also used to form vaccines by isolating their tumor cell membranes, which can activate tumor-specific CD8⁺ cytotoxic T lymphocyte immunity to eradicate malignant cells through thermoresponsive hydrogel-based delivery systems.¹³⁸ Moreover, mitoxantrone and curcumin are employed to trigger ICD, after which tumor cell membranes are extracted to form membranes-coated vaccines with tumor-specific antigens, such as HPV16 E7_44-62 peptides. Sodium alginate hydrogel is used to deliver this vaccine, achieving controlled release of a spectrum of tumor antigens from the tumor cell membranes, thus eliciting antitumor immunity and inhibiting the growth of HPV-related tumors.⁵⁷

Tumor Derived EVs-Based Vaccines

EVs are lipid bilayer-bounded vesicles derived from the endosomal compartment.¹³⁹ EVs function as sophisticated biomolecular shuttles, encapsulating a diverse repertoire of signaling moieties—including proteomic complexes and nucleic acid species—that undergo intercellular trafficking from source cells to acceptor cell populations.¹⁴⁰ Tumor-derived EVs have been found to contribute to tumorigenesis through substance transfer or signaling transduction between cells.¹⁴¹ However, in some cases, tumor-derived EVs can stimulate specific antitumor immunity by providing multiple TAAs and TSAs. Study has reported that tumor-secreted EVs-encapsulated antigens are delivered by bio-adhesive macroporous hydrogels, which can adhere to tissues and recruit immune cells through controlled liberation of antigens and chemokines. This further results in the recruitment of numerous DCs to capture these antigens in situ, then eliciting tumor-specific CD8⁺T immune response.⁸¹

Tumor Cell Lysates-Based Vaccines

Compared to other tumor products, tumor cell lysates provide a broad array of TAAs and TSAs, making them a cost-effective and safe source of tumor antigens.¹⁴² A hydrogel vaccine system composed of tumor cell lysates can continuously release these tumor antigens to trigger antitumor immune response. In melanoma-bearing mice, vaccines made from tumor cell lysates encapsulated in hydrogel effectively stimulate DC maturation, thus promoting CTL infiltration at the tumor site.^77,143–145 In colon cancer mice model, vaccines formed from tumor cell lysates enhance the activity of CTLs through thermo-responsive hydrogel delivery, thereby suppressing tumor cells growth.^60,80 Additionally, tumor cell lysates-based hydrogel vaccines can elicit clonally restricted antitumor immunity for prophylactic suppression of locoregional recurrence and distal metastatic dissemination, when injected at the surgical site in postsurgical mice.¹⁴⁶

Currently, tumor cell-based vaccines are more widely used due to their comprehensive tumor antigen repertoire (Figure 3). Moreover, chemotherapy drugs, such as DOX, are often combined with tumor cell-based vaccines to treat cancers. This combinatorial immunotherapeutic platform augments tumor-associated antigen immunogenicity, while concurrently mitigating systemic cytotoxicity inherent to traditional chemotherapeutic regimens. While hydrogel-based platforms offer advantages in spatiotemporal regulation of tumor-associated antigen liberation and augmentation of whole-cell vaccine immunogenicity, existing challenges must be addressed, including the potential for autoimmunity or immunosuppressive effects, as well as the invasive procedure required to obtain autologous tumor cells through tumor biopsies or surgery.

Figure 3 Categories of hydrogel-based cancer vaccines. Created in BioRender. Wenqin, Z. (2025) https://BioRender.com/ p0bndby. Abbreviations: DCs, dendritic cells; EVs, extracellular vesicles.

Overall, hydrogels encapsulating DNA, RNA, proteins or peptides, DCs, or tumor cells combined with immunoadjuvants are widely applied in cancer vaccine research. Each approach has inherent strengths and limitations. A comparison of their specific advantages and disadvantages is summarized in Table 5.

Table 5 Comparison of Different Kinds of Hydrogel-Based Cancer Vaccines

Relevant Tumor Immune Mechanism Mediated by Hydrogel-Based Cancer Vaccines

After being injected into the host through hydrogel delivery, most contemporary cancer vaccines are engineered to orchestrate antitumor immune responses through spatiotemporally controlled liberation of tumor-associated antigens. The efficacy of these cancer vaccines primarily depends on the host’s cellular immunity, particularly the activation of CTL-mediated immunity against tumors. In addition, immune mechanisms regarding other innate, adaptive, and humoral elements have also been found in various studies of hydrogel vaccines-based tumor immunotherapy (Figure 4).

Figure 4 Related tumor immune mechanism mediated by hydrogel-based cancer vaccines. Once injected into tumor mice, vaccines constructed by tumor-based antigens like DNA, RNA, protein, tumor cells and immunoadjuvants can be controlled released by hydrogel in vivo. (a) These antigens are absorbed by immature DCs, thus promoting the maturation of DCs. (b) Mature DCs process and present these antigens to naïve T cells, that further boosts the activation of CTLs and memory T cells to attack tumor cells. (c) The release of cancer vaccine encapsulated by hydrogel can stimulate M1 polarization to inhibit tumor cells. (d) The release of tumor-based antigens also stimulates the activation of plasma B cells to secret antibodies. (e) Antibodies produced by humoral immunity can induce ADCC and ADCP of M1, NK cells and complement to kill tumor cells, accompanied by M1 macrophages secreting TNF-α and NK cells secreting IFN-γ. Created in BioRender. Wenqin, Z. (2025) https://BioRender.com/ ydv8muh. Abbreviations: DCs, dendritic cells; CTL, cytotoxic T lymphocytes; NK cell, natural killer cell; TNF-α, tumor necrosis factor α; IFN-γ, interferon-γ; ADCP, antibody-dependent cellular phagocytosis; ADCC, antibody dependent cellular cytotoxicity.

Activation of DCs

As critical APCs, DCs serve as pivotal immunoregulatory sentinels, orchestrating crosstalk between innate pathogen recognition and adaptive lymphocyte activation. Within adaptive immunity, DCs play an essential role in capturing and presenting tumor antigens and migrating to lymph nodes, thus transmitting antigenic information to naive T cells.¹⁴⁷ The establishment of clonally restricted antitumor immunity is contingent upon the complete maturation of DCs and their efficient processing of antigens. Numerous studies have revealed that cancer vaccines can stimulate DC activation, thereby promoting effective anti-tumor immune response through hydrogel delivery. For example, DOX and CpG embedded within a hydrogel enhance tumor antigen uptake by DCs and their maturation through in situ injection.¹³³ Cancer vaccine like Bridge-Vax, when combined with GM-CSF, have been reported to boost DCs activation via hydrogel delivery.¹³⁷ Tumor EVs and GM-CSF encapsulated in macroporous hydrogels have been found to recruit and activate DCs to capture and present EVs containing antigens.⁸¹ In addition, cGAMP nanoparticles-constructed hydrogel, containing STING agonist and ICD inducer, contributes to localized STING pathway activation, thus boosting DCs maturation through STING-IRF3-dependent type I interferon secretion.¹⁴⁸ These studies emphasize that DCs activation is crucial in the process of cancer vaccines-induced antitumor immunity.

Activation of Effector or Memory T Cells

Among the antitumor cellular immune response, effector CD8⁺ T cells function as central cytotoxic effectors, executing tumoricidal activity through secreting granzymes and perforin.¹⁴⁹ Peptide like melittin, self-assembling peptide RADA₃₂, tumor lysates, and CpG co-constituted in hydrogel vaccines have been shown to boost CTLs infiltration into TME, thus suppressing tumor growth in melanoma model.¹⁴³ Resected autologous tumors are used to construct personalized vaccines, such as Angel-Vax, which, when delivered via hydrogel, trigger CTLs-mediated immune response against remaining tumors in mice.¹²⁷ A nanofibrous trivalent peptide-based hydrogel vaccine has also been reported to amplify CTL immune response, thereby restraining the growth of B16 tumor cells.⁶⁸

The adaptive immune response induces clonal diversification of naïve CD8⁺ T cells into effector populations, while concurrently establishing heterogeneous memory T cell compartments to build immune memory. Upon encountering the same tumor stimuli, memory T cells are activated more rapidly and effectively.¹⁵⁰ Hydrogel vaccines, such as those based on ACCO and CpG,¹³² and autologous tumor cells,¹²⁸ can establish long-lasting and specific immune memory targeting tumor antigens, thereby preventing tumor recurrence and metastasis. DOX, nanoparticles, and immune adjuvants like imiquimod,¹⁵¹ or tumor cell-derived cytomembranes and CpG¹⁵² encapsulated in hydrogel also facilitate memory T cells activation. The studies indicate that hydrogel-based cancer vaccines can activate effector or memory T cells to participate in tumor immunity during cancer treatment.

Macrophage Polarization

Macrophages can exert either anti-tumor or pro-tumor functions depending on their activation phenotype. Tumor-associated macrophages (TAMs), predominantly M2-polarized myeloid subsets within the tumor microenvironment (TME), establishes an immunosuppressive circuit, enabling tumor immune evasion and therapeutic resistance.¹⁵³ TAMs exhibit phenotypic plasticity in response to extrinsic signaling cues, undergoing immunostimulatory reprogramming into pro-inflammatory M1-like macrophages, which exert anti-tumor effects, or alternative M2 macrophages, which promote tumor progression.¹⁵⁴ The M2-like properties of TAMs can pose challenges to cancer vaccines. As a result, researchers are focusing on developing cancer vaccines that induce M1 macrophage polarization, enhancing the therapeutic efficacy. For instance, hydrogel loaded with DOX has been shown to trigger ICD of malignant cells, boosting the polarization of M1-like phenotypes in situ vaccination in tumor models.^134,155 BCG lysates encapsulated in hydrogel also induce M1 macrophage polarization when injected near tumors in melanoma model.⁸⁷ A DC vaccine based on CaCO₃ biomineralized hydrogel has been shown to facilitate M1 macrophage polarization to reverse the suppressive TME.¹¹⁸ These studies indicate that various types of cancer vaccines embedded in hydrogel have the potential to improve the suppressive TME by inducing M1 macrophage polarization.

Humoral Immunity

Some studies suggest that cancer vaccines not only activate the host’s cellular immunity but also participate in humoral immunity to achieve therapeutic efficacy.¹⁵⁶ Humoral immunity mainly involves antibody-mediated B cells immune response. Tumor-bearing hosts can produce antibodies targeting multiple tumor antigens.¹⁵⁷ A self-assembling D-tetra-OVA encapsulated in hydrogel has demonstrate spatiotemporally controlled humoral immunomodulation in vivo.¹⁵⁸ Co-assembled peptides and antigens embedded in hydrogels were found to boost antibody generation.¹¹² OVA expressing plasmid and GM-CSF encapsulated in hydrogel can induce OVA antibody production to eradicate melanoma.⁹⁴ These studies demonstrate that self-assembling peptides and protein antigen delivered by hydrogel can also induce antibody production in established tumor models. These antibodies may execute tumoricidal activity through polyfunctional mechanisms, such as complement production, ADCP, or ADCC.

Innate and Adaptive Immune

While antitumor immunity mainly refers to adaptive T cell-mediated immunity, the initiation, coordination, and perpetuation of these responses also require the involvement of innate immune cells.¹⁵⁹ Innate immune cells DCs, macrophages and monocytes, serve as primary immunologic gatekeepers, encountering external antigens and transfers them to T cells, thereby eliciting adaptive immunity. Simultaneously, innate immune cells are capable of initiating self-immune response such as ADCP and ADCC.¹⁶⁰ These mechanisms mediate target cell elimination and pathogen clearance through cytolytic activity and cellular engulfment executed by innate immunologic sentinels, including NK cells and macrophages. Multifunctional vaccines, such as NOCC-CpG/OX-M based on hydrogel, promote M1 polarization through ADCP and ADCC, activating a cascade of myeloid-driven immunostimulation that licenses neoantigen-specific CTL clonal expansion via DC-mediated cross-presentation.¹⁶¹ Besides, cytokines like IL-6 and GM-CSF also enhance innate immunity, thus priming the host’s adaptive immunity. Li et al reported that HPV E7 peptide and the immunomodulatory agent β-glucan encapsulated in hydrogel can drive the production of myeloid-derived proinflammatory mediators (IL-1β, TNF-α, IL-6) that license DCs immunogenic maturation, thus improving the specific anti-tumor adaptive T cell response.¹⁶²

Collectively, hydrogel-based delivery significantly enhances cancer vaccine efficacy by amplifying immune responses compared to non-hydrogel counterparts. Key advantages are detailed Table 6.

Table 6 Comparison Between Hydrogel and Non-Hydrogel-Based Cancer Vaccines

Conclusions and Future Remarks

The comprehensive analysis describes the characteristics of physicochemical and immunomodulatory attributes of oncovaccines and polymeric hydrogel networks, providing an overview of current types of hydrogel-based cancer vaccines, finally summarizing the relevant anti-tumor immune mechanisms involved in cancer vaccines therapy. In general, hydrogels mimic the extracellular matrix, offering excellent biocompatibility as a delivery carrier. Vaccination of hydrogel-based cancer vaccines achieves a minimally invasive strategy for in vivo tumor treatment, even allowing in situ administration at tumor sites. Injectable hydrogels maintain the structure and properties of cancer vaccines, protecting them from degradation in vivo. Coupled with various immunoadjuvants, the immunogenicity of cancer vaccines is significantly enhanced, thus triggering potent antitumor immunity. Furthermore, the controlled spatiotemporal release of vaccines components by hydrogels ensures sustained stimuli for prolonged antitumor immune response, eliminating the need for repeated injections of cancer vaccines. Prophylactic and therapeutic cancer vaccines, delivered effectively via hydrogels, can prime tumor-targeted adaptive immunity, ultimately suppressing primary tumor progression, postsurgical neoplastic resurgence, and distal metastatic dissemination in tumor-bearing model. To optimize the efficacy of tumor antigen-based vaccines, chemotherapeutic drugs such as DOX, cyclophosphamide, taxol, or immune checkpoint inhibitors (ICI) like anti-PD-L1and anti-CTLA4 antibodies are often integrated into hydrogel-based cancer vaccines.^{133,144,163,164} Such combined application of these therapeutic strategies improves the outcomes of tumor treatment.⁵⁸ In conclusion, bioengineered hydrogel scaffolds containing cancer vaccines show significant promise as a potential tool in precision immuno-oncology.

The design of hydrogel-based cancer vaccines demands precise engineering of physicochemical architecture, as elements including polymer composition, porosity, and mechanical properties critically govern immune cell recruitment, activation, and spatial distribution. The choice of polymeric constituents-including HA, alginate, PEG or polypeptide derivatives-governs biocompatibility, degradation kinetics, and ligand presentation. Natural polymers such as HA contain endogenous CD44-binding motifs that facilitate DCs adhesion and TLR-mediated activation.¹⁶⁵ Synthetic alternatives like PEG-acrylate¹⁶⁶ enable modular conjugation of peptide antigens or immunostimulants (eg, CpG-ODN). Critically, polymer hydrophilicity and surface charge determine protein adsorption patterns, thereby modulating antigen retention and bioavailability. Cationic hydrogels preferentially adsorb negatively charged nucleic acid adjuvants, potentiating STING or TLR9 signaling in APCs.¹⁶⁷ Pore architecture critically regulates cellular infiltration and mass transport dynamics. Macropores (>50um) enable rapid recruitment of DCs, macrophages, and lymphocytes, whereas interconnected nanopores (10–100 nm) sustain prolonged elution of tumor antigens and cytokines.¹⁶⁸ This structural hierarchy synergizes with payload kinetics to determine immune response quality. Future iterations should prioritize in vivo-degradable polymers featuring tunable viscoelasticity and heterotypic porosity to orchestrate sequential immunity: rapid innate cell recruitment, efficient antigen presentation, and durable effector T-cell memory.

The clinical translation of hydrogel vaccines confronts significant scalability challenges in manufacturing, storage stability, and distribution logistics. Production limitations include batch-to-batch crosslinking variability compromising antigen loading efficiency and sterilization-induced degradation of thermosensitive immunomodulators.¹⁶⁹ Solutions may encompass continuous microfluidic fabrication with real-time rheological monitoring, aseptic photoinitiated click chemistry, and lyophilization maintaining >95% bioactivity. Storage/transport barriers stem from temperature-dependent structural collapse,¹⁷⁰ evidenced by 40–60% reduced swelling ratios and >30% antigen leakage during freeze-thaw cycles, which may be addressed through trehalose-based cryoprotection, thermo-responsive solid-state formulations, and passively cooled smart packaging. Economically, while production costs exceed traditional platforms, hydrogel vaccines demonstrate compelling value via 85–92% cold chain reduction, 3–5 times antigen retention enabling 40% fewer boosters, and 4–7% wastage rates versus 18–50% for cold chain-dependent alternatives.¹⁷¹ Their 24-month ambient stability contrasts sharply with conventional vaccines’ 3-6-month refrigerated shelf life, achieving reductions of distribution cost in resource-limited regions.¹⁷² Consequently, despite higher initial costs, hydrogel platforms enable transformative decentralized vaccination with amplified economic advantages during pandemics and for thermolabile biotherapeutics. Hydrogel vaccines enable a transformative shift toward thermostable, decentralized immunization. Scalable clinical translation hinges on overcoming manufacturing constraints via continuous production and stabilized dry-state architectures. Economic validation confirms viability across high-value oncology applications and global health settings where cold chain dependencies limit vaccine access.