Research progress and prospect of tumor nanovaccine combination therapy strategy
Yanyan Yin , Jun Guo , Shuo Zhang , Meng Xu , Yun Fu , Mengyi Zhang , Zhipeng Ma , Jiajia Ji , Siyuan Wu , Jinjie Zhang , Jianbo Li , Lei Wang
Currently, cancer represents a significant threat to human health and life [1]. The conventional therapeutic modalities for the treatment of tumors encompass surgical, chemotherapeutic, and radiotherapeutic interventions, amongst others. However, traditional tumor therapy has been unable to meet the needs of tumor treatment. For example, the shift or high degree of deterioration of the tumor patients is not suitable for surgery and radiation therapy; chemotherapy drugs lack targeting and are also lethal to normal tissue cells. It is, therefore, imperative that an efficacious and safe anti-tumor strategy for clinical use is developed. With the exponential growth of oncology and immunology, immunotherapy for cancer has become a new and important means of clinical treatment of tumors [2-5]. An immunotherapy approach that leverages a patient's endogenous immune response represents a promising avenue for tumor destruction. This strategy has been exemplified by several Food and Drug Administration (FDA) approved agents that target cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed death 1 (PD-1), and programmed death-ligand 1 (PD-L1). These agents have demonstrated clinical efficacy in the treatment of solid tumors [6-15].
Despite improving outcomes for patients with various cancer types, immune checkpoint inhibitor (ICI) has limitations, with only a minority of its patients achieving a lasting response. For example, even for melanoma with the highest ICI response rate, about 70% of cancer patients have a nonobjective response to inhibitor therapy of PD-1, and about 30% of patients with an objective response eventually have tumor recurrence [6,8]. In addition, ICI has been shown to be largely ineffective in patients who are not infiltrated by immune cells. This is because, in non-responders, PD-1 signaling is not the sole limiting factor in the cancer-immune cycle. Consequently, the blockade of PD-1 or PD-L1 alone is an inadequate strategy for the restoration of anti-tumor immunity [16,17]. Notably, based on the existence of tumor-related physical and physiological barriers, the clinical treatment effect of chimeric antigen receptor T-cell immunotherapy (CAR-T) has not fully met expectations [18-20].
In contrast to ICIs, the objective of cancer vaccines is to selectively target antigen-presenting cells (APCs) in lymph nodes with antigens and adjuvants. Therefore, it can effectively avoid the interference of solid tumor-related physical barriers. Furthermore, tumor vaccines can elicit durable immune memory responses, thereby exerting control over tumor recurrence and metastasis [21-23]. At present, tumor nanovaccines can be mainly divided into inorganic nanovaccines, polymer nanovaccines, biomimetic nanovaccines, and metal nanovaccines according to the nanocarriers [24]. In the preclinical research stage, the research on tumor nanovaccines mainly focuses on their safety and efficacy [25,26]. Some anti-tumor vaccines have entered this stage and have made some progress, such as vaccines against ovarian cancer and melanoma. For example, lipid-based nanovaccines (NCT04573140, NCT05726864, etc.) and biomimetic nanovaccines (NCT00512889) have entered phase Ⅰ clinical trials [27]. However, due to the antigen/adjuvant coating complexity, lymph nodes targeting efficiency problem of limited and low immunogenicity of antigen, the clinical application of tumor vaccine is still very limited [28,29]. Therefore, so far, the FDA approved only a carrying Sipuleucel-T (tumor-related antigen) dendritic cells (DCs) vaccine [30].
With the deepening of the research, the nanomaterials showed great potential to overcome the above difficulties. Compared with traditional vaccines, nanovaccines are capable of specifically targeting lymph nodes due to their controllable nanoscale dimensions and can be engineered to modify nanomaterials [31,32]. Conversely, the protection and encapsulation of nanomaterials enable the avoidance of premature antigens and adjuvant release, which is a key advantage of nanovaccines. Therefore, the most effective induction of an appropriate immune response in vivo is guaranteed. However, due to the presence of immunosuppressive microenvironments in tumors, the trials of nanovaccines using cancer vaccines alone in patients with refractory advanced tumors have not been successful [33]. Among them, the upregulation of inhibitory immune checkpoints on immune cells represents a pivotal mechanism whereby the anti-tumor immune response is suppressed, and immune evasion is facilitated [34]. It has been found that PD-1 expressed on the surface of immune cells can recognize and interact with tumor-associated PD-L1, thus significantly inhibiting immune activity [35]. Therefore, based on the aforementioned obstacles, the combined utilization of nanovaccines and tumor ICIs can effectively counteract immunosuppression and induce targeted immune stimulation, thereby enhancing the efficacy in preventing tumor metastasis. Furthermore, previous research has demonstrated that the utilization of ICIs can augment the efficacy of nanovaccines in eradicating tumor cells following stimulation [36-40].
In addition, tumor nanovaccines have been combined with chemotherapy and radiotherapy (RT). Treatments can also play a synergistic role in achieving a higher clinical therapeutic effect than a single treatment [41-43]. For instance, in the context of tumor nanvaccines, the characteristics of immune escape observed on the surface of neoplastic cells can be addressed through the enhancement of the tumor microenvironment (TME). This may be achieved by utilizing chemotherapy, RT, and other modalities, which can facilitate the release of tumor-associated antigens (TAAs), thereby enhancing the recognition and attack of tumor cells by the immune system [44,45]. In conclusion, the combined treatment strategy based on tumor nanvaccines has great potential for future use in oncology.
In this paper, the therapeutic mechanism of tumor nanovaccines combined with ICIs and the factors influencing the therapeutic effect was reviewed. It also considers the potential applications of tumor nanvaccines in conjunction with other therapeutic modalities. Finally, the existing problems of tumor nanovaccine are explained, and the future development of combined therapy has prospected.
Notwithstanding the evidence that existing tumor nanovaccines have been shown to elicit T cell-mediated immune responses within the context of the human body. However, the efficacy of nanovaccines is still limited by the over-expression of immune checkpoint proteins and immune-suppressing factors present in tumor cells, in addition to a substantial infiltrate of immune-suppressing cells, including myeloid-derived suppressor cells (MDSC) and regulatory T cell (Treg) [46-48].
As a significant factor contributing to tumor immune tolerance, the inhibition of immune checkpoints is a crucial element in improving therapeutic efficacy [49-52]. Currently, clinical immunotherapy of tumors uses immune-inducing drugs and immune-suppressive modulators, such as anti-CTLA-4 drugs in combination with anti-PD-1/PD-L1 therapy [53-55]. However, systemic administration based on combination therapy may diminish the therapeutic effect of immunotherapy and, more seriously, induce severe off-target immunotoxicity [56,57]. Therefore, on account of the characteristics of "immune targeting", tumor nanovaccine combined with ICI therapy shows great potential. In addition, studies have found that ICIs can effectively alleviate the immunosuppressive appearance of the TME, thereby improving the therapeutic effect of tumor nanovaccines on primary tumors. Kang et al. developed an engineered tumor nanovaccine (αHSP70P-CM-cap) termed the "artificial apoptotic cancer cell", which was created by combining an immunogenic B16OVA tumor cell membrane-associated antigen with a functional peptide (αHSP70p) derived from α-helix HSP70 [58]. After injection of αHSP70p-CM-CaP into a mouse model of lung metastasis of melanoma, it was found that after three cycles, the nanovaccine failed to alleviate tumor progression due to the interference of tumor immunosuppressive microenvironment. In contrast, when anti-PD-1 drugs are combined with αHSP70p-CM-CaP, approximately 90% of B16OVA melanoma mice had complete tumor regression. Additionally, in comparison with the control group, there was a notable increase in the proportion of immune cells, specifically CD62 L and CD44, within the lymph node CD8+ T cell population, reaching a level exceeding 40%. This effectively prevented tumor recurrence. In addition, nanovaccines can effectively reverse the immunosuppressive microenvironment by promoting immunogenic cell death (ICD) and increasing immune cell infiltration, thus sensitizing tumors to ICIs [59,60]. Song et al. developed a vesicle gel (iGel) that reshaped the immunosuppressive microenvironment by inducing ICD, recruiting APC activation, producing cytotoxic T cells, and depleting and inhibiting MDSC (Fig. 1) [61].
Long-term immune memory is a key factor in controlling tumor recurrence and metastasis. The immune checkpoint effectively suppresses the antigen-specific cytotoxic T lymphocyte (CTL) response [62]. Additionally, the absence of an effective cytotoxic CD8+ T cell response hinders the full efficacy of ICI therapy in tumor suppression, resulting in only a fraction of patients experiencing a complete immune response.
Currently, rapid, stable, has a long way of CD8+ memory T cells roughly divided into two kinds: Multi-dose scheme (primary strengthen) and in vitro antigen-pulsed adoptive transfer therapy. However, repeated high-dose administration may induce more severe tumor resistance. The process of isolating T cells from cancer patients, cultivating and expanding them in vitro, and subsequently reintroducing them into patients is a multifaceted procedure that requires meticulous coordination and attention to detail. If not conducted correctly, this process has the potential to induce adverse effects on the immune system, such as cytokine release syndrome [63]. Due to the particularity of tumor nanocarrier, the immune system can be trained to produce effector memory T Cells and sufficient CD8+ T cells by selecting or designing different nanomaterials to deliver antigens and related adjuvants [64,65]. Therefore, combined tumor nanovaccines can make up for the deficiency of ICI in delaying tumor progression caused by CD8+ T cell depletion.
In addition, another limiting factor in the maintenance of immune memory effects is immune resistance. The activation of the PD-1/PD-L1 pathway, which impairs the anti-tumor function of T cells, is a pivotal mechanism underlying tumor resistance. In order to achieve an effective anti-tumor immune memory effect, researchers have employed the use of ICIs as auxiliary components in tumor vaccines that are produced using nanotechnology. Hu et al. developed a lipid-zinc phosphate hybrid nanoparticle-based nanovaccine and combined it with the immune checkpoint antagonist D-peptide antagonist (DPPA-1) to mitigate the negative feedback effects associated with immunotherapy. Consequently, this approach has been shown to enhance immune tolerance, thereby facilitating a more extensive and durable CD8+ T cell-mediated immune response [66]. Moreover, ICIs have been demonstrated to potently suppress the PD-1/PD-L1 and CTLA-4 immunosuppressive checkpoints. Consequently, tumor-specific T cells are enabled to identify tumor-specific antigens (TSAs) and the production of a long-lasting immune response by tumor nanovaccines is promoted [67-69].
Given the heterogeneity of tumors, the choice of tumor type is crucial for the efficacy of the combined use of tumor nanovaccines and ICIs. First of all, for tumors with high immunosuppression (such as melanoma and colon cancer), the administration of tumor nanovaccines or ICIs alone often cannot effectively control the metastasis and recurrence of tumors in the long term [70-73]. Therefore, personalized treatment modalities for tumor types of patients are particularly important.
Among them, melanoma exhibits the highest rate of immune checkpoint response, characterized by a profound accumulation of immunosuppressive factors in its immune microenvironment, including vascular endothelial growth factor (VEGF), transforming growth factor β (TGF-β), and interleukin 10 (IL-10) [74]. Among them, the source of MDSC is a major cause of immune checkpoint resistance. Consequently, in patients with advanced melanoma who have been treated with ICIs, even in combination with anti-CTLA-4 and anti-PD-1, approximately half of the patients do not experience a sustained benefit [75]. In summary, reversing the immunosuppressive microenvironment, especially targeting MDSC, is of great significance for prolonging the survival of patients with advanced melanoma. Studies have found that natural killer T cells (iNKTs) can mediate the conversion of immunosuppressive MDSCs into immunogenic APCs in a CD1d-dependent manner [76,77]. Based on this, Rein and his team designed an mRNA nanovaccine [78]. This nanovaccine is an effective delivery system for nucleoside-modified mRNA and iNKT ligand glycosphingolipid antigen (α-GC) to the tumor site. The system is composed of liposomes comprising 1,2-distearoyl-3-trimethylammonium-propane (DOTAP) and cholesterol, which facilitate the effective delivery of nucleoside-modified mRNA and iNKT ligand glycosphingolipid antigen (α-GC) to the tumor site via the tumor vasculature. After intravenous injection, the vaccine unit against PD-L1 can prevent iNKT incompetent induction, highly increase the infiltration CTL, and induce the expression of NK cells and other immune cells, and, more importantly, the content of MDSC is significantly reduced. In addition, in the melanoma of preclinical studies, nanometer joint tumor vaccine and ICIs were effective in reducing the progression and metastasis of tumors and induced long-term immune memory [79-81]. Therefore, nanovaccines and ICI therapy for tumors highly immunosuppression is a potential therapeutic modality.
Secondly, before the application of combination therapy, the selection and design of specific nanovaccines according to different cancer characteristics are crucial for the efficacy of combination therapy. The selection of nanovaccines is mainly based on tumor antigens or related adjuvants, such as peptide antigens, protein antigens and nucleic acid sequences. The potential of peptide-based nanovaccines lies in their ability to elicit tumor-specific immune responses by targeting different peptide antigens on various tumor cells. This also provides a basis for the design of personalized nanovaccines. For instance, the E6 and E7 proteins, recognized as pivotal oncogenes in HPV-associated malignancies, exert a critical influence on the regulation of the host cell cycle through diverse pathways. Consequently, these proteins hold significant potential as therapeutic targets for peptide vaccines against cervical cancer [82]. Therefore, when designing nanovaccines against cervical cancer, most of the antigens target the E6 and E7 epitopes. At the same time, the combination of a peptide antigen nanovaccine and ICI therapy is particularly crucial for patients with weak antigens or significant suppression of immune function, as the peptide antigen itself lacks immunogenicity. Gong et al. devised a nanotransformer vaccine (NTV) comprising a polymer-peptide conjugate NT and a chicken ovalbumin-derived peptide (OVA241–270) [83]. Administration of NTV induced a potent immune response marked by CD8+ T cell expansion, exhibiting substantial effectiveness in inhibiting tumor growth in both murine B16F10-OVA and human tumor virus-E6/E7 models. Nevertheless, persistent tumor progression was observed following the third NTV vaccination. It is worth noting that the combination therapy with anti-PD-L1 markedly extended overall survival by over 83 days and resulted in complete tumor regression in approximately half of the mice within the B16F10 model.
The efficacy of tumor nanovaccines and ICI in eradicating tumor cells primarily relies on the patient's immune system. The effectiveness of combination therapy is directly influenced by the patient's immune activity. In cancer patients with a history of organ transplantation, immunosuppression, although beneficial for preventing rejection of the allogeneic graft, also suppresses immune surveillance of the malignant tumor [84]. For instance, a study revealed that out of nine kidney transplant patients with cancer treated with ICIs, one patient succumbed two days after receiving the first injection, another developed hemorrhagic shock four days into treatment, and three out of seven remaining patients experienced graft rejection. Among these three patients with graft rejection, two suffered graft loss while only one achieved an objective (partial) cancer response lasting for three months [85]. Consequently, in clinical trials on the safety and efficacy of immunotherapies, such as powerful immune activators and ICIs, organ transplant patients with advanced malignancies are frequently excluded. Currently, there are no treatment guidelines for patients with previous organ transplants who use tumor nanovaccines or ICIs. At the same time, in view of the increasing number of organ transplant patients, it is crucial to thoroughly evaluate the feasibility of tumor nanovaccines and their combination therapies in this patient population. Firstly, it is essential to gain an understanding of the mechanisms underlying the activation of tumor-specific T cell responses and alloreactive T cells following immunotherapy, in order to assess its potential use in the organ transplant patient population. Treg are regulatory T cells, characterized by the expression of Foxp3, CD25, and CD4+.
Long-term research has confirmed the important role of Treg in infections, tumors, organ transplants, the prevention of autoimmune diseases, and the maintenance of the body's immune balance [86]. In the process of tumor immunity, Treg can participate in the occurrence and development of tumors by suppressing anti-tumor immune responses. Treg expresses inhibitory factors (CTLA4, secreted IL-33, and TGF-β) to suppress excessive immune responses, which may also promote tumor cell immune escape [87]. Additionally, Treg can continuously infiltrate the TME via chemokines, thereby contributing to the suppression of anti-tumor immune responses. Therefore, targeting Treg is currently a research hotspot in tumor immunotherapy. For example: (1) Depleting Treg in tumors; (2) disrupting Treg infiltration into tumor sites; (3) enhancing the sensitivity of Treg in tumors to immune checkpoint blockers; (4) targeting the costimulatory signals of T cells; (5) targeting the immunosuppressive cytokines secreted by Treg; (6) altering Treg fragility; (7) targeting Treg metabolism [88].
Conversely, an effective reversal of Treg immunosuppression may induce immune rejection in organ-rejection patients. Recent studies have shown that the regulatory cell mechanism can be used to induce graft immune tolerance and induce long-term graft survival without the use of immunosuppressants. This natural immune regulatory mechanism is called regulatory cell-mediated immune tolerance [89]. Furthermore, related therapies have been used in organ transplantation. For example, Treg reinfusion therapy and CAR-Treg therapy. In addition, the PD-1/PD-L1 axis is also important for maintaining immune tolerance in organ transplant patients [90]. For example, PD-1 can bind to PD-L1 in cells and PD-L2 in APCs. In models where PD-L1 inhibits T cell activity, its function depends on Tregs. Like CTLA-4, PD-L1 signaling plays a key role in promoting Tregs. Given these characteristics, immunotherapy is generally excluded in patients with tumors that require the maintenance of chronic immune tolerance. For example, the FDA-approved ipilimumab. Given the increased risk of malignancies (especially skin cancer) in transplant recipients who are chronically treated with immunosuppressive therapy, there is an urgent need to evaluate the safety and efficacy of immunotherapy such as tumor nanovaccines in these high-risk populations. Nevertheless, some clinical evidence on immunotherapy in organ transplant patients with tumors suggests that immunotherapy has therapeutic potential [91]. A 69-year-old woman who received a kidney transplant in 2001 was found to have recurrent squamous cell carcinoma (SCC) of the skin during subsequent examinations and underwent surgical removal and local fluorouracil treatment in 2004. However, in 2009, the patient developed lymph node metastasis of the tumor. She subsequently underwent various treatments, including RT, cetuximab, erlotinib, and the combination of capecitabine and interferon (IFN), but none of these treatments had any significant effect on her SCC skin lesions or metastatic tumors. In 2015, after a thorough assessment of the potential risks of ICI therapy (including graft rejection), she was treated with nivolumab. Although initially there were side effects such as skin itching, after 11 cycles of nivolumab treatment, the side effects disappeared and there was no tumor progression. Therefore, for organ transplant patients who have been using immunosuppressants for a long time, the use of immunotherapy does not appear to cause rejection of the relevant organs. Another patient who had undergone an orthotopic heart transplant and subsequently developed non-small cell lung cancer (NSCLC) had tumor recurrence after chemotherapy, RT, and surgical therapy. Therefore, 21 cycles of nivolumab treatment were administered, no immune-related diseases or graft rejection were found, and the tumor was controlled.
However, it is worth noting that the combination of two immunotherapies at the same time may cause severe immune rejection in organ transplant patients [92]. To illustrate, in 2016, a kidney transplant patient with metastatic melanoma experienced a severe acute rejection following the administration of RT, ipilimumab, and nivolumab concurrently. Furthermore, the available evidence indicates that PD-1 inhibitors are associated with a higher incidence of immune rejection compared to CTLA-4 inhibitors. Nevertheless, in three documented instances of concomitant administration of CTLA-4 and PD-1 inhibitors, acute allograft rejection was not observed in one case [93]. This provides hope for the combination of tumor nanovaccines with other therapies such as anti-CTLA-4. Clinical trials could be conducted by administering the tumor nanovaccine in batches to patients after a thorough assessment of their immune status, the timing of organ transplantation, the type of organ transplant, complications, etc., and by monitoring the immune response and safety after each vaccination and selecting suitable combination therapies (e.g., preferentially anti-CTLA-4). However, there is currently a lack of clinical studies on the combination of tumor nanovaccine and therapy for organ transplant patients. However, further discussion and exploration of its effects and efficacy in organ transplant cancer patients is beneficial for the development and optimization of anti-tumor response treatment regimens and minimizes the risk of allograft rejection in this population. Second, immunotherapy may not yield a superior therapeutic outcome in patients with tumors exhibiting weak immunogenicity. For instance, NSCLC patients harboring epidermal growth factor receptor/anaplastic lymphoma kinase (EGFR/ALK) molecular alterations may demonstrate diminished response rates [94,95]. Therefore, the utilization of tumor nanovaccines to enhance the immunogenicity and subsequently augment the efficacy of ICIs represents a potential combinatorial approach for treating NSCLC.
Limited research has been conducted to determine the optimal timing of combination therapy involving ICIs. One study demonstrated that concurrent inhibition of the PD-1 receptor and priming with antigens resulted in reduced antitumor efficacy of the nanovaccine and anti-PD-1 combination. This was attributed to an increased proportion of antigen-specific CD8+ T cell apoptosis. For example, in the spontaneous B-cell lymphoma model of the Em-myc transgenic C57 BL/6 mouse, treatment with the 4–1BB agonist mAb alone is sufficient to drive anti-tumor immunity, but when combined with anti-PD-1 treatment, the mAb's T-cell-promoting effect and anti-tumor activity are reduced [96]. Based on this, Xie et al. explored the optimal timing and sequence of combined anti-PD-1 therapy during nanovaccine administration in a mouse tumor model of E.G7-OVA [97]. To this end, two dosing regimens were set up: (1) Simultaneous injection of the nanovaccine and anti-PD-1 and (2) sequential injection of the nanovaccine followed by anti-PD-1 one week later (sequential administration). It was found that simultaneous administration of anti-PD-1 and the nanovaccine resulted in tumor recurrence immediately after the anti-PD-1 administration, while sequential administration resulted in complete tumor regression in 20% of mice after the administration. In addition, another group of researchers found that sequential injection increased the frequency of IFN-γ and CD8+ TILs compared to simultaneous injection of the nanovaccine and anti-PD-1. They also found that on day 20, the anti-tumor effect obtained with simultaneous injection was not superior to that obtained with the nanovaccine alone [98]. In summary, the combination of tumor nanovaccine and ICIs needs to be flexibly adjusted according to the individual patient's condition. Nanovaccination is performed first to activate the immune response, and then ICIs are used to ensure that the synergistic effect of the two is maximized.
In addition, the investigators suggest that the natural rhythms of innate and adaptive immune responses orchestrate the immune response and that treatment effects can be amplified and driven by properly dosing the various therapies in combination therapy [99]. In recent years, it has been found that the duration of IFN signaling is different, and it will play opposite roles in the immune activation system. In simple terms, a brief IFN signaling to the immune activation (type Ⅰ and type Ⅱ) is essential, but persistent IFN signaling (type Ⅱ IFN signaling, for example) may result in resistance [100-102]. Therefore, in combination therapy, tumor nanovaccines for the immune system are not the more beneficial. Because, with the increase of DC LPS exposure time, related IFN levels will also increase, for example, DC LPS exposure 8 h, CD4+ T cells to produce IFN (IFN-γ), 48 h to produce interleukins (IL-12). Therefore, in the joint application of ICIs, tumor vaccine dose and carried by the quantity of antigen and adjuvant also should be fully considered. However, despite the importance of the immune cycle revealed by many current studies, most immunotherapy still focuses on the traditional ‘continuous dose to maximum tolerated dose’ perspective, which wastes the opportunity to utilize the potential golden window. Therefore, how to seize this golden window period is a worthwhile research question for combined tumor nanovaccine and ICI therapy.
The interaction between RT and the immune system has long been postulated to have a subtle synergistic effect. As early as 1953, R.H. Mole proposed the concept of a remote effect, which has been the subject of considerable research since that time [103]. However, due to the body's immune tolerance mechanism, the late effects induced by RT have not been the subject of extensive investigation. It was not until the advent of immunotherapy that this effect began to be exploited, albeit gradually.
Studies have found that RT can induce tumor cells to produce TAA and TSA. This provides a good condition for the combined application of tumor nanovaccines and RT, especially in situ tumor vaccines. For example, the investigators used local RT in mice and found that RT-induced the activation of dendritic cells (DCs) in a high-mobility-group box 1 (HMGB1)-dependent manner, which was loaded with TAA released by damaged tumor cells and was sensitive to Toll-like receptor agonists (TLRa) [104]. Another group of researchers discovered that following tumor RT, the injection of cation-modified attenuated Salmonella into the tumor increased the concentration of tumor antigens surrounding the tumor, enhanced communication between antigens and DCs, boosted anti-tumor immune response, and ultimately achieved a reduction in tumor metastasis and recurrence [105]. In addition, Luo et al. constructed an in situ nanovaccine based on the peptide Fbp-GDFDFDpY (Fbp-pY) using radiotherapy, which further promoted the accumulation of antigens in the lymph nodes, remodeled the tumor microenvironment, repolarized the alternatively activated macrophages (M2) macrophages to classical activated macrophages (M1), and suppressed Tregs and MDSC by down-regulating the expression of cyclooxygenase 2 (COX-2) to improve the efficacy of immunotherapy (Fig. 2) [106].
In addition, RT can also induce reactive oxygen species (ROS) to damage the DNA of tumor cells, thereby recruiting APCs to the TME. However, RT can also recruit immunosuppressive cells such as Treg to the TME [107]. It has been reported that the DNA damage response inhibits tumor cells from secreting IFN-Ⅰ, thereby limiting the recruitment of APCs [108]. Therefore, regulating RT-induced IFN-Ⅰ signaling is beneficial for immune stimulation. It has been found that the Mn2+-activated cyclic guanosine adenylate synthase-STING pathway (cGAS-STING) pathway can promote the immune response induced by RT by affecting the IFN-Ⅰ signaling pathway, which causes macrophages to re-polarise from the tumor-promoting M2 to the tumor-resistant M1, thereby promoting the immune response induced by RT. Therefore, manganese-based nanovaccines can synergize with RT to fight tumors in the proximal and distal regions. Luo et al. showed a significant synergistic effect in a mouse model by combining PC7A nanovaccine with local ionizing radiation to synergize the function of the lymphatic system and STING at the tumor site [109]. Meanwhile, another group of researchers designed a nanovaccine drug delivery system (PLGA/STING@EPBM) coated with an engineered peptide-based biomimetic cancer cell membrane (EPBM), which in turn delivered STING agonists and tumor antigens to CLEC9A DCs. This nanovaccine combined with RT also showed significant synergistic antitumor effects [110]. Tumor nanovaccines can also enhance the effect of RT by inducing O2 production in the TME. Gu et al. designed a DC-specific nanovaccine by decorating OVA with mannose-modified MnO2 to target and activate the cGAS-STING pathway. In addition to reversing the immune microenvironment, the MnO2 in this nanovaccine can also synergistically enhance the sensitivity to RT caused by hypoxia by producing O2 [42].
Although combination RT shows potential efficacy, its possible side effects should also be taken seriously. First, between subcutaneous or intramuscular injections of tumor nanovaccines especially mRNA-lipid nanoparticle (mRNA-LNP) vaccines, this may cause DCs and neutrophils to accumulate, which in turn causes a subcutaneous inflammatory response. This side effect may aggravate the subcutaneous damage caused by RT [111]. In addition, since both tumor nanovaccines and RT have the potential to induce autoimmune diseases, immune-related side effects such as skin rashes, breathing difficulties and autoimmune inflammation (e.g., pneumonia, hepatitis, or enteritis) may increase significantly in this combination therapy [112]. Therefore, the efficacy of tumor nanovaccines combined with RT needs to be further evaluated.
Phototherapy can kill tumor cells and make them release antigens, which then make the immune system respond [113,114]. However, the immune response induced by photothermal therapy (PTT) is not strong due to immunosuppression. For example, in breast cancer, although surgical treatment is the main treatment for primary breast cancer, the removal of residual tumor cells around the cavity can lead to a high degree of recurrence and metastasis [115]. In addition, the inflammatory response in the wound bed after surgery also exacerbates local immunosuppression, which further promotes the recurrence and metastasis of tumor cells [116].
PTT has shown potential in breast cancer because it can ensure non-invasive tumor killing and induce distal effects through TAAs released by tumor cell death [117]. However, due to the immunosuppressive characteristics of the breast cancer microenvironment, the immunomodulatory effect of photothermal therapy is not completely effective [118,119]. Tumor nanovaccines can not only reverse the immunosuppression of the TME by directly inducing ICD but also form in situ recombinant nanovaccines with TAAs through immune adjuvants or other immunological components carried by nanocarriers, thereby further inducing stronger immunological effects and effectively controlling tumor recurrence and metastasis [120]. Jia et al. developed a thermosensitive hydrogel that simultaneously carries a TLR-7/8 agonist: R848 (a photothermal agent), indocyanine green (ICG), and a TLR-9 agonist (CpG oligodeoxynucleotides (CPG ODNs)), to achieve synergistic photothermal immunotherapy [121]. When further near-infrared (NIR) laser irradiation is applied, the high temperature (above 45 ℃) generated by ICG promotes the release of R848 and CPG ODNs from the gel, which not only kills the tumor in situ but also acts like a vaccine together with the TAAs released after tumor death, further killing distant tumors. Complete tumor cure without recurrence was observed in 80% of mice in a breast cancer metastasis model. In another study, the researchers, through a simple chemical coupling, the amphiphilic polymer TLR7/8a, eight polyTLR7/a) and R9-GPLGLAG-polyethylene glycol (PEG) by Au-S keys and AuNRs chemical coupling, produced can capture antigen nano platform AuNRs-IMDQ-R9-PEG. By PTT and NIR laser radiation (808 nm), after the destruction of tumor cells and tumor cells, the release of the antigen was AuNRs-IMDQ-R9 capture, which was directly in situ to form a nanovaccine. This greatly enhanced the treatment distal mediated immune therapy effect and significantly improved the bilateral 4T1 breast cancer tumor animal survival [122].
Similarly, immunosuppression of melanoma is the main reason for the poor immunosuppressive effect induced by PTT. Based on this, our research group has designed a folic acid-modified thermosensitive liposome (FA-TSL)/gold nanocage (AuNC)/simvastatin (SV) nano platform as a novel anti-tumor immune system from scratch. After 808 nm laser-mediated PTT using AuNCs on tumors, tumor cell-derived protein antigens (TDPAs) are released while the FA-TSL protection shell is removed. Simultaneously, exposed AuNC/SV immediately captured TDPAs to form an in-situ recombinant vaccine (AuNC/SV/TDPAs). In bilateral melanoma mouse models, this vaccine effectively migrates to lymph nodes and promotes cross-presentation of TDPAs, inducing a robust antitumor immune response [123].
At present, personalized nanovaccines derived from tumor cell membranes have made some progress in inhibiting tumor recurrence and metastasis. However, because of the complexity of the tumor immunosuppression microenvironment, the effectiveness of the derivative of solid tumor vaccine is still unsatisfactory. Thus, researchers are trying to unite phototherapy and tumor cells to enhance the curative effect of personalized cancer therapy. The MPDA-R848 (MR) nanoparticle (NP) was obtained by Li et al., for instance, through hydrogen bonding interactions and π-π stacking, followed by loading R848 and TLR7/8 agonist into the lumen of MPDANP. Subsequently, a short ultrasonic treatment was applied to coat MRNPs onto the surface of homologous 4T1 cell tumor cell membrane (CM) via physical extrusion. Ultimately, the solar-thermal MR@CNPs tumor nanovaccine was successfully developed. This nanovaccine demonstrated potential in both tumor treatment and prevention of postoperative tumor recurrence as it achieved 100% prevention against reattack from 4T1 cells in a postoperative tumor model (Fig. 3) [124].
The non-invasive ultrasonic acoustic dynamics therapy (SDT) treatment has demonstrated the ability to induce antitumor immunity [125-127]. The therapeutic mechanism of SDT is mainly divided into two parts: the use of sonosensitizers and the production of highly toxic ROS, mainly singlet oxygen (1O2), which induce ICD and release abundant TAAs, thereby increasing tumor immunogenicity and promoting tumor infiltration by CTL; It kills cancer cells directly or indirectly by inhibiting the formation of new blood vessels in tumor tissue and inducing tumor-specific immunity [128]. Ultimately, this results in a tumor-specific immune response for effective eradication of cancer [129,130]. However, the single use of SDT immune efficacy to inhibit the growth of primary tumor metastasis is not particularly strong [131]. In recent years, titanium dioxide (TIO2) has been one of the most widely studied nanomaterials in SDT [132]. It has strong stability and low cytotoxicity and can also be used as an immune adjuvant and carrier of related antigens [133-135]. Based on this, researchers have used titanium dioxide to construct a nanovaccine to achieve the synergistic effect of tumor nanovaccine and SDT on primary tumors. Wang et al. constructed a multifunctional tumor nanovaccine BMT@LA NCs [136]. The BMT@LA replication exhibits vaccine-like characteristics, wherein, under the influence of ultrasonic waves, BMT and LA generate 1O2 and nitric oxide (NO) gas at the tumor site. Additionally, this process enhances cellular oxidative stress levels and induces double-stranded DNA rupture, ultimately leading to apoptosis in cancer cells. Simultaneously, tumor-related antigens stimulate antigen-specific T-cell immune responses by promoting the release of apoptotic cells. At the same time, tumor nanovaccines can also enhance the tumor-associated antigens released from tumor cells killed due to acoustic kinetic therapy, which in turn induces an immune response. For example, the nanovaccine constructed by Cui et al. based on anti-PD-L1, Fc-Ⅲ-4C peptide linker and poly(l-glutamic acid)-graft-R848 activated the in vivo immune mechanism under the dual stimulation of in situ antigen and immune adjuvant under the action of ultrasound and further induced a strong antigen-specific immunomemory effect, preventing the tumor from recurring in vivo (Fig. 4) [137].
Studies have shown that chemotherapy may improve the efficacy of immunotherapy by inducing ICD and killing tumor cells, thereby releasing TAAs or TSAs [138]. It has been reported that doxorubicin (DOX) triggers ICD in tumor cells, resulting in increased expression of calreticulin (CRT) on their surface, which in turn assists DCs in capturing and processing tumor antigens to activate the immune system [139]. Based on this, Wang et al. constructed tumor nanovaccines using CRT-rich fibrosarcoma cell membranes, which synergistically enhanced the recruitment of DCs and the delivery of antigens to DCs in combination with DOX, thereby effectively inhibiting tumor recurrence [140]. In addition, a clinical study showed that in breast cancer patients, the administration of cyclophosphamide (CY), DOX, and granulocyte-macrophage colony-stimulating factor (GM-CSF) secreting tumor vaccine via time-continuous administration revealed that CY and DOX enhanced the ability of the tumor vaccine to induce immunity, and the combination therapy showed better efficacy than the individual administration. Meanwhile, in non-small cell lung cancer [141], acute myeloid leukemia [142], and melanoma [143] patients in clinical trials, tumor vaccine, and chemotherapy drug combination showed a better effect; it also offers tumor nanovaccine combination with chemotherapy may. However, the immune-adjuvant effect mediated by chemotherapy drugs is severely limited due to their toxic side effects such as bone marrow suppression. Therefore, how to achieve a synergistic and less toxic combination of immunotherapy and chemotherapy has become an urgent issue. Li et al. found that cancer cells cultured in vitro, after being treated with chemotherapeutic drugs, promote the release of TAAs, TSAs, and damage-associated molecular patterns (DAMPs), which in turn form a nanovaccine that can improve the efficacy of anti-PD-1 therapy, developing the concept of “immunogenic equivalence” [144]. Another group of researchers also observed no tumor recurrence and effective treatment in a mouse CT26 model after culturing CT26 cells in vitro and then applying tumor nanovaccines composed of oxaliplatin in vitro [145]. This treatment strategy in vitro directly avoids the immune-related toxic side effects caused by chemotherapeutic drugs, thus providing new ideas for the personalized treatment of cancer patients. A detailed overview of the specific therapeutic mechanisms and functions of tumor nanovaccine combination therapies is provided in Table S1 (Supporting information) [146-161].
In combination therapy based on tumor nanovaccines, in order to achieve the best synergistic effect, the nanovaccine must first exert the greatest effect, which leads to a critical choice of nanovaccine type. Because the nanovaccine design for different tumor types affects the choice of combination therapy.
In PTT, gold nanomaterials with a hollow mesoporous structure have application potential in terms of combined PTT and tumor-targeted nanovaccines [152]. First, gold nanomaterials have excellent photothermal conversion efficiency and can directly kill tumors in PTT. At the same time, their hollow mesoporous structure can efficiently load immunological adjuvants to construct tumor nanovaccines. Therefore, metal nanovaccines based on gold nanomaterials are more conducive to combined PTT. In addition, PTT, chemotherapy, and RT can kill tumors in situ, and the tumors will release a large amount of TAAs. Personalized and specific immunotherapy can be achieved by preparing an in situ cancer vaccine using TAAs. Therefore, the selection of suitable nanomaterials that can effectively capture TAAs produced by related therapies is also the key to the success of combination therapy. For example, based on the good adhesion of related polymers (such as poly-dopamine), polymeric vaccines can adsorb TAAs produced by photothermal effects to a greater extent, thereby inducing a stronger immune response and ultimately achieving a more lasting post-immunization effect [162]. In addition, manganese-based metal nanovaccines are more suitable for synergistic RT and ICIs. Titanium dioxide-based nanovaccines are more suitable for combination with SDT [136].
Based on this, we will give a detailed introduction to the current types of tumor nanovaccines to provide better options for combination therapy. Current tumor nanovaccines mainly focus on polymer nanovaccines, biomimetic nanovaccines, and metal nanovaccines.
In building a tumor nanovaccine, polymer nanoparticles, due to their self-assembly and customizable features, can be used in the surface coating or adsorption of antigens and adjuvants. In addition, polymer nanoparticles have good nanoscale and biocompatibility to better target lymph nodes and thus play a better curative effect of nanometer vaccine [163,164]. Currently, the polymer-carriers commonly used in tumor nanovaccines mainly include biodegradable polymers, cationic polymers, and single-chain polymers.
Among them, the most commonly used biodegradable polymer for poly lactic acid/glycolic acid copolymer (PLGA) has been approved by the FDA [165,166]. PLGA is readily metabolized and exhibits favorable biocompatibility, as both lactic acid and glycolic acid released from its hydrolysis are naturally occurring substances within the human body [167]. Nevertheless, conventional PLGA-based nanovaccines exhibit a relatively low encapsulation efficiency. Furthermore, PLGA, as a neutral material, lacks the capacity to target specific tumor cells and induces a limited immune response [168]. Therefore, the researchers usually modify PLGA. For example, PLGA-based multi-component nanosystems can be constructed by controlling the proportion of monomers in PLGA formulation or combining PLGA with lipids, metal nanoparticles, etc., to improve their targeting and drug release through synergistic effects [169-171]. For example, Liu and others chose PLGA in the molar ratio of lactic acid and ethanol control at 75:25, constructing the pH-responsive PLGA nanoparticle vaccine [172]. Compared with traditional PLGA nanoparticles, as a result of pH-responsive PLGA nanovaccine having a thin shell and bigger cavity, the antigen coating effect is better. Nanovaccines, at the same time, due to their high concentration of lactic acid, are better at ensuring stability in the circulation of the blood, further effectively promoting antigen cross-presented and macrophage maturation and activation and enhancing the antigen-specific immune response. In addition, different formulations of PLGA monomers, such as Han and others, are used to build cationic solid lipid nanoparticles [173]. They used twenty-eight alkyl dimethyl ammonium bromide (DDAB) on the surface of the PLGA decorate, and according to the static adsorption of DDAB cation will negatively charged antigen OVA (OVA257–264) was loaded into the PLGA nanoparticle surface. This nanovaccine further enhanced antigen transport to lymphatic node (LN) by passive targeting and increased the antigen uptake of pure OVA by bone marrow-derived dendritic cells (BMDC) 12-fold. At the same time, the immunogenicity of the vaccine was enhanced through p38 signaling in BMDC.
In addition to PLGA, cationic polymers have been extensively studied in the field of nanovaccines. These polymers can establish electrostatic interactions with cell membranes, enhancing uptake and targeting of the nanovaccine to tissues. Some cationic polymers also exhibit a "proton sponge effect" that promotes the escape of nanovaccines from endosomes or lysosomes, thereby improving vaccine immunogenicity [174,175]. At present, the most commonly used cationic polymer is polyethyleneimine (PEI) [176,177]. PEI in the 1990s was the first for nucleic acid delivery of cationic polymer; it can be either as a delivery antigen carrier or also be used to strengthen the congenital immune adjuvant [178]. PEI has a high density of positive charge, good security, and can be modified to make nanometer vaccine workers into objects [179]. In order to continuously enhance the effectiveness and safety of PEI, researchers have dedicated decades to embellishing and constructing a range of nanovaccine platforms based on this material. For instance, Li et al. successfully developed a personalized mRNA cancer vaccine utilizing PEI [177]. Using fluorine alkane (F-PEI) modification, Li et al. reduced the toxicity of PEI while also utilizing it as an agonist for the Toll-like receptor 4 (TLR4)-mediated signaling pathway. Additionally, the modified F-PEI can self-assemble with protein or peptide antigens to form nanovaccines without requiring additional adjuvants. Furthermore, the constructed B16-OVA melanoma model showed complete eradication of established tumors when combined with ICIs.
In addition to PEI fluoroalkanes, some researchers have attempted to polyethylene glycolized PEI to improve its systemic circulation time [180]. The researchers Nam et al. developed a programmable and personalized nanovaccine utilizing PEGylated PEI [181]. This PEG-modified PEI nanovaccine eliminates the inherent cytotoxicity associated with PEI. Crucially, this kind of PEG modified PEI after nano only within a single tumor vaccine injection, it can be caused in the systemic circulation is as high as about 30% of new antigen-specific CD8+ T cell responses, and to maintain its rise in 8 weeks CD3+ T cell responses, in MC6 colon cancer tumors in mice model shows strong antitumor efficacy.
Single-stranded polymer SCNP represents a promising alternative for use as a nanovaccine carrier, offering a distinctive advantage in particle size. Compared with conventional polymer nanoparticles, SCNPS have a smaller particle size and higher cellular uptake efficiency. At the same time, SCNPS can more easily enter and flow through lymphatic channels, guide vaccine antigens to sites such as lymph nodes, and promote immune stimulation and antigen presentation [182]. The PMBEOx-cook group, synthesized by Li et al. was utilized to construct personalized mott SCNPs/R837 by grafting thioglycolic acid onto poly(2-methyl-2-oxazoline)-block-poly(2‑butyl‑2-oxazoline-co-2‑butyl‑2-oxazoline). These nanoparticles were then combined with TLR7 agonist imiquimod (R837) [183]. Compared with the conventional PLGA nanoparticle vaccine, SCNPs/R837, about 30 nm in size, can effectively will TAA and R837 delivery to the lymph nodes and enhance the antitumor immune response, at the same time combined with ICIs, showing a lasting immune response. Although the water-soluble SCNP has been explored for biomedical applications, including drug delivery and imaging reagents in the body, as a nanovaccine, research is very few. Therefore, SCNPS has great potential for further research.
With the advancement of nanotechnology, researchers have turned to biomimetic nano-materials in order to enhance targeted delivery of antigens and adjuvants to lymph nodes while minimizing side effects. At present, biomimetic nanomaterials are primarily classified into two categories: nanomaterials coated with cell membranes and nanomaterials derived from natural sources [184-188]. In recent years, researchers have discovered that various cell membranes can function as envelope antigens and associated adjuvants to augment the anti-tumor efficacy of nanovaccines, encompassing tumor cells, macrophages, leukocytes, and erythrocytes [189-194].
Among them, the cell membrane of tumor cells is of particular interest to cancer researchers due to its ability not only to present tumor antigens but also to facilitate homologous tumor targeting. This has led to a growing interest in nanovaccines. Yang et al. employed mannose-modified B16F10 cell membranes to coat PLGA nanoparticles loaded with imiquimod (R837), a TLR7 agonist, thereby fabricating a nanovaccine [195]. The presence of mannose on tumor cell membranes can enhance nanovaccine uptake by APCs like DCs.
Although nanovaccine derived from tumor cell membrane can effectively promote the effectiveness of the nanovaccine, due to the tumor cell membrane surface through the expression of CD47 transmembrane protein and signal conditioning of bone marrow cells protein α (SIRPα) after combination, can signal that “don't eat me”, so as to avoid the removal of the immune system [196]. Therefore, researchers began to try to genetically modify the tumor cell membrane. To illustrate, Liu et al. employed the CRISPR-Cas9 gene editing technology to inactivate the CD9-SIRPα tumor phagocytosis checkpoint in vitro and also utilized mitoxantrone to induce ICD of tumor cells in vitro and inactivate the CD47 gene. Finally, the cell membranes of the CD47KO/CRT double bioengineered B16F10 tumor cells, which express the “eat me” signal, were extracted. The CD47KO/CRT double bioengineered tumor cell membranes were then coated onto immune adjuvant nanoparticles using a physical extrusion method, thus preparing a nano vaccine [197]. The double genetically engineered cell membrane has the potential to serve as an antigen for tumor vaccines and to activate immune cells. This is achieved by eliminating the “don't eat me” signal on tumor cells or increasing the “eat me” signal, which helps to avoid immune escape and promotes the host's anti-tumor immune-killing effect. Following subcutaneous administration, this nanovaccine establishes an antigen repository and activates DC for an extended period, facilitating cross-presentation of antigens and markedly attenuating tumor progression in a melanoma murine model.
In addition to the tumor cells' sources of nanometer materials, natural sources of nano biomaterials can effectively improve the antitumor immune response and reduce side effects. Recent research shows that protein nanomaterials in biological compatibility, stability, and immunogenicity showed a huge advantage [198,199]. However, some protein carriers may induce the body to produce antibodies against the carrier protein after entering the body, thereby preventing the effective presentation of the relevant peptide antigen. Among them, albumin, as a typical representative of protein nanomaterials, can effectively avoid the disadvantages. Albumin is one of the most important proteins in the blood plasma because the body itself has a high level of albumin, making it a large amount of albumin injected into the body and little or no trigger the body's immune response. At the same time, the history of albumin sensitivity is rare in individuals, and albumin taps cheaply. In addition, albumin can, with many receptor expressions in the tumor cells, provide advantages for nano preparation of active targeting [200-202]. Therefore, albumin can be used as a tumor vaccine and has the potential to be used as a nanomaterial. Ji et al. disguised the model CP (keyhole limpet hemocyanin, KLH) and serum albumin (SA) as hybrid nanocrystals (SA@N) and, at the same time, modified PCSK9 peptide on its surface to form an albumin-based nanovaccine (SA@NVax) [203]. SA@NVax can be used to "own" SA. The KLH coverage effectively restrains KLH extracellular immune recognition, thereby eliminating the production of antibodies against KLH and, to a larger extent, promoting PSCK9 antitumor immune responses in the body. It also provides a new direction for the design of nanovaccines, especially protein-based nanovaccines.
Metal nanomaterials can be used as new materials for tumor nanovaccines due to their controllable size, certain biodegradability, stability, and inherent immunogenicity [204-209]. Firstly, metal nanoparticles can serve as immune adjuvants to activate and enhance the activity of immune cells, thereby augmenting the immunogenicity of vaccines.
For instance, manganese-based nanomaterials are crucial in regulating the innate immune response by acting as adjuvants. In human or mouse cells, exogenous Mn2+-induced activation of the cGAS-STING pathway significantly enhances the ability of host cells to recognize tumor antigens and to infiltrate cytotoxic T cells into the tumor, increasing specific killing [210-212]. In addition, Mn2+ exerts a supportive role in the survival and proliferation of memory T cells. Moreover, Mn2+ significantly augments the cytotoxicity of NK cells against tumors and enhances the host's immune surveillance towards malignancies [213,214]. Therefore, Mn2+ nanovaccines have been developed, such as the metal micellar nanovaccine ONc-Mn-A-malF127 created by Li et al. [215]. This vaccine self-assembles Mn, IFN STING agonist ABZI, and naphthyl cyanine (ONc)-modified nanoparticles within malF127 micelles. It can be activated in situ through photothermal means. The administration of ONc-Mn-A-malF127 significantly enhances the immune response, evidenced by a 4-fold increase in IFNβ levels. In a murine cancer model, a single intravenous dose of ONc-Mn-A-malF127 nanovaccine effectively eliminates both primary and distant tumors by targeting CD8+ T cell-sensitive and resistant tumor cells. Its derivative material, manganese dioxide, can also further alleviate the hypoxia within the tumor by producing [216]. Additionally, the unique optical, electrical, and thermal properties exhibited by metallic materials offer promising opportunities for enhancing the therapeutic efficacy of tumor nanovaccines. Gold nanomaterials have excellent photothermal conversion efficiency and can directly respond to photothermal to kill tumors. At the same time, their hollow mesoporous structure can efficiently load immune adjuvants to construct tumor nanovaccines. Therefore, metal nanovaccines based on gold nanomaterials are more conducive to combined PTT. For instance, Lu et al. successfully engineered dopamine (DA)-coated gold nanoparticles (Au NPs) loaded with cytidine phosphate-guanine oligodeoxynucleotide (CpG-ODN), which demonstrated in situ radiosensitization and photothermal effects when used as tumor nanovaccines [41]. This vaccine can not only precisely induce radiation therapy (RT)/PTT to eliminate local tumors but also release tumor-derived protein antigens (TDPAs) to maintain a long-lasting tumor-killing effect.
Additionally, the surface properties and structure of metal nanoparticles can be adjusted to optimize antigen spatial display and immune stimulation. Currently, the zeolite imidazole framework (ZIF), formed through coordination between zinc ions and 8-methylimidazole (MeIM), has emerged as an advanced functional material [217,218]. By encapsulating CpG ODNs in the ZIF-8/CpG ODNs complex, Zhang et al. developed a novel delivery system for CpG ODNs. The system showed excellent stability under physiological conditions and efficiently delivered CpG-ODNs specifically into the acidic environment of TLR9-localized endolysosomes without being cytotoxic [219]. Meanwhile, ZIF-8 greatly improved the uptake of CpG ODNs inside RAW264.7 cells. Additionally, Zhong et al. collaboratively utilized aluminum adjuvant and ZIF-8 to create a nanoporous shell that can encapsulate OVA through a biomimetic mineralization process. Afterward, CpG ODNs were absorbed onto the surface by electrostatic interaction to form a pH-responsive vaccine [220]. The vaccine elicited robust and specific humoral as well as cytotoxic T lymphocyte responses, leading to significant inhibition of EG7-OVA tumor growth.
The application prospects and clinical value of metal as a material for tumor nanovaccines are extensive. By employing rational design and optimizing the structure and properties of metal nanomaterials, we anticipate the development of safer and more effective tumor vaccines, thereby offering novel strategies and methodologies for cancer treatment.
The tumor nanovaccine is a highly efficacious method for anticancer treatment, with the utilization of nanomaterials effectively enhancing the vaccine's immune response in terms of antigen presentation and immune stimulation, among other aspects. Furthermore, owing to the rapid advancements in nanotechnology, various categories of carriers have been developed for tumor nanovaccines, including biomimetic nanocarriers, polymeric nanocarriers, and inorganic nanocarriers. Despite being at the forefront of treatment methods, there are still certain challenges that need to be addressed regarding tumor nanovaccines. For instance, due to the absence of specific antigens, it remains challenging to develop more effective tumor nanovaccines for certain cancer types, such as gastric cancer and liver cancer. The extraction of neoantigens is a costly and time-consuming process. The clinical efficacy of tumor nanovaccines remains uncertain. Further investigation is required to determine the exact mechanisms by which chemotherapy, RT, and PTT enhance the immune response, as well as the optimal administration sequence and dosage of therapeutic methods following a nanovaccine combination. Moreover, despite its promising potential in clinical trials, there are limited reports on the application of nanovaccine combination therapy. Extensive research is necessary to further refine and advance this treatment approach. Firstly, it is imperative to develop targeted tumor nanovaccines for different cancer types. Secondly, with ongoing advancements in nanobiology, the preparation and design of tumor nanovaccines will be personalized according to individual patient needs while incorporating gene sequencing technology to expand the development and utilization of tumor antigens. Lastly, when combining nanovaccines with chemotherapy, RT, PTT, or other immunotherapies, researchers should thoroughly consider how to maximize each combined therapy's advantages in their respective roles while optimizing efficacy and minimizing adverse reactions. Meanwhile, although there is already evidence that nanovaccines are effective when used in combination with other therapies such as chemotherapy and immunotherapy, cost-effectiveness analyses have not yet received sufficient attention. As clinical research progresses, the assessment of the cost-effectiveness of nanovaccine combination therapies will become increasingly important. Researchers should focus on the total cost involved in combination therapies compared to monotherapies, including drug costs, patient monitoring, follow-up, and the management of possible side effects. In addition, effectively assessing the cost-effectiveness of such combination strategies will help accelerate their clinical application. Meanwhile, the development of nanovaccine combination therapies for specific tumor types and the implementation of large-scale randomized controlled trials will provide the necessary data support for further economic analysis. By optimizing treatment regimens to balance efficacy and cost, researchers can effectively address potential economic barriers and promote the widespread use of nanovaccines in clinical practice.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Yanyan Yin: Writing – original draft. Jun Guo: Writing – original draft. Shuo Zhang: Conceptualization. Meng Xu: Data curation. Yun Fu: Formal analysis. Mengyi Zhang: Methodology, Investigation, Formal analysis. Zhipeng Ma: Methodology. Jiajia Ji: Conceptualization. Siyuan Wu: Validation. Jinjie Zhang: Writing – review & editing, Conceptualization. Jianbo Li: Conceptualization. Lei Wang: Writing – review & editing.
This work was financially supported by the Key Scientific Research Project of Henan Provincial Universities in 2024 (No. 24A350013), the Project of Basic Research Fund of Henan Institute of Medical and Pharmaceutical Sciences (No. 2024BP0202), the Key Scientific and Technological Project of Henan Province (No. 242102311213), the Henan Province Postdoctoral Program (No. 343915). The image of the graphical abstract in this article was created by Figdraw.
Supplementary material associated with this article can be found, in the online version, at doi:
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Figure 1 The chemotherapeutic drugs gemcitabine (GEM) and clofarabine (CNL) can be used to deplete MDSCs and TAMs, thereby restoring TIME. Synergistically enhance the immune response stimulated by tumor nanovaccines loaded with R837. In addition, combination checkpoint therapy can enhance the immune response against cancer cells. Copied with permission [61]. Copyright 2019, Springer Nature Publishing Group.
Figure 2 Schematic diagram of the effect of tumor nanovaccines combined with RT. RT can be induced by tumor ICD and inflammation to produce a vaccine effect and reshape the TME. In addition, the radiation induced by nanometer fiber combined with autologous tumor antigens is packaged to produce a nanovaccine. The nanometer acts as a vaccine antigen repository for continuous immune stimulation. Copied with permission [106]. Copyright 2023, Wiley Publishing Group.
Figure 3 The tumor nanovaccine combined therapy utilizes the PTT effect to eradicate solid tumors, through the preparation of a nanovaccine consisting of MPDA-R848@CM (MR@C), which is further enhanced by NIR laser irradiation and subsequent antitumor immune response to inhibit tumor metastasis. Copied with permission [124]. Copyright 2022, American Chemical Society Publishing Group.
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