Dictating the spatial-temporal delivery of molecular adjuvant and antigen for the enhanced vaccination.

The incorporation of molecular adjuvants has revolutionized vaccine by boosting overall immune efficacy. While traditional efforts have been concentrated on the quality and quantity of vaccine components, the impact of adjuvant and antigen delivery kinetics on immunity remains to be fully understood. Here, we employed poly (lactic-co-glycolic acid) nanoparticle (PLGA NP) -stabilized Pickering emulsion (PPE) to refine the delivery kinetics of molecular adjuvant CpG and antigen, aiming to optimize immune responses. The hierarchical structure of PPE enabled spatially differential loading of CpG and antigen. The component inserted on the oil-water interphase exhibited a rapid release profile, while the one encapsulated in the PLGA NPs demonstrated a sustained release. This led to distinct intracellular spatial-temporal release kinetics. Compared to the PPE with sustained CpG release and burst release of antigen, we found that the PPE with rapid CpG release and sustained antigen release triggered an early and robust activation of Toll-like receptor 9 (TLR9) in direct way. This fostered a more immunogenic microenvironment, significantly outperforming the inverted delivery profile in dendritic cells (DCs) activation, resulting in higher CD40 expression, elevated proinflammatory cytokine levels, sustained antigen cross-presentation, an enhanced Th1 response, and increased CD8+ T cells. Moreover, prior exposure of CpG led to suppressed tumor growth and enhanced efficacy in Varicella-zoster virus (VZV) vaccine. Our findings underscore the importance of tuning adjuvant and antigen delivery kinetics in vaccine design, proposing a novel path for enhancing vaccination outcomes.

Natural killer cells in cancer immunotherapy.

Natural killer (NK) cells, as innate lymphocytes, possess cytotoxic capabilities and engage target cells through a repertoire of activating and inhibitory receptors. Particularly, natural killer group 2, member D (NKG2D) receptor on NK cells recognizes stress-induced ligands-the MHC class I chain-related molecules A and B (MICA/B) presented on tumor cells and is key to trigger the cytolytic response of NK cells. However, tumors have developed sophisticated strategies to evade NK cell surveillance, which lead to failure of tumor immunotherapy. In this paper, we summarized these immune escaping strategies, including the downregulation of ligands for activating receptors, upregulation of ligands for inhibitory receptors, secretion of immunosuppressive compounds, and the development of apoptosis resistance. Then, we focus on recent advancements in NK cell immune therapies, which include engaging activating NK cell receptors, upregulating NKG2D ligand MICA/B expression, blocking inhibitory NK cell receptors, adoptive NK cell therapy, chimeric antigen receptor (CAR)-engineered NK cells (CAR-NK), and NKG2D CAR-T cells, especially several vaccines targeting MICA/B. This review will inspire the research in NK cell biology in tumor and provide significant hope for improving cancer treatment outcomes by harnessing the potent cytotoxic activity of NK cells.

Polydopamine nanoparticles cross-linked hyaluronic acid photothermal hydrogel with cascading immunoinducible effects for in situ antitumor vaccination.

Tumor vaccine, which can effectively prevent tumor recurrence and metastasis, is a promising tool in tumor immunotherapy. However, heterogeneity of tumors and the inability to achieve a cascade effect limit the therapeutic effects of most developing tumor vaccine. We have developed a cascading immunoinducible in-situ mannose-functionalized polydopamine loaded with imiquimod phenylboronic hyaluronic acid nanocomposite gel vaccine (M/P-PDA@IQ PHA) through a boronic ester-based reaction. This reaction utilizes mannose-functionalized polydopamine loaded with imiquimod (M/P-PDA@IQ NAs) as a cross-linking agent to react with phenylboronic-grafted hyaluronic acid. Under near-infrared light irradiation, the M/P-PDA@IQ PHA caused local hyperthermia to trigger immunogenic cell death of tumor cells and tumor-associated antigens (TAAs) releasing. Subsequently, the M/P-PDA@IQ NAs which were gradually released by the pH/ROS/GSH-triggered degradation of M/P-PDA@IQ PHA, could capture and deliver these TAAs to lymph nodes. Finally, the M/P-PDA@IQ NAs facilitated maturation and cross-presentation of dendritic cells, as well as activation of cytotoxic T lymphocytes. Overall, the M/P-PDA@IQ PHA could serve as a novel in situ vaccine to stimulate several key nodes including TAAs release and capture, targeting lymph nodes and enhanced dendritic cells uptake and maturation as well as T cells activation. This cascading immune activation strategy can effectively elicit antitumor immune response.

TripHLApan: predicting HLA molecules binding peptides based on triple coding matrix and transfer learning.

Human leukocyte antigen (HLA) recognizes foreign threats and triggers immune responses by presenting peptides to T cells. Computationally modeling the binding patterns between peptide and HLA is very important for the development of tumor vaccines. However, it is still a big challenge to accurately predict HLA molecules binding peptides. In this paper, we develop a new model TripHLApan for predicting HLA molecules binding peptides by integrating triple coding matrix, BiGRU + Attention models, and transfer learning strategy. We have found the main interaction site regions between HLA molecules and peptides, as well as the correlation between HLA encoding and binding motifs. Based on the discovery, we make the preprocessing and coding closer to the natural biological process. Besides, due to the input being based on multiple types of features and the attention module focused on the BiGRU hidden layer, TripHLApan has learned more sequence level binding information. The application of transfer learning strategies ensures the accuracy of prediction results under special lengths (peptides in length 8) and model scalability with the data explosion. Compared with the current optimal models, TripHLApan exhibits strong predictive performance in various prediction environments with different positive and negative sample ratios. In addition, we validate the superiority and scalability of TripHLApan's predictive performance using additional latest data sets, ablation experiments and binding reconstitution ability in the samples of a melanoma patient. The results show that TripHLApan is a powerful tool for predicting the binding of HLA-I and HLA-II molecular peptides for the synthesis of tumor vaccines. TripHLApan is publicly available at https://github.com/CSUBioGroup/TripHLApan.git.

MDSCs in bone metastasis: Mechanisms and therapeutic potential.

Bone metastasis (BM) is a frequent complication associated with advanced cancer that significantly increases patient mortality. Myeloid-derived suppressor cells (MDSCs) play a pivotal role in BM progression by promoting angiogenesis, inhibiting immune responses, and inducing osteoclastogenesis. MDSCs induce immunosuppression through diverse mechanisms, including the generation of reactive oxygen species, nitric oxide, and immunosuppressive cytokines. Within the bone metastasis niche (BMN), MDSCs engage in intricate interactions with tumor, stromal, and bone cells, thereby establishing a complex regulatory network. The biological activities and functions of MDSCs are regulated by the microenvironment within BMN. Conversely, MDSCs actively contribute to microenvironmental regulation, thereby promoting BM development. A comprehensive understanding of the indispensable role played by MDSCs in BM is imperative for the development of novel therapeutic strategies. This review highlights the involvement of MDSCs in BM development, their regulatory mechanisms, and their potential as viable therapeutic targets.

Preimmunization with Listeria-vectored cervical cancer vaccine candidate strains can establish specific T-cell immune memory and prevent tumorigenesis.

BACKGROUND: Although HPV prophylactic vaccines can provide effective immune protection against high-risk HPV infection, studies have shown that the protective effect provided by them would decrease with the increased age of vaccination, and they are not recommended for those who are not in the appropriate age range for vaccination. Therefore, in those people who are not suitable for HPV prophylactic vaccines, it is worth considering establishing memory T-cell immunity to provide long-term immune surveillance and generate a rapid response against lesional cells to prevent tumorigenesis. METHODS: In this study, healthy mice were preimmunized with LM∆E6E7 and LI∆E6E7, the two Listeria-vectored cervical cancer vaccine candidate strains constructed previously by our laboratory, and then inoculated with tumor cells 40 d later. RESULTS: The results showed that preimmunization with LM∆E6E7 and LI∆E6E7 could establish protective memory T-cell immunity against tumor antigens in mice, which effectively eliminate tumor cells. 60% of mice preimmunized with vaccines did not develop tumors, and for the remaining mice, tumor growth was significantly inhibited. We found that preimmunization with vaccines may exert antitumor effects by promoting the enrichment of T cells at tumor site to exert specific immune responses, as well as inhibiting intratumoral angiogenesis and cell proliferation. CONCLUSION: Altogether, this study suggests that preimmunization with LM∆E6E7 and LI∆E6E7 can establish memory T-cell immunity against tumor antigens in vivo, which provides a viable plan for preventing tumorigenesis and inhibiting tumor progression.

Drug-Loaded Tumor-Derived Microparticles Elicit CD8+ T Cell-Mediated Anti-Tumor Response in Hepatocellular Carcinoma.

Background: Hepatocellular Carcinoma (HCC) poses significant challenges due to limited effective treatments and high recurrence rates. Immunotherapy, a promising approach, faces obstacles in HCC patients due to T-cell exhaustion and immunosuppression within the tumor microenvironment. Methods: Using doxorubicin-loaded tumor-derived microparticles (Dox-TMPs), the mice with H22 ascites model and subcutaneous tumors model were treated. Following the treatment, mice were re-challenged with H22 cells to compare the therapeutic effects and recurrence among different groups of mice, alongside examining the changes in the proportions of immune cells within the tumor microenvironment. Furthermore, Dox-TMPs were combined with anti-PD-1 to further validate their anti-tumor efficacy. In vitro studies using various liver cancer cell lines were conducted to verify the tumor-killing effects of Dox-TMPs. Additionally, CD8+ T cells from the abdominal cavity of tumor-free mice were co-cultured with H22 cells to confirm their specific tumor-killing abilities. Results: Dox-TMPs demonstrate effective anti-tumor effects both in vitro and in vivo. In vivo, their effectiveness primarily involves enhancing CD8+ T cell infiltration, alleviating T cell immunosuppression, and improving the immune microenvironment to combat tumors. When used in combination with anti-PD-1, their anti-tumor effects are further enhanced. Moreover, some mice treated with Dox-TMPs developed anti-tumor immunity, displaying a self-specific T-cell immune response upon re-challenged with tumor cells. This suggests that Dox-TMPs also have the potential to act as a long-term immune response against tumor recurrence, indicating their capability as a tumor vaccine. Conclusion: Dox-TMPs exhibit a dual role in liver cancer by regulating T cells within the tumor microenvironment, functioning both as an anti-tumor agent and a potential tumor vaccine.

Bioorthogonal/Ultrasound Activated Oncolytic Pyroptosis Amplifies In Situ Tumor Vaccination for Boosting Antitumor Immunity.

Personalized in situ tumor vaccination is a promising immunotherapeutic modality. Currently, seeking immunogenic cell death (ICD) to generate in situ tumor vaccines is still mired by insufficient immunogenicity and an entrenched immunosuppressive tumor microenvironment (TME). Herein, a series of tetrazine-functionalized ruthenium(II) sonosensitizers have been designed and screened for establishing a bioorthogonal-activated in situ tumor vaccine via oncolytic pyroptosis induction. Based on nanodelivery-augmented bioorthogonal metabolic glycoengineering, the original tumor is selectively remolded to introduce artificial target bicycle [6.1.0] nonyne (BCN) into cell membrane. Through specific bioorthogonal ligation with intratumoral BCN receptors, sonosensitizers can realize precise membrane-anchoring and synchronous click-activation in desired tumor sites. Upon ultrasound (US) irradiation, the activated sonosensitizers can intensively disrupt the cell membrane with dual type I/II reactive oxygen species (ROS) generation for a high-efficiency sonodynamic therapy (SDT). More importantly, the severe membrane damage can eminently evoke oncolytic pyroptosis to maximize tumor immunogenicity and reverse immunosuppressive TME, ultimately eliciting powerful and durable systemic antitumor immunity. The US-triggered pyroptosis is certified to effectively inhibit the growths of primary and distant tumors, and suppress tumor metastasis and recurrence in "cold" tumor models. This bioorthogonal-driven tumor-specific pyroptosis induction strategy has great potential for the development of robust in situ tumor vaccines.

IL-2 promotes expansion and intratumoral accumulation of tumor infiltrating dendritic cells in pancreatic cancer.

This study aims to investigate the diagnostic potential of IL-2 for PDAC and develop a method to improve the dendritic cell (DC) based vaccine against PDAC. The gene expression data and clinical characteristics information for 178 patients with PDAC were obtained from The Cancer Genome Atlas (TCGA). DCs were isolated from Human peripheral blood mononuclear cells (PBMCs) and were cultured in 4 different conditions. DCs were pulsed by tumor cell lysates or KRAS G12D1 - 23 peptide, and then used to activate T cells. The mixture of DCs and T cells were administered to xenograft mouse model through the tail vein. The infiltration of DCs and T cells were detected by immunohistochemistry. The generation of KRAS G12D mutation specific cytotoxic T cells was determined by in vitro killing assay. We observed that PDAC patients with higher IL-2 mRNA levels exhibited improved overall survival and increased infiltration of CD8 + T cells, NK cells, naïve B cells, and resting myeloid DCs in the tumor microenvironment. IL-2 alone did not enhance DC proliferation, antigen uptake, or apoptosis inhibition unless co-cultured with PBMCs. DCs co-cultured with PBMCs in IL-2-containing medium demonstrated the strongest tumor repression effect in vitro and in vivo. Compared to DCs obtained through the traditional method (cultured in medium containing GM-CSF and IL-4), DCs cultured with PBMCs, and IL-2 exhibited increased tumor infiltration capacity, potentially facilitating sustained T cell immunity. DCs cultured in the PBMCs-IL-2 condition could promote the generation of cytotoxic T cells targeting tumor cells carrying KRAS G12D mutation.

Ag85B-ENO146-82 therapeutic vaccines enhance anti-tumor immunity by inducing CD8+ T cells and remodeling tumor microenvironment.

Lung cancer is the leading cause of cancer-related morbidity and mortality in China. However, the effect of traditional cancer treatment is limited. Herein, we designed a therapeutic cancer vaccine based on the tumor-associated antigen mENO1, which can prevent lung cancer growth in vivo, and explored the underlying mechanism of Ag85B-ENO146-82 therapy. Lewis lung carcinoma (LLC) tumor-bearing immunocompetent C57BL/6 mice that received Ag85B-ENO146-82 treatment showed antitumor effect. Further, we detected CD8+ T, CD4+ T in LLC-bearing C57BL/6 mice to understand the impact of Ag85B-ENO146-82 therapy on antitumor capacity. The Ag85B-ENO146-82 therapy induced intensive infiltration of CD4+ and CD8+ T cells in tumors, increased tumor-specific IFN-γ and TNF-α secretion by CD8+ T cells and promoted macrophage polarization toward M1 phenotype. Flow cytometric analysis revealed that CD8+ T effector memory (TEM) cells and central memory (TCM) cells were upregulated. qPCR and ELISA analysis showed that the expression of IFN-γ and TNF-α were upregulated, whereas of IL1ß, IL6 and IL10 were downregulated. This study demonstrated that Ag85B-ENO146-82 vaccine augmented antitumor efficacy, which was CD8+ T cells dependent. Our findings paved the way for therapeutic tumor-associated antigen peptide vaccines to enhance anti-tumor immunotherapy for treatment of cancer.

Photodynamic Therapy Derived Personalized Whole Cell Tumor Vaccine Prevents Postsurgery Tumor Recurrence and Metastasis.

In order to avoid the time-consuming and laborious identification of tumor-specific antigens (TSAs) during the traditional vaccine fabrication process, a versatile photodynamic therapy (PDT)-based method is developed to construct a whole-tumor antigen tumor vaccine (TV) from surgically resected tumor tissues for personalized immunotherapy. Mucoadhesive nanoparticles containing small-molecular photosensitizer are fabricated and directly co-incubated with suspended tumor cells obtained after cytoreduction surgery. After irradiation with a 405 nm laser, potent immunogenic cell death of cancer cells could be induced. Along with the release of TSAs, the as-prepared TV could activate safe and robust tumor-specific immune responses, leading to efficient suppression of postsurgery tumor recurrence and metastasis. The as-prepared TV cannot only be applied alone through various administration routes but also synergize with immunoadjuvant, chemotherapeutics, and immune checkpoint blockers to exert more potent immune responses. This work provides an alternative way to promote the clinical translation of PDT, which is generally restricted by the limited penetration of light. Moreover, the versatile strategy of vaccine fabrication also facilitates the clinical application of personalized whole-cell tumor vaccines.

Turning Threat to Therapy: A Nanozyme-Patch in Surgical Bed for Convenient Tumor Vaccination by Sustained In Situ Catalysis.

Complete surgical resection of tumor is difficult as the invasiveness of cancer, making the residual tumor a lethal threat to patients. The situation is deteriorated by the immune suppression state after surgery, which further nourishes tumor recurrence and metastasis. Immunotherapy is promising to combat tumor metastasis, but is limited by severe toxicity of traditional immunostimulants and complexity of multiple functional units. Here, it is reported that the simple "trans-surgical bed" delivery of Cu2- xSe nanozyme (CSN) by a microneedle-patch can turn the threat to therapy by efficient in situ vaccination. The biocompatible CSN exhibits both peroxidase and glutathione oxidase-like activities, efficiently exhausting glutathione, boosting free radical generation, and inducing immunogenic cell death. The once-for-all inserting of the patch on surgical bed facilitates sustained catalytic action, leading to drastic decrease of recurrence rate and complete suppression of tumor-rechallenge in cured mice. In vivo mechanism interrogation reveals elevated cytotoxic T cell infiltration, re-educated macrophages, increased dendritic cell maturation, and memory T cells formation. Importantly, preliminary metabolism and safety evaluation validated that the metal accumulation is marginable, and the important biochemical indexes are in normal range during therapy. This study has provided a simple, safe, and robust tumor vaccination approach for postsurgical metastasis control.

Hybrid Ginseng-derived Extracellular Vesicles-Like Particles with Autologous Tumor Cell Membrane for Personalized Vaccination to Inhibit Tumor Recurrence and Metastasis.

Personalized cancer vaccines based on resected tumors from patients is promising to address tumor heterogeneity to inhibit tumor recurrence or metastasis. However, it remains challenge to elicit immune activation due to the weak immunogenicity of autologous tumor antigens. Here, a hybrid membrane cancer vaccine is successfully constructed by membrane fusion to enhance adaptive immune response and amplify personalized immunotherapy, which formed a codelivery system for autologous tumor antigens and immune adjuvants. Briefly, the functional hybrid vesicles (HM-NPs) are formed by hybridizing ginseng-derived extracellular vesicles-like particles (G-EVLPs) with the membrane originated from the resected autologous tumors. The introduction of G-EVLPs can enhance the phagocytosis of autologous tumor antigens by dendritic cells (DCs) and facilitate DCs maturation through TLR4, ultimately activating tumor-specific cytotoxic T lymphocytes (CTLs). HM-NPs can indeed strengthen specific immune responses to suppress tumors recurrence and metastasis including subcutaneous tumors and orthotopic tumors. Furthermore, a long-term immune protection can be obtained after vaccinating with HM-NPs, and prolonging the survival of animals. Overall, this personalized hybrid autologous tumor vaccine based on G-EVLPs provides the possibility of mitigating tumor recurrence and metastasis after surgery while maintaining good biocompatibility.

Overview of tumor immunotherapy based on approved drugs.

Tumor immunotherapy has become a new hotspot for cancer treatment. Various immunotherapies, such as immune checkpoint inhibitors, oncolytic viruses (OVs), cytokines, and cancer vaccines, have been used to treat tumors. They operate through different mechanisms, along with certain toxicities and side effects. Understanding the mechanisms by which immunotherapy modulates the immune system is essential for improving the efficacy and managing these adverse effects. This article discusses various currently approved cancer immunotherapy mechanisms and related agents approved by the Food and Drug Administration, the European Medicines Agency, and the Medicines and Medical Devices Agency. We also review the latest progress in immune drugs approved by the National Medical Products Administration, including monoclonal antibodies, cytokines, OVs, and chimeric antigen receptor-T cell therapy, to help understand the clinical application of tumor immunotherapy.

Engineered bacterial outer membrane vesicles: a versatile bacteria-based weapon against gastrointestinal tumors.

Outer membrane vesicles (OMVs) are nanoscale lipid bilayer structures released by gram-negative bacteria. They share membrane composition and properties with their originating cells, making them adept at traversing cellular barriers. These OMVs have demonstrated exceptional membrane stability, immunogenicity, safety, penetration, and tumor-targeting properties, which have been leveraged in developing vaccines and drug delivery systems. Recent research efforts have focused on engineering OMVs to increase production yield, reduce cytotoxicity, and improve the safety and efficacy of treatment. Notably, gastrointestinal (GI) tumors have proven resistant to several traditional oncological treatment strategies, including chemotherapy, radiotherapy, and targeted therapy. Although immune checkpoint inhibitors have demonstrated efficacy in some patients, their usage as monotherapy remains limited by tumor heterogeneity and individual variability. The immunogenic and modifiable nature of OMVs makes them an ideal design platform for the individualized treatment of GI tumors. OMV-based therapy enables combination therapy and optimization of anti-tumor effects. This review comprehensively summarizes recent advances in OMV engineering for GI tumor therapy and discusses the challenges in the clinical translation of emerging OMV-based anti-tumor therapies.

Nanovaccines: An effective therapeutic approach for cancer therapy.

Cancer vaccines hold considerable promise for the immunotherapy of solid tumors. Nanomedicine offers several strategies for enhancing vaccine effectiveness. In particular, molecular or (sub) cellular vaccines can be delivered to the target lymphoid tissues and cells by nanocarriers and nanoplatforms to increase the potency and durability of antitumor immunity and minimize negative side effects. Nanovaccines use nanoparticles (NPs) as carriers and/or adjuvants, offering the advantages of optimal nanoscale size, high stability, ample antigen loading, high immunogenicity, tunable antigen presentation, increased retention in lymph nodes, and immunity promotion. To induce antitumor immunity, cancer vaccines rely on tumor antigens, which are administered in the form of entire cells, peptides, nucleic acids, extracellular vesicles (EVs), or cell membrane-encapsulated NPs. Ideal cancer vaccines stimulate both humoral and cellular immunity while overcoming tumor-induced immune suppression. Herein, we review the key properties of nanovaccines for cancer immunotherapy and highlight the recent advances in their development based on the structure and composition of various (including synthetic and semi (biogenic) nanocarriers. Moreover, we discuss tumor cell-derived vaccines (including those based on whole-tumor-cell components, EVs, cell membrane-encapsulated NPs, and hybrid membrane-coated NPs), nanovaccine action mechanisms, and the challenges of immunocancer therapy and their translation to clinical applications.

Converting bacteria into autologous tumor vaccine via surface biomineralization of calcium carbonate for enhanced immunotherapy.

Autologous cancer vaccine that stimulates tumor-specific immune responses for personalized immunotherapy holds great potential for tumor therapy. However, its efficacy is still suboptimal due to the immunosuppressive tumor microenvironment (ITM). Here, we report a new type of bacteria-based autologous cancer vaccine by employing calcium carbonate (CaCO3) biomineralized Salmonella (Sal) as an in-situ cancer vaccine producer and systematical ITM regulator. CaCO3 can be facilely coated on the Sal surface with calcium ionophore A23187 co-loading, and such biomineralization did not affect the bioactivities of the bacteria. Upon intratumoral accumulation, the CaCO3 shell was decomposed at an acidic microenvironment to attenuate tumor acidity, accompanied by the release of Sal and Ca2+/A23187. Specifically, Sal served as a cancer vaccine producer by inducing cancer cells' immunogenic cell death (ICD) and promoting the gap junction formation between tumor cells and dendritic cells (DCs) to promote antigen presentation. Ca2+, on the other hand, was internalized into various types of immune cells with the aid of A23187 and synergized with Sal to systematically regulate the immune system, including DCs maturation, macrophages polarization, and T cells activation. As a result, such bio-vaccine achieved remarkable efficacy against both primary and metastatic tumors by eliciting potent anti-tumor immunity with full biocompatibility. This work demonstrated the potential of bioengineered bacteria as bio-active vaccines for enhanced tumor immunotherapy.

Biology and function of exosomes in tumor immunotherapy.

Exosomes are nano-scale extracellular vesicles that are found widely in various biological fluids. As messengers, exosomes deliver characteristic biological information from donor cells, facilitating their accumulation and subsequent transfer of information to tumor immune cells. Immunotherapy is a cutting-edge strategy for cancer therapy, but it has not yet reached its full potential owing to severe side effects and limited efficacy. Exosomes possess antigens and immunostimulatory molecules and can serve as cell-free vaccines to induce antitumor immunity. In addition, given their stability, low immunogenicity, and targeting ability, exosomes represent ideal drug delivery systems in tumor immunotherapy by delivering cargoes, including non-coding ribonucleic acids (RNAs), membrane proteins, chemotherapeutic agents, and immune cell death inducers. Exosomes can also be engineered to precisely target tumor cells. However, as a rising star in tumor immunotherapy, exosomes are also impeded by some challenges, including the lack of uniform technical standards for their isolation and purification, the need to improve exosomal cargo loading for efficient exosome delivery, and the expansion of clinical trials, which are currently in their infancy. Long-term, multi-center, and large-scale clinical trials are needed to evaluate the performance of exosomes in the future. Nonetheless, exosomes have demonstrated encouraging performance in tumor immunotherapy. In this review, we summarize the potential and challenges of exosomes in tumor immunotherapy, with the aim to shed light on exosomes as new-era tumor immunotherapy tools.

An epitope encoded by uORF of RNF10 elicits a therapeutic anti-tumor immune response.

Tumor-specific antigens (TSAs) are crucial for tumor-specific immune response that reduces tumor burden and thus serve as important targets for immunotherapy. Identification of novel TSAs can provide new strategies for immunotherapies. In this study, we demonstrated that the upstream open reading frame (uORF) of RNF10 encodes an antigenic peptide (RNF10 uPeptide), capable of eliciting a T cell-mediated anti-tumor immune response. We initially demonstrated the immunogenicity of the RNF10 uPeptide in a CT26 tumor mouse model, by showing that its epitope was specifically recognized by CD8+ T cells. Vaccination of mice with the long form of the RNF10 uPeptide conferred strong anti-tumor activity. Next, we proved that the human RNF10 uORF could be translated. In addition, we predicted the binding of an RNF10 uPeptide epitope to HLA-A∗02:01 (HLA-A2). This HLA-A2-restricted epitope of the RNF10 uPeptide induced a potent specific human T cell response. Finally, we showed that an HLA-A2-restricted cytotoxic T cell (CTL) clone, derived from a pancreatic cancer patient, recognized the RNF10 uPeptide epitope (RLFGQQQRA) and lysed HLA-A2+ pancreatic carcinoma cells expressing the RNF10 uPeptide. These results indicate that the RNF10 uPeptide could be a promising target for pancreatic carcinoma immunotherapy.

Redirecting Antigens by Engineered Photosynthetic Bacteria and Derived Outer Membrane Vesicles for Enhanced Cancer Immunotherapy.

Significant strides have been made in the development of cancer vaccines to combat malignant tumors. However, the natural immunosuppressive environment within tumors, known as the tumor microenvironment (TME), hampers the uptake and presentation of antigens by antigen-presenting cells (APCs) within the tumor itself. This limitation results in inadequate activation of immune responses against cancer. In contrast, immune cells in peritumoral tissue maintain their normal functions. In this context, we present an interesting approach to enhance cancer immunotherapy by utilizing engineered photosynthetic bacteria (PSB) and their outer membrane vesicles (OMVPSB) to capture and transport antigens to the outer regions of the tumor. We modified PSB with maleimide (PSB-MAL), which, when exposed to near-infrared (NIR) laser-mediated photothermal therapy (PTT), induced extensive cancer cell death and the release of tumor antigens. Subsequently, the NIR-phototactic PSB-MAL transported these tumor antigens to the peripheral regions of the tumor under NIR laser exposure. Even more intriguingly, PSB-MAL-derived OMVPSB-MAL effectively captured and delivered antigens to tumor-draining lymph nodes (TDLNs). This facilitated enhanced antigen presentation by mature and fully functional APCs in the TDLNs. This intricate communication network between PSB-MAL, the OMVPSB-MAL, and APCs promoted the efficient presentation of tumor antigens in the tumor periphery and TDLNs. Consequently, there was a notable increase in the infiltration of cytotoxic T lymphocytes (CTLs) into the tumor, triggering potent antitumor immune responses in both melanoma and breast cancer models. This cascade of events resulted in enhanced suppression of tumor metastasis and recurrence, underscoring the robust efficacy of our approach. Our interesting study, harnessing the potential of bacteria and OMVs to redirect tumor antigens for enhanced cancer immunotherapy, provides a promising path toward the development of personalized cancer vaccination strategies.