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One driver of the high failure rates of clinical trials for therapeutic cancer vaccines is likely the inability to sufficiently engage conventional dendritic cells (cDCs), the antigen-presenting cell (APC) subset that is specialized in priming antitumor T cells. Here, we demonstrate that, relative to vaccination with an injectable mesoporous silica rod (MPS) vaccine alone (Vax), combining MPS vaccines with CD122-biased IL-2/anti-IL-2 antibody complexes (IL-2cx) drives ~3-fold expansion of cDCs at the vaccination sites, vaccine-draining lymph nodes, and spleens of treated mice. Furthermore, relative to Vax alone, Vax+IL-2cx led to a ~3-fold increase in the numbers of CD8 + T cells and ~15-fold increase in the numbers of NK cells at the vaccination site. Notably, with both the model protein antigen OVA as well as various peptide neoantigens, Vax+IL-2cx induced ~5 to 30-fold greater numbers of circulating antigen-specific CD8 + T cells relative to Vax alone. We further demonstrate that Vax+IL-2cx leads to significantly improved efficacy in the MC38 colon carcinoma model relative to either monotherapy alone, driving complete regressions in 50% of mice in a cDC-dependent manner. Relative to vaccine alone, Vax+IL-2cx led to comparable numbers of CD8 + T cells, but markedly greater numbers of NK cells and activated cDCs in the B16F10 melanoma tumor microenvironment post-therapy. Taken together, these findings suggest that the administration of factors that engage both the cDC-CD8 + T cell and cDC-NK cell axes can boost the potency of therapeutic cancer vaccines., Competing Interests: Competing interests statement:D.J.M. declares the following competing interests: Novartis, sponsored research, licensed IP; Immulus, equity; IVIVA, SAB; Attivare, SAB, equity; Lyell, licensed IP, equity. R.S.L. and S.J.T. are employed by Genentech, Inc. The other authors declare no competing interests.

Cancer vaccines are a promising strategy to increase tumor-specific immune responses in patients who do not adequately respond to checkpoint inhibitors. Cancer vaccines that contain patient-specific tumor antigens are most effective but also necessitate the production of patient-specific vaccines. This study aims to develop a versatile cancer vaccine format in which patient-specific tumor antigens can be site-specifically conjugated by a proximity-based Sortase A (SrtA)-mediated ligation (PBSL) approach to antibodies that specifically bind to antigen-presenting cells to stimulate immune responses. DEC205 and CD169 are both receptors expressed on antigen-presenting cells that can be targeted to deliver antigens and stimulate T-cell responses. We used the CRISPR/HDR platform to produce mouse heavy chain IgG2a antibodies with DEC205 or CD169 specificity containing an SrtA recognition motif followed by a SpyTag at the C-terminus. Using a recombinant protein of SrtA linked to SpyCatcher, we applied proximity-based SrtA-mediated ligation to ligate fluorescein isothiocyanate (FITC)-labeled or antigenic peptides to the antibodies. Ligated antibodies bound to DEC205-expressing dendritic cells or CD169-expressing macrophages both in vitro and in vivo . More importantly, immunization with DEC205- or CD169-specific Abs linked to T-cell epitopes efficiently stimulated T-cell responses in vivo . To conclude, we have developed a cancer vaccine format using PBSL that enables the rapid incorporation of tumor antigens and could potentially be implemented for the synthesis of personalized cancer vaccines.

Cancer nanovaccines have emerged as an indispensable weapon for tumor treatment. However, insufficient immunogenicity and immunosuppression hamper the therapeutic effects of nanovaccines. Here, biodegradable nanovaccines (OMPP) composed of ovalbumin (OVA)-manganese oxide nanoparticles, amphiphilic poly(γ-glutamic acid) (γ-PGA), and ε-polylysine (PL) are constructed to realize enhanced cancer immunotherapy. Interestingly, amphiphilic γ-PGA and PL could serve as both carriers and immunoadjuvants to promote the cytosolic delivery of antigens and enhance the maturation of dendritic cells. Additionally, taking advantage of the photothermal property of OMPP, immunogenic cell death and in situ release of tumor-associated antigens can be triggered under near-infrared light irradiation for personalized tumor treatment. Moreover, OMPP nanovaccines can efficiently alleviate tumor hypoxia and downregulate programmed death-ligand 1 expression to reprogram the immunosuppressive tumor microenvironment. OMPP-mediated therapy has been shown to provoke robust immune responses to suppress B16-OVA melanoma and prevent postsurgical tumor recurrence. This work presents a facile strategy for the fabrication of nanovaccines by integrating carrier and adjuvant while exploring the inherent properties to promote antigen release and modulate immunosuppression, which demonstrates great potential for effective cancer immunotherapy.

A range of advanced nanovaccines (NV) combined with immunotherapies has recently emerged for treating malignant tumors and has demonstrated promising tumor-suppressive effects. Nevertheless, their effectiveness is often limited by immunosuppression within the tumor microenvironment. To overcome this challenge, new approaches for NV development are required to improve antigen cross-presentation and to remodel the tumor microenvironment. In this issue of Cancer Research, Zhou and colleagues have developed a photo-enhanceable inflammasome-activating nanovaccine (PIN) designed for precise, in situ delivery of a tumor antigen and a hydrophobic small molecule that activates the NLRP3 inflammasome pathway. Near infrared light exposure enables the accumulation of PINs at tumor sites by inducing a photo-triggered charge reversal in the BODIPY-modified PAMAM nanocarrier. Systemic administration of PINs resulted in effective intratumoral activation of the NLRP3 inflammasome and antigen cross-presentation in antigen-presenting cells upon light exposure, leading to enhanced immune responses through increased proinflammatory cytokine production without significant systemic toxicity. Importantly, PINs also enhanced the efficacy of immune checkpoint blockade and promoted the development of long-term immune memory in mouse models of melanoma and hepatocellular carcinoma. Overall, inflammasome-activating NVs represent a cancer immunotherapy strategy by harnessing the innate immune system to achieve robust responses against tumors. Ongoing research and development are crucial to addressing current limitations and advancing this innovative technology toward clinical application. See related article by Zhou et al., p. 3834., (©2024 American Association for Cancer Research.)

A variety of state-of-the-art nanovaccines (NV) combined with immunotherapies have recently been developed to treat malignant tumors, showing promising results. However, immunosuppression in the tumor microenvironment (TME) restrains cytotoxic T-cell infiltration and limits the efficacy of immunotherapies in solid tumors. Therefore, tactics for enhancing antigen cross-presentation and reshaping the TME need to be explored to enhance the activity of NVs. Here, we developed photo-enhanceable inflammasome-activating NVs (PIN) to achieve precise in situ delivery of a tumor antigen and a hydrophobic small molecule activating the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3 inflammasome (NLRP3) pathway. Near-infrared light irradiation promoted PIN accumulation in tumor sites through photo-triggered charge reversal of the nanocarrier. Systematic PIN administration facilitated intratumoral NLRP3 inflammasome activation and antigen cross-presentation in antigen-presenting cells upon light irradiation at tumor sites. Furthermore, PIN treatment triggered immune responses by promoting the production of proinflammatory cytokines and activating antitumor immunity without significant systematic toxicity. Importantly, the PIN enhanced the efficacy of immune checkpoint blockade and supported the establishment of long-term immune memory in mouse models of melanoma and hepatocellular carcinoma. Collectively, this study reports a safe and efficient photoresponsive system for codelivery of antigens and immune modulators into tumor tissues, with promising therapeutic potential. Significance: The development of a photoresponsive nanovaccine with spatiotemporal controllability enables robust tumor microenvironment modulation and enhances the efficacy of immune checkpoint blockade, providing an effective immunotherapeutic strategy for cancer treatment. See related commentary by Zhen and Chen, p. 3709., (©2024 The Authors; Published by the American Association for Cancer Research.)

DNA vaccines are prospective for their efficient manufacturing process, but their immunogenicity is limited as they cannot efficiently induce CD8 + T cell responses. A promising approach is to induce cross-presentation by targeting antigens to DCs. Flt3L can expand the number of type 1 conventional DCs and thereby improve cross-presentation. In this study, we first constructed a DNA vaccine expressing soluble PD1 and found that the therapeutic effect of targeting DCs with only the sPD1 vaccine was limited. When combined the vaccine with Flt3L, the anti-tumor effect was significantly enhanced. Considering the complexity of tumors and that a single method may not be able to activate a large number of effective CD8 + T cells, we combined different drugs and the vaccine with Flt3L based on the characteristics of different tumors. In 4T1 model, we reduced Tregs through cyclophosphamide. In Panc02 model, we increased activated DCs by using aCD40. Both strategies triggered strong CD8 + T cell responses and significantly improved the therapeutic effect. Our study provides important support for the clinical exploration of DC-targeted DNA vaccines in combination with Flt3L., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Remarkable progress has been made in tumour immunotherapy in recent decades. However, the clinical outcomes of therapeutic interventions remain unpredictable, largely because of inefficient immune responses. To address this challenge and optimise immune stimulation, we present a novel administration route for enhancing the bioavailability of immunotherapeutic drugs. Our approach involves the development of an oral tumour vaccine utilising virus-like particles derived from the Hepatitis B virus core (HBc) antigen. The external surfaces of these particles are engineered to display the model tumour antigen OVA, whereas the interiors are loaded with cytosine phosphoguanosine oligodeoxynucleotide (CpG ODN), resulting in a construct called CpG@ OVA HBc with enhanced antigenicity and immune response. For oral delivery, CpG@ OVA HBc is encapsulated in a crosslinked dextran hydrogel called CpG@ OVA HBc@Dex. The external hydrogel shield safeguards the biomimetic virus particles from degradation by gastric acid and proteases. Upon exposure to intestinal flora, the hydrogel disintegrates, releasing CpG@ OVA HBc at the intestinal mucosal site. Owing to its virus-like structure, CpG@ OVA HBc exhibits enhanced adhesion to the mucosal surface, facilitating uptake by microfold cells (M cells) and subsequent transmission to antigen-presenting cells. The enzyme-triggered release of this oral hydrogel ensures the integrity of the tumour vaccine within the digestive tract, allowing targeted release and significantly improving bioavailability. Beyond its efficacy, this oral hydrogel vaccine streamlines drug administration, alleviates patient discomfort, and enhances treatment compliance without the need for specialised injection methods. Consequently, our approach expands the horizons of vaccine development in the field of oral drug administration., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Neoantigen vaccines can induce or enhance highly specific antitumor immune responses with minimal risk of autoimmunity. We have developed a neoantigen DNA vaccine platform capable of efficiently presenting both HLA class I and II epitopes and performed a phase 1 clinical trial in triple-negative breast cancer patients with persistent disease on surgical pathology following neoadjuvant chemotherapy, a patient population at high risk of disease recurrence., Methods: Expressed somatic mutations were identified by tumor/normal exome sequencing and tumor RNA sequencing. The pVACtools software suite of neoantigen prediction algorithms was used to identify and prioritize cancer neoantigens and facilitate vaccine design for manufacture in an academic GMP facility. Neoantigen DNA vaccines were administered via electroporation in the adjuvant setting (i.e., following surgical removal of the primary tumor and completion of standard of care therapy). Vaccines were monitored for safety and immune responses via ELISpot, intracellular cytokine production via flow cytometry, and TCR sequencing., Results: Eighteen subjects received three doses of a neoantigen DNA vaccine encoding on average 11 neoantigens per patient (range 4-20). The vaccinations were well tolerated with relatively few adverse events. Neoantigen-specific T cell responses were induced in 14/18 patients as measured by ELISpot and flow cytometry. At a median follow-up of 36 months, recurrence-free survival was 87.5% (95% CI: 72.7-100%) in the cohort of vaccinated patients., Conclusion: Our study demonstrates neoantigen DNA vaccines are safe, feasible, and capable of inducing neoantigen-specific immune responses., Clinical Trial Registration Number: NCT02348320., Competing Interests: Declarations Ethics approval and consent to participate The clinical protocol was reviewed and approved by the Institutional Review Board (ID# 201505074) at Washington University School of Medicine. The research conformed to the principles of the Helsinki/Tokyo/Venice Declaration on experimentation in humans. Consent for publication Written consent for publication was obtained from all participating patients. Competing interests K.S., M.G., and O.G. are consultants for the Jaime Leandro Foundation. All other authors declare that they have no competing interests., (© 2024. The Author(s).)

The clinical efficacy of cancer vaccines is closely related to immunoadjuvants that play a crucial role in magnifying and prolonging the immune response. Muramyl dipeptide (MDP), a minimal and conserved peptidoglycan found in almost all bacteria, can trigger robust immune activation by uniquely antagonizing the nucleotide-binding oligomerization domain 2 (NOD2) pathway. However, its effectiveness has been hindered by limited solubility, poor membrane penetration, and rapid clearance from the body. Here, we introduce MDP-presenting polymersomes as artificial nanobacteria (NBA) to boost the antitumor immune response. The NBA, featuring abundant MDP molecules, induces superior stimulation of immune cells including macrophages and bone marrow-derived dendritic cells (BMDCs) compared to free MDP, likely via facilitating immune cell uptake and cooperatively stimulating systemic NOD2 signaling. Importantly, systemic administration of NBA significantly enhances the chemo-immunotherapy of B16-F10 melanoma-bearing mice pretreated with doxorubicin by reversing the immunosuppressive tumor microenvironment. Furthermore, NBA carrying ovalbumin and B16-F10 cell lysates induces robust OVA-IgG antibody production and effectively inhibit tumor growth, respectively. The artificial nanobacteria hold great promise as a potent systemic immunoadjuvant for cancer immunotherapy.

Due to the high heterogeneity and the immunosuppressive microenvironment of tumors, most single antigen tumor vaccines often fail to elicit potent antitumor immune responses in clinical trials, resulting in unsatisfactory therapy effects. Hence, personalized tumor vaccines have become a promising modality for cancer immunotherapy. Here, we have developed a tumor in situ hydrogel vaccine (AH/DA-OR) capable of rapid hemostasis for personalized tumor immunotherapy, composed of dopamine-grafted hyaluronic acid (HA/DA) combined with sodium alginate (ALG), with coloaded oxaliplatin (OXA) and resiquimod (R848). The ALG and HA framework imparts excellent biocompatibility to the hydrogel, and dopamine (DA) modification endows it with rapid hemostatic functionality. Following local peritumor injection of AH/DA-OR into the tumor, the in situ hydrogel vaccine achieved the sustained release of the chemotherapeutic agent, OXA, inducing immunogenic cell death in tumor cells and effectively releasing personalized tumor-associated antigens to activate immune responses. Simultaneously, local R848 adjuvant sustained release at the tumor site enhanced immune responses, minimized drug side effects, and amplified immunotherapy effects. Finally, the hydrogel vaccine effectively activated host immune responses to suppress CT26 colorectal cancer growth in vivo, also exhibiting superior inhibition of untreated tumor growth at distant sites. This strategy of rapid hemostasis of tumor in situ hydrogel vaccine holds significant clinical potential and provides a paradigm for achieving secure and robust immunotherapy.

Background: For best efficacy, vaccines must provide long-lasting immunity. To measure longevity, memory from B and T cells are surrogate endpoints for vaccine efficacy. When antibodies are insufficient for protection, the immune response must rely on T cells. The magnitude and differentiation of effective, durable immune responses depend on antigen-specific precursor frequencies. However, development of vaccines that induce durable T-cell responses for cancer treatment has remained elusive., Methods: To address long-lasting immunity, patients with HER2+ (human epidermal growth factor receptor 2) advanced stage cancer received HER2/neu targeted vaccines. Interferon-gamma (IFN-γ) enzyme-linked immunosorbent spot measuring HER2/neu IFN-γ T cells were analyzed from 86 patients from three time points: baseline, 1 month after vaccine series, and long-term follow-up at 1 year, following one in vitro stimulation. The baseline and 1-month post-vaccine series responses were correlated with immunity at long-term follow-up by logistic regression. Immunity was modeled by non-linear functions using generalized additive models., Results: Antigen-specific T-cell responses at baseline were associated with a 0.33-log increase in response at long-term follow-up, 95% CI (0.11, 0.54), p=0.003. 63% of patients that had HER2/neu specific T cells at baseline continued to have responses at long-term follow-up. Increased HER2/neu specific T-cell response 1 month after the vaccine series was associated with a 0.47-log increase in T-cell response at long-term follow-up, 95% CI (0.27, 0.67), p=2e-5. 74% of patients that had an increased IFN-γ HER2 response 1 month after vaccines retained immunity long-term. As the 1-month post-vaccination series precursor frequency of HER2+IFN-γ T-cell responses increased, the probability of retaining these responses long-term increased (OR=1.49 for every one natural log increase of precursor frequency, p=0.0002), reaching an OR of 20 for a precursor frequency of 1:3,000 CONCLUSIONS: Patients not destined to achieve long-term immunity can be identified immediately after completing the vaccine series. Log-fold increases in antigen-specific precursor frequencies after vaccinations correlate with increased odds of retaining long-term HER2 immune responses. Further vaccine boosting or immune checkpoint inhibitors or other immune stimulator therapy should be explored in patients that do not develop antigen-specific T-cell responses to improve overall response rates., Competing Interests: Competing interests: JBL has received grant funding from Merck, AstraZeneca, Precigen, ArsenalBio, Volastra, Nurix, Aminex Therapeutics through his institution and is a consultant for Verismo Therapeutics. JD is employed by Grail. SS has received grant funding from Veana, IMV Inc, and Stanford Burnham Prebys. MLD has grant funding from Precigen, Veanna, Bavarian Nordic, and Aston Sci. MLD also holds shares in Epithany and is an inventor on patents held by the University of Washington. The authors declare there are no other competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Immunogenic cell death (ICD) and ferroptosis have recently emerged as key factors in the anticancer immune response. Among the treatments able to induce ICD and the associated release of danger signals is photodynamic therapy (PDT). Ferroptosis for its part results from lipid peroxidation and is induced by CD8 + T cells to kill nearby cancer cells on IFN-γ production. We aimed to combine the two concepts, that is, to evaluate whether the strong pro-oxidant effects of PDT may promote ferroptosis and antigen release and to develop a procedure for in situ PDT to prepare the soil for highly endocytotic immature dendritic cell (iDC) adoptive transfer. This approach was implemented for managing peritoneal carcinomatosis, a lesion often associated with poor outcomes., Methods: We used three-dimensional (3D) heterotypic spheroids made of cancer cells, exposed them to a white light-activated OR141 photosensitizer (PS), and subsequently complexified them by adding iDC and naive lymphocytes. We next used a model of mouse peritoneal carcinomatosis and administered PDT using laparoscopy to locally induce photoactivation using the endoscope light. The immune response following adoptive transfer of iDC was tracked both in vivo and ex vivo using isolated immune cells from in situ vaccinated mice., Results: Cancer cells undergoing PDT-induced cell death significantly increased ICD markers and the infiltration of iDCs in spheroids, relying on ferroptosis. These actions induced the sequential activation of CD8 + and CD4 + T cells as revealed by a significant spheroid 3D structure deterioration and, remarkably, were not recapitulated by conventional ferroptosis inducer RSL3. Using LED light from an endoscope for in situ photoactivation of PS enabled us to apply the vaccination modality in mice with peritoneal tumors. Consecutive intraperitoneal injection of iDCs resulted in delayed tumor growth, increased survival rates, and prevented tumor relapse on rechallenge. CD8 + T cell response was supported by depletion experiments, nodal detection of early activated T cells, and ex vivo T cell-induced cytotoxicity toward spheroids., Conclusions: The combination of in situ PDT locally delivered by an endoscope light and iDC administration induces a durable memory immune response against peritoneal carcinomatosis thereby opening new perspectives for the treatment of a life-threatening condition., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The successful application of mRNA vaccines in preventing and treating infectious diseases highlights their potential as therapeutic vaccines for cancer treatment. However, unlike infectious diseases, effective antitumor therapy, particularly for solid tumors, necessitates the activation of more powerful cellular and humoral immunity to achieve clinical efficacy. Here, we report a spleen-targeted mRNA vaccine (Mn@mRNA-LNP) designed to deliver tumor antigen-encoding mRNA and manganese adjuvant (Mn 2+ ) simultaneously to dendritic cells (DCs) in the spleen. This delivery system promotes DC maturation and surface antigen presentation and stimulates the production of cytotoxic T cells. Additionally, Mn 2+ codelivered in the system serves as a safe and effective immune adjuvant, activating the stimulator of interferon genes (STING) signaling pathway and promoting the secretion of type I interferon, further enhancing the antigen-specific T cell responses. Mn@mRNA-LNP effectively inhibits tumor progression in established melanoma and colon tumor models as well as in a model of tumor recurrence after resection. Notably, the combination of Mn@mRNA-LNP with immune checkpoint inhibitors further enhances complete tumor suppression and prolonged the overall survival in mice. Overall, this "All-in-One" mRNA vaccine significantly boosts antitumor immunity responses by improving spleen targeting and immune activation, providing an attractive strategy for the future clinical translation of therapeutic mRNA vaccines.

Glioma is one of the common tumors in the central nervous system, and its treatment methods (surgery, radiotherapy, and chemotherapy) lack specificity and have a poor prognosis. With the development of immunology, cell biology, and genomics, tumor immunotherapy has ushered in a new era of tumor therapy, achieving significant results in other invasive cancers such as advanced melanoma and advanced non-small cell lung cancer. Currently, the clinical trials of immunotherapy in glioma are also progressing rapidly. Here, this review summarizes promising immunotherapy methods in recent years, reviews the current status of clinical trials, and discusses the challenges and prospects of glioma immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Peng, Jiang and Liu.)

Messenger ribonucleic acid (mRNA) therapeutics are attracting attention as promising tools in cancer immunotherapy due to their ability to leverage the in vivo expression of all known protein sequences. Even small amounts of mRNA can have a powerful effect on cancer vaccines by promoting the synthesis of tumor-specific antigens (TSA) or tumor-associated antigens (TAA) by antigen-presenting cells (APC). These antigens are then presented to T cells, eliciting strong antitumor immune stimulation. The potential of mRNA can be further enhanced by expressing immunomodulatory agents, such as cytokines, antibodies, and chimeric antigen receptors (CAR), enhancing tumor immunity. Recent research also explores mRNA-encoded tumor death inducers or tumor microenvironment (TME) modulators. Despite its promise, the clinical translation of mRNA-based anticancer strategies faces challenges, including inefficient targeted delivery in vivo, failure of endosomal escape, and inadequate intracellular mRNA release, resulting in poor transfection efficiencies. Inspired by the approval of lipid nanoparticle-loaded mRNA vaccines against coronavirus disease 2019 (COVID-19) and the encouraging outcomes of mRNA-based cancer therapies in trials, innovative nonviral nanotechnology delivery systems have been engineered. These aim to advance mRNA-based cancer immunotherapies from research to clinical application. This review summarizes recent preclinical and clinical progress in lipid and polymeric nanomedicines for delivering mRNA-encoded antitumor therapeutics, including cytokines and antibody-based immunotherapies, cancer vaccines, and CAR therapies. It also addresses advanced delivery systems for direct oncolysis or TME reprogramming and highlights key challenges in translating these therapies to clinical use, exploring future perspectives, including the role of artificial intelligence and machine learning in their development., (© 2024 The Author(s). WIREs Nanomedicine and Nanobiotechnology published by Wiley Periodicals LLC.)

Treatment with T cells genetically engineered to express tumor-reactive T cell receptors (TCRs), known as TCR-gene therapy (TCR-T), is a promising immunotherapeutic approach for patients with cancer. The identification of optimal TCRs to use and tumor antigens to target are key considerations for TCR-T. In this issue of the JCI, Bear and colleagues report on their use of in vitro assays to characterize four HLA-A*03:01- or HLA-A*11:01-restricted TCRs targeting the oncogenic KRAS G12V mutation. The TCRs were derived from healthy donors or patients with pancreatic cancer who had received a vaccine against mutant KRAS. The most promising TCRs warrant testing in patients with KRAS G12V-positive cancers.

In this issue, Gainor and colleagues report on the immunogenicity of personalized neoantigen-encoding mRNA vaccines that elicit measurable polyfunctional CD8+ and CD4+ T-cell responses in patients whose tumors have been resected. Reactivity is substantiated to 20% to 30% of the predicted MHC-I and MHC-II epitopes in four patients with NSCLC postsurgically treated with the vaccine alone and in 12 patients with melanoma treated with their individualized vaccines plus pembrolizumab in the context of a phase 1 clinical trial (NCT03313778). See related article by Gainor et al., p. 2209., (©2024 American Association for Cancer Research.)

Microbial systems have been synthetically engineered to deploy therapeutic payloads in vivo 1,2 . With emerging evidence that bacteria naturally home in on tumours 3,4 and modulate antitumour immunity 5,6 , one promising application is the development of bacterial vectors as precision cancer vaccines 2,7 . Here we engineered probiotic Escherichia coli Nissle 1917 as an antitumour vaccination platform optimized for enhanced production and cytosolic delivery of neoepitope-containing peptide arrays, with increased susceptibility to blood clearance and phagocytosis. These features enhance both safety and immunogenicity, achieving a system that drives potent and specific T cell-mediated anticancer immunity that effectively controls or eliminates tumour growth and extends survival in advanced murine primary and metastatic solid tumours. We demonstrate that the elicited antitumour immune response involves recruitment and activation of dendritic cells, extensive priming and activation of neoantigen-specific CD4 + and CD8 + T cells, broader activation of both T and natural killer cells, and a reduction of tumour-infiltrating immunosuppressive myeloid and regulatory T and B cell populations. Taken together, this work leverages the advantages of living medicines to deliver arrays of tumour-specific neoantigen-derived epitopes within the optimal context to induce specific, effective and durable systemic antitumour immunity., Competing Interests: Competing interests A.R., J.I., T.D. and N.A. have filed a provisional patent application with the US Patent and Trademark Office related to this work. The other authors declare no competing interests., (© 2024. The Author(s).)

Afamitresgene autoleucel (TECELRA ® ), a genetically modified human leukocyte antigen (HLA)-restricted autologous melanoma-associated antigen 4 (MAGE-A4)-directed T cell immunotherapy, is being developed by Adaptimmune Therapeutics plc, for the treatment of solid tumours expressing the MAGE-A4 antigen. In August 2024, afamitresgene autoleucel was approved in the USA under accelerated approval for the treatment of adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are HLA-A*02:01P, -A*02:02P, -A*02:03P or -A*02:06P positive and whose tumour expresses the MAGE-A4 antigen as determined by FDA-approved or cleared companion diagnostic devices. This article summarizes the milestones in the development of afamitresgene autoleucel leading to this first approval for the treatment of advanced synovial sarcoma., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Dendritic cells (DCs) are essential for antitumor T-cell responses to immune checkpoint inhibitor therapies. We have previously reported that the secreted protein neudesin suppresses DC function. In contrast, neudesin has been found to be abundantly expressed in human cancers. In this study, we evaluated the role of neudesin in cancer immunity. Cancer-related database analysis revealed that patients with melanoma with low neudesin expression exhibited increased infiltration of DCs and CD8 + T cells and improved outcomes of checkpoint inhibitor therapy. In mouse tumor models, neudesin deficiency delayed tumor growth and increased the proportions of Type 1 conventional DCs (cDC1s) and tumor antigen-specific CD8 + T cells in tumors and tumor-infiltrating lymph nodes. Neudesin-deficient antitumor cDC1 vaccine enhanced the systemic immunity more effectively than the wild-type cDC1 vaccine. Overall, our findings highlight the importance of neudesin in cancer immunity, providing a novel target for immunotherapy., Competing Interests: Declaration of competing interest NK is an employee of Nippon Shinyaku Co. Ltd. (Kyoto, Japan). All other authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Glioblastoma multiforme (GBM) is the most common CNS cancer, it has dismal survival rates despite several effective mediators: intensified cytotoxic therapy, chimeric antigen receptor (CAR)-T cell therapy, viral therapy, adoptive cell therapy, immune checkpoint blockade therapy, radiation therapy and vaccine therapy. This review examines the basic concepts underlying immune targeting and examines products such as checkpoint blockade drugs, CAR-T cells, oncolytic viruses, combinatory multimodal immunotherapy and cancer vaccines. New approaches to overcoming current constraints and challenges in GBM therapy are discussed, based on recent studies into these tactics, findings from ongoing clinical trials, as well as previous trial results., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Peptide-based anticancer vaccines have shown some efficacy in generating cancer-specific immune responses in various cancer studies, but clinical success is limited, one of the reasons is due to its prone degradation and weak immunogenicity. So some tumor epitope peptide vaccines often require coupling or forming fusion proteins with corresponding protein carriers to enhance their stability and immunogenicity. Given the scarcity of validated carriers for clinical trials, there is an urgent requirement for the development of novel protein carrier. Our previous work has demonstrated that VEGF165b mutant could be used as an effective immunization adjunct to enhance anti-tumor immune response. By analyzing and evaluating the gene structure of VEGF, we speculated that mVEGF165b has the potential to be utilized as a tumor peptide vaccine carrier. An mVEGF165b-MUC1 chimeric tumor vaccine was produced by fusing the MUC1 peptide （(MUC1, a T-cell epitope dominant peptide from Mucin1） to the C-terminus of mVEGF165b, expressing the fusing protein in pichia yeast, followed by purification with a HiTrap heparin affinity chromatography column. We found that immunizing mice with mVEGF165b-MUC1 fusion protein induced high-titer antibodies against VEGF in a preventive context, which in turn reduced the proportion of Tregs and further stimulated mice to produce T-cell responses specific to mucin1. The high-titer VEGF antibody stimulated by mVEGF165b also promoted tumor blood vessel maturation and facilitated T-cell infiltration. In conclusion，immunized with mVEGF165b-MUC1 protein are beneficial for eliciting immune responses targeting Mucin1, mVEGF165b have the potential to be utilized as a peptide tumor vaccine carrier., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest for this article., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

We previously developed an innovative strategy to induce CD8 + T lymphocyte-immunity through in vivo engineering of extracellular vesicles (EVs). This approach relies on intramuscular injection of DNA expressing antigens of interest fused at a biologically-inactive HIV-1 Nef protein mutant (Nef mut ). Nef mut is very efficiently incorporated into EVs, thus conveying large amounts of fusion proteins into EVs released by transfected cells. This platform proved successful against highly immunogenic tumor-specific antigens. Here, we tested whether antigen-specific CD8 + T cell immune responses induced by engineered EVs can counteract the growth of tumors expressing two "self" tumor-associated antigens (TAAs): HOXB7 and Her2/neu. FVB/N mice were injected with DNA vectors expressing Nef mut fused to HOXB7 or Her2/neu, singly and in combination, before subcutaneous implantation of breast carcinoma cells co-expressing HOXB7 and Her2/neu. All mice immunized with the combination vaccine remained tumor-free, whereas groups vaccinated with single Nef mut -fused antigens were only partly protected, with stronger antitumor effects in Her2/neu-immunized mice. Double-vaccinated mice also controlled tumor growth upon a later tumor cell re-challenge. Importantly, co-vaccination also contained tumors in a therapeutic immunization setting. These results showed the efficacy of EV-based vaccination against two TAAs, and represent the first demonstration that HOXB7 may be targeted in multi-antigen immunotherapy strategies., Competing Interests: Competing interests The authors declare no competing interests. Ethics approval and consent to participate The authors declare that all methods were performed in accordance with the relevant guidelines and regulations and that the study on animals was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Italian Ministry of Health, authorization 78/2020, released on February 11th, 2020., (© 2024. The Author(s).)

Over the past few decades, research on cancer immunotherapy has firmly established immune cells as key players in effective cancer treatment. Peptide vaccines directly targeting immune cells have demonstrated immense potential due to their specificity and applicability. However, developing peptide vaccines to generate tumor-reactive T cells remains challenging, primarily due to suboptimal immunogenicity and overcoming the immunosuppressive tumor microenvironment (TME). In this review, we discuss various elements of effective peptide vaccines, including antigen selection, peptide epitope optimization, vaccine adjuvants, and the combination of multiple immunotherapies, in addition to recent advances in tumor neoantigens as well as epitopes bound by non-classical human leukocyte antigen (HLA) molecules, to increase the understanding of cancer peptide vaccines and provide multiple references for the design of subsequent T cell-based peptide vaccines., Competing Interests: Declaration of competing interest The authors have declared no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this article, we discuss new findings which suggest that type I regulatory T (Tr1) cells can interfere with cancer vaccine efficacy in mice by exerting strong regulatory control over antitumor immune responses., (© 2024 the Australian and New Zealand Society for Immunology, Inc.)

GBM is the most common, aggressive, and intracranial primary brain tumor; it originates from the glial progenitor cells, has poor overall survival (OS), and has limited treatment options. In this decade, GBM immunotherapy is in trend and preferred over several conventional therapies, due to their better patient survival outcome. This review explores the clinical trials of several immunotherapeutic approaches (immune checkpoint blockers (ICBs), CAR T-cell therapy, cancer vaccines, and adoptive cell therapy) with their efficacy and safety. Despite significant progress, several challenges (viz., immunosuppressive microenvironment, heterogeneity, and blood-brain barrier (BBB)) were experienced that hamper their immunotherapeutic potential. Furthermore, these challenges were clinically studied to be resolved by multiple combinatorial approaches, discussed in the later part of the review. Thus, this review suggests the clinical use and potential of immunotherapy in GBM and provides the holistic recent knowledge and future perspectives., Competing Interests: Declaration of competing interest All authors declare that there is no competing and conflict of interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Pathogen-mimicking nanoparticles have emerged at the forefront of vaccine delivery technology, offering potent immune activation and excellent biocompatibility. Among these innovative carriers, mannan, a critical component of yeast cell walls, shows promise as an exemplary vaccine carrier. Nevertheless, it faces challenges like unpredictable immunogenicity, rapid elimination, and limited antigen loading due to high water solubility. Herein, mannan with varying carbon chain ratios is innovatively modified, yielding a series of dodecyl chains modified mannan (Mann-C 12 ). Through meticulous screening, a mannan variant with a 40% grafting ratio is pinpointed as the optimal vaccine carrier. Further RNA sequencing confirms that Mann-C 12 exhibits desired immunostimulatory characteristics. Coupled with antigen peptides, Mann-C 12 /OVA 257-280 nanovaccine initiates the maturation of antigen-presenting cells by activating the TLR4 and Dectin-2 pathways, significantly boosting antigen utilization and sparking antigen-specific immune responses. In vivo, experiments utilizing the B16-OVA tumor model underscore the exceptional preventive capabilities of Mann-C 12 /OVA 257-280 . Notably, when combined with immune checkpoint blockade therapy, it displays a profound synergistic effect, leading to marked inhibition of tumor growth. Thus, the work has yielded a pathogen-like nanovaccine that is both simple to prepare and highly effective, underscoring the vast potential of mannan-modified nanovaccines in the realm of cancer immunotherapy., (© 2024 Wiley‐VCH GmbH.)

Therapeutic vaccine becomes a promising strategy to fight cancer by enhancing and sustaining specific anti-tumor immune responses. However, its efficacy is often impeded by low immunogenicity, the immunosuppressive tumor microenvironment (TME), and immune-related adverse events. Herein, we introduce 1-tetradecanol (TD)-wrapped, CpG-loaded porous Prussian blue nanoparticles (pPBNPs-CpG@TD) as a nanoimmunomodulator to initiate photothermal-induced immunogenic cell death (ICD) and photothermal-responsive release of CpG for augmenting the ICD effect. It was revealed that the dual-photothermal action significantly potentiated the in situ anti-tumor vaccine-like immunotherapy in terms of enhanced immunogenicity, promoted dendritic cell maturation, and increased T lymphocyte infiltration, consequently eliciting a robust immune response for inhibiting both primary and rechallenge tumors on a subcutaneous 4T1 tumor-bearing mouse model. The development and use of photoactive nanoimmunomodulators represents a novel and effective strategy to boost immunogenicity and counteract immunosuppressive TME, marking a significant advancement in the realm of ICD-driven in situ anti-tumor vaccine-like immunotherapy., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The preferable antigen delivery profile accompanied by sufficient adjuvants favors vaccine efficiency. Mitochondria, which feature prokaryotic characteristics and contain various damage-associated molecular patterns (DAMPs), are easily taken up by phagocytes and simultaneously activate innate immunity. In the current study, we established a mitochondria engineering platform for generating antigen-enriched mitochondria as cancer vaccine. Ovalbumin (OVA) and tyrosinase-related protein 2 (TRP2) were used as model antigens to synthesize fusion proteins with mitochondria-localized signal peptides. The lentiviral infection system was then employed to produce mitochondrial vaccines containing either OVA or TRP2. Engineered OVA- and TRP2-containing mitochondria (OVA-MITO and TRP2-MITO) were extracted and evaluated as potential cancer vaccines. Impressively, the engineered mitochondria vaccine demonstrated efficient antitumor effects when used as both prophylactic and therapeutic vaccines in murine tumor models. Mechanistically, OVA-MITO and TRP2-MITO potently recruited and activated dendritic cells (DCs) and induced a tumor-specific cell-mediated immunity. Moreover, DC activation by mitochondria vaccine critically involves TLR2 pathway and its lipid agonist, namely, cardiolipin derived from the mitochondrial membrane. The results demonstrated that engineered mitochondria are natively well-orchestrated carriers full of immune stimulants for antigen delivery, which could preferably target local dendritic cells and exert strong adaptive cellular immunity. This proof-of-concept study established a universal platform for vaccine construction with engineered mitochondria bearing alterable antigens for cancers as well as other diseases., (© 2024. The Author(s).)

Selective in vivo immune cell manipulation offers a promising strategy for cancer vaccines. In this context, spatiotemporal control over recruitment of specific cells, and their direct exposure to appropriate immunoadjuvants and antigens are key to effective cancer vaccines. We present an implantable 3D-printed cancer vaccine platform called the 'NanoLymph' that enables spatiotemporally-controlled recruitment and manipulation of immune cells in a subcutaneous site. Leveraging two reservoirs each for continuous immunoadjuvant release or antigen presentation, the NanoLymph attracts dendritic cells (DCs) on site and exposes them to tumor-associated antigens. Upon local antigen-specific activation, DCs are mobilized to initiate a systemic immune response. NanoLymph releasing granulocyte-macrophage colony-stimulating factor and CpG-oligodeoxynucleotides with irradiated whole cell tumor lysate inhibited tumor growth of B16F10 murine melanoma in a prophylactic and therapeutic vaccine setting. Overall, this study presents the NanoLymph as a versatile cancer vaccine development platform with replenishable and controlled local release of antigens and immunoadjuvants., Competing Interests: Declaration of competing interest CYXC and AG are inventors of intellectual property licensed by Continuity Biosciences. AG is a co-founder of Continuity Biosciences. The other authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In situ vaccination is an attractive type of cancer immunotherapy, and methods of persistently dispersing immune agonists throughout the entire tumor are crucial for maximizing their therapeutic efficacy. Based on the probiotics usually used for dietary supplements, an immunomodulator-boosted Lactococcus lactis (IBL) strategy is developed to enhance the effectiveness of in situ vaccination with the immunomodulators. The intratumoral delivery of OX40 agonist and resiquimod-modified Lactococcus lactis (OR@Lac) facilitates local retention and persistent dispersion of immunomodulators, and dramatically modulates the key components of anti-tumor immune response. This novel vaccine activated dendritic cells and cytotoxic T lymphocytes in the tumor and tumor-draining lymph nodes, and ultimately significantly inhibited tumor growth and prolonged the survival rate of tumor-bearing mice. The combination of OR@Lac and ibrutinib, a myeloid-derived suppressor cell inhibitor, significantly alleviated or even completely inhibited tumor growth in tumor-bearing mice. In conclusion, IBL is a promising in situ tumor vaccine approach for clinical application and provides an inspiration for the delivery of other drugs., (© 2024 Wiley‐VCH GmbH.)

Although therapeutic nanovaccines have made a mark in cancer immunotherapy, the shortcomings such as poor homing ability of lymph nodes (LNs), low antigen presentation efficiency and low antitumor efficacy have hindered their clinical transformation. Accordingly, we prepared advanced nanovaccines (CMB and CMC) by integrating carbon dots (CDs) with tumor-associated antigens (B16F10 and CT26). These nanovaccines could forwardly target tumors harbouring LNs, induce strong immunogenicity for activating cytotoxic T cells (CTLs), thereby readily eliminating tumor cells and suppressing primary/distal tumor growth. This work provides a promising therapeutic vaccination strategy to enhance cancer immunotherapy., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Immunotherapy emerges as a promising frontier in cancer therapy and prevention. This study investigates the capacity of tumor-antigenic nanoparticles, specifically ovalbumin-tethered spiked virus-like poly(lactic-co-glycolic acid) nanoparticles (OVA-sVLNP), to effectively elicit humoral and cellular immune responses against tumors., Methods: OVA-sVLNP were synthesized through thiol-maleimide crosslinking using a single emulsion method. Comprehensive characterization was performed through Nuclear Magnetic Resonance (NMR), dynamic light scattering, Cryo-electron microscopy (Cryo-EM), confocal microscopy, and flow cytometry. Immunogenicity was evaluated using an enzyme-linked immunosorbent assay (ELISA) for quantifying immunoglobulin levels (IgG, IgG1, IgG2a) and cytokines in mouse sera. Flow cytometry profiled cellular immune responses in mouse spleens, and organ biosafety was assessed using immunohistochemistry and hematoxylin and eosin (H&E) staining., Results: OVA-sVLNP had a mean particle size of 193.8 ± 11.9 nm, polydispersity index of 0.307 ± 0.04, and zeta potential of -39.6 ± 10.16 mV, remaining stable for one month at 4°C. In vitro studies revealed significant upregulation of CD80/CD86 in dendritic cells, indicating robust activation. In vivo, the optimal concentration (V25) induced potent IgG, IgG1, and IgG2a antibodies, significant populations of CD3 + CD4 + , CD3 + CD8 + , and a rare subset of CD3 + CD4 + CD8 + memory T cells. Notably, Th9 induction resulted in the secretion of IL-9, IL-10, and other cytokines, which are crucial for orchestrating cytotoxic T cell activity and antitumor effects. Overall, higher doses did not improve outcomes, highlighting the significance of optimal dosing., Conclusion: This study demonstrated potent immunogenicity of OVA-sVLNP, characterized by the induction of specific IgG antibodies and the stimulation of cellular immune responses, particularly tumor-killing Th9 cells. The simplicity and cost-effectiveness of the manufacturing process augment the potential of OVA-sVLNP as a viable candidate for antitumor vaccines, opening new avenues for cancer prevention and cell-based therapeutic strategies., Competing Interests: The authors declare no conflicts of interest., (© 2024 Lin et al.)

The stimulator of interferon genes (STING) pathway is crucial for tumor immunity, leading to the exploration of STING agonists as potential immunotherapy adjuvants. However, their clinical application faces obstacles including poor pharmacokinetics, transient activation, and an immunosuppressive tumor microenvironment (TME). Addressing these limitations, our study aims to develop an injectable silk fibroin hydrogel-based in situ vaccine. It incorporates a nanoscale STING agonist, an immunogenic cell death (ICD) inducer, and an immunomodulator to ensure their controlled and sustained release. cGAMP nanoparticles (cGAMPnps) with a core-shell structure ensure optimal delivery of cGAMP to dendritic cells (DCs), thereby activating the STING pathway and fostering DC maturation. ICD-associated damage-associated molecular patterns amplify and prolong STING activation via enhanced type I IFN and other inflammatory pathways, along with delayed degradation of cGAMP and STING. Furthermore, the STING-driven vascular normalization by cGAMPnps and ICD, in conjunction with immunomodulators like antiprogrammed cell death protein 1 antibody (anti-PD-1 Ab) or OX40 ligand (OX40L), effectively remodels the immunosuppressive TME. This in situ gel vaccine, when used independently or with surgery as neoadjuvant/adjuvant immunotherapy, enhances DC and CD8 + T-cell activation, suppressing tumor progression and recurrence across various immunologically cold tumor models. It revolutionizes the application of STING agonists in cancer immunotherapy, offering substantial promise for improving outcomes across a broad spectrum of malignancies.

Pancreatic cancer remains one of the deadliest malignancies, with a consistently low five-year survival rate for the past several decades. This is in stark contrast to other cancers, which have seen significant improvement in survival and prognosis due to recent developments in therapeutic modalities. These modest improvements in pancreatic cancer outcomes have primarily resulted from minor advances in cytotoxic chemotherapeutics, with limited progress in other treatment approaches. A major focus of current therapeutic research is the further development of immunomodulatory therapies characterized by antibody-based approaches, cellular therapies, and vaccines. Although initial results utilizing immunotherapy in pancreatic cancer have been mixed, recent clinical trials have demonstrated significant improvements in patient outcomes. In this review, we detail these three approaches to immunomodulation, highlighting their common targets and distinct shortcomings, and we provide a narrative summary of completed and ongoing clinical trials that utilize these approaches to immunomodulation. Within this context, we aim to inform future research efforts by identifying promising areas that warrant further exploration.

Malignant tumors, characterized by uncontrolled cell proliferation, are a leading global health challenge, responsible for over 9.7 million deaths in 2022, with new cases expected to rise to 35 million annually by 2050. Immunotherapy is preferred to other cancer therapies, offering precise targeting of malignant cells while simultaneously strengthening the immune system's complex responses. Advances in this novel field of science have been closely linked to a deeper knowledge of tumor biology, particularly the intricate interplay between tumor cells, the immune system, and the tumor microenvironment (TME), which are central to cancer progression and immune evasion. This review offers a comprehensive analysis of the molecular mechanisms that govern these interactions, emphasizing their critical role in the development of effective immunotherapeutic products. We critically evaluate the current immunotherapy approaches, including cancer vaccines, adoptive T cell therapies, and cytokine-based treatments, highlighting their efficacy and safety. We also explore the latest advancements in combination therapies, which synergistically integrate multiple immunotherapeutic strategies to overcome resistance and enhance therapeutic outcomes. This review offers key insights into the future of cancer immunotherapy with a focus on advancing more effective and personalized treatment strategies., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Angus Nnamdi Oli et al.)

Objectives: Leukemia cell-derived exosomes (LEXs), carrying leukemia cell-specific antigens, can serve as a source of antigen for dendritic cell (DC) vaccine loading. However, LEX-targeted DC-based vaccines have demonstrated limited antitumor immune effects in clinical trials, attributed to the low immunogenicity of LEXs and the scant levels of costimulatory molecules on DCs. The costimulatory molecules CD80 and CD86, which are crucial to DC function, play a significant role in enhancing immune efficacy. In this study, we explored the anti-leukemia immune response of costimulatory molecule gene-modified LEX-targeted DCs (LEX-8086) in vitro and in animal models., Methods: DCs were incubated with LEX-8086 to produce LEX-8086-targeted DCs (DCs LEX-8086 ). ELISA, cytotoxicity assays and flow cytometry utilized to assess the antitumor efficacy of DCs LEX8086 in vitro. Flow cytometry was used to evaluate the immunomodulatory function of DCs LEX8086 in animal models., Results: Our findings indicated that LEX-8086 enhanced the maturation and antigen-presenting ability of DCs. Immunization with DCs LEX8086 significantly activated CD8 + T cells and boosted the CTL response in vitro. More importantly, DCs LEX-8086 effectively suppressed tumor growth and exerted anti-leukemia effects in both prophylactic and therapeutic animal models. Furthermore, DCs LEX-8086 promoted the proportion of CD4 + T cells, CD8 + T cells and M1 macrophages in the tumor environments both prophylactically and therapeutically. Treatment with DCs LEX-8086 showed no significant difference in the levels of M2 macrophages but decreased the proportion of Tregs within the tumor bed during therapeutic experiments., Conclusion: The results suggested that DCs LEX-8086 induces a more effective anti-leukemia immunity compared to DCs LEX-null in vivo and in vitro. DCs LEX-8086 might achieve antitumor effects by elevating the numbers of CD4 + T cells, CD8 + T cells, and M1 macrophages in tumors. Our findings indicate that DCs LEX-8086 could be leveraged to develop a new, highly effective vaccine for anti-leukemia immunity., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Whole tumor cell vaccines hold promise by presenting a broader spectrum of autologous-origin tumor antigens to combat postoperative recurrence and metastasis. However, challenges such as intractable adjuvant modification and obscure interactions with antigen-presenting cells in the postoperative microenvironment impede their translation into effective personalized immunotherapies. In this study, we propose cancer vaccines derived from manganese oxide-immobilized resected tumor cells, featuring whole tumor antigens and adjustable stiffness to modulate interactions with antigen-presenting cells in the postoperative microenvironment. These vaccines effectively stimulate dendritic cell phagocytosis and function through sequential stiffness-mediated mechanotransduction and interferon signaling. We evaluated their efficacy using an orthotopic triple-negative breast cancer mouse model and found that combining the vaccines with radiotherapy effectively inhibits postoperative tumor recurrence and metastasis. Our study underscores the potential of utilizing mechanotransduced adjuvants alongside directly inactivated whole-cell vaccines as a universal solution for preventing postoperative tumor recurrence.

Cancer immunotherapy involves a cutting-edge method that utilizes the immune system to detect and eliminate cancer cells. It has shown substantial effectiveness in treating different types of cancer. As a result, its growing importance is due to its distinct benefits and potential for sustained recovery. However, the general deployment of this treatment is hindered by ongoing issues in maintaining minimal toxicity, high specificity, and prolonged effectiveness. Nanotechnology offers promising solutions to these challenges due to its notable attributes, including expansive precise surface areas, accurate ability to deliver drugs and controlled surface chemistry. This review explores the current advancements in the application of nanomaterials in cancer immunotherapy, focusing on three primary areas: monoclonal antibodies, therapeutic cancer vaccines, and adoptive cell treatment. In adoptive cell therapy, nanomaterials enhance the expansion and targeting capabilities of immune cells, such as T cells, thereby improving their ability to locate and destroy cancer cells. For therapeutic cancer vaccines, nanoparticles serve as delivery vehicles that protect antigens from degradation and enhance their uptake by antigen-presenting cells, boosting the immune response against cancer. Monoclonal antibodies benefit from nanotechnology through improved delivery mechanisms and reduced off-target effects, which increase their specificity and effectiveness. By highlighting the intersection of nanotechnology and immunotherapy, we aim to underscore the transformative potential of nanomaterials in enhancing the effectiveness and safety of cancer immunotherapies. Nanoparticles' ability to deliver drugs and biomolecules precisely to tumor sites reduces systemic toxicity and enhances therapeutic outcomes.

The field of cancer immunotherapy has seen incredible advancements in the past decades. mRNA-based cancer vaccines generating de novo T cell responses, particularly against tumor-specific antigens (TSAs), have demonstrated promising clinical outcomes and overcome diverse challenges. Despite the high potential of neoantigens to provide personalized immunotherapies through their tumor specificity and immunogenicity, challenges related to the scarcity of immunogenic neoepitopes have prompted continuous research towards finding new tumor-associated antigens (TAAs) and broader therapeutic frameworks, which may now learn from the genuine successes obtained with neoantigens. As an example, human endogenous retroviruses (HERVs) have emerged as potential alternatives to tumor neoantigens due to their high tumoral expression and ability to elicit both T cell reactivity and B cell responses associated with the efficacy of existing immunotherapies. This review aims to assess the status and limitations of TSA-directed mRNA cancer vaccines and the lessons that can be derived from these and checkpoint inhibitor studies to guide TAA vaccine development. We expect that shared B cell, CD4 and CD8 T cell antigen presentation will be key to stimulate continuous T cell expansion and efficacy for tumors that do not contain pre-existing tertiary lymphoid structures. When these structures are present in highly mutated tumors, the current checkpoint-based immunotherapies show efficacy even in immune privileged sites, and vaccines may hold the key to broaden efficacy to more tumor types and stages.

Background: We previously developed a nanobody targeting CTLA-4 and demonstrated that it can boost antitumour T-cell responses in vitro; however, the resulting responses after the injection of T cells into cancer models are usually weak and transient. Here, we explored whether fusing our nanobody to IL-12 would enable it to induce stronger, longer-lasting T-cell immune responses after exposure to immature dendritic cell and tumour cell fusions., Results: The fusion protein enhanced the response of CD8 + T cells to tumour antigens in vitro and led to stronger, more persistent immune responses after the T cells were injected into mice bearing different types of xenografts., Conclusion: Our in vitro and in vivo results suggest the anticancer potential of our nanobody-interleukin fusion system and support the clinical application of this fusion approach for various nanobodies., (© 2024. The Author(s).)

Background: Triple-negative breast cancer (TNBC) exhibits a lower survival rate in comparison to other BC subtypes. Utilizing dendritic cell (DC) vaccines as a form of immunotherapy is becoming a promising new approach to cancer treatment. However, inadequate immunogenicity of tumor antigens leads to unsatisfactory effectiveness of the DC vaccines. Exosomes are the basis for the latest improvements in tumor immunotherapy. This study examined whether TNBC-derived exosomes elicit immunogenicity on the maturation and function of monocyte-derived DCs and the impact of the exosome-treated monocyte-derived DCs (moDCs) on T cell differentiation., Methods: exosomes were isolated from MDA-MB-231 TNBC cancer cells and characterized. Monocytes were separated from peripheral blood mononuclear cells and differentiated into DCs. Then, monocyte-derived DCs were treated with TNBC-derived exosomes. Furthermore, the mRNA levels of the genes and cytokines involved in DC maturation and function were examined using qRT-PCR and ELISA assays. We also cocultured TNBC-derived exosome-treated moDCs with T cells and investigated the role of the treatment in T cell differentiation by evaluating the expression of some related genes by qRT-PCR. The concentration of the cytokines secreted from T cells cocultured with exosome-treated moDCs was quantified by the ELISA assays., Results: Our findings showed that TNBC-derived exosomes induce immunogenicity by enhancing moDCs' maturation and function. In addition, exosome-treated moDCs promote cocultured T-cell expansion by inducing TH1 differentiation through increasing cytokine production., Conclusion: TNBC-derived exosomes could improve vaccine-elicited immunotherapy by inducing an immunogenic response and enhancing the effectiveness of the DC vaccines. However, this needs to be investigated further in future studies., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Tumor antigen peptide vaccines have shown remarkable efficacy, safety, and reliability in recent studies. However, the screening process for immunopotent antigenic peptides is cumbersome, limiting their widespread application. Identifying neoantigen peptides that can effectively trigger an immune response is crucial for personalized cancer treatment., Methods: Whole exome sequencing was performed on patient-derived colon cancer cells to predict 9-amino-acid (9aa) neoantigen peptides. In vitro simulation of endogenous antigen presentation by antigen-presenting cells (dendritic cells) to CD8+ T cells was conducted, aiming to activate the CD8+ immune response to the predicted antigens. The immunological effects of each neoantigen were assessed using flow cytometry and ELISpot assays, while the relationship between neoantigen immunogenicity and MHC molecular affinity was examined., Results: 1. Next-generation sequencing (NGS) predicted 9-amino acid (9aa) neoantigen peptides for subsequent immunological analysis.2. Higher mDC Levels in Experimental Group: CD11c+CD83+ mature dendritic cells (mDCs) were 96.6% in the experimental group, compared to 0.051% in the control group. CD80 fluorescence intensity was also significantly higher in the experimental group, confirming a greater mDC presence.3. Neoantigen Peptides Promote CD4+, CD8+ T, and NK Cell Proliferation: After 14 days, flow cytometry showed higher percentages of CD4+ T (37.41% vs 7.8%), CD8+ T (16.67% vs 14.63%), and NK cells (33.09% vs 7.81%) in the experimental group, indicating that the neoantigen peptides induced proliferation of CD4+, CD8+ T cells, and NK cells. 4. The results, analyzed using two-way ANOVA, showed that the standardized T-value for HLA molecular affinity variation in the 1-4 range (Group B) was significantly higher than for ≤1 (Group A, p < 0.0001) and >4 (Group C, p < 0.05). Regarding HLA-allele genotypes, HLA-Type 1 had a significantly higher standardized T-value than HLA-Type 2 ( p < 0.05) and HLA-Type 3 ( p < 0.0001). HLA-Type 1 was identified as the allele associated with the highest T-value., Conclusion: 1. The most immunogenic neoantigens typically exhibit an MHC molecular affinity variation between 1 and 4, indicating that stronger immunogenicity correlates with higher MHC molecular affinity variation. 2. Each patient's HLA molecules were classified into Types 1, 2, and 3, with Type 1 showing the highest binding capacity for neoantigens. Our findings indicate that the most immunogenic neoantigens were associated with HLA Type 1. 3. Neoantigen peptides were shown to activate the proliferation of both CD8+ T-cells and induce proliferation of CD4+ T-cells and NK cells. 4. Variation in MHC molecular affinity and HLA neoantigen genotype are anticipated to serve as valuable variables for screening highly immunogenic neoantigens, facilitating more efficient preparation of effective polypeptide tumor vaccines., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Huang, Li, Li, Zhu, Yang, Hu, Sun, Liu and Cao.)

mRNA neoantigen cancer vaccine inducing neoantigen-specific T cell responses holds great promise for cancer immunotherapy; however, its clinical translation remains challenging because of suboptimal neoantigen prediction accuracy and low delivery efficiency, which compromise the in vivo therapeutic efficacy. We present a lipopolyplex (LPP)-formulated mRNA cancer vaccine encoding tandem neoantigens as a cancer therapeutic regimen. The LPP-formulated mRNA vaccines elicited robust neoantigen-specific CD8 + T cell responses in three syngeneic murine tumor models (CT26, MC38, and B16F10) to suppress tumor growth. Prophylactic cancer vaccine treatment completely prevented tumor development, and long-lasting memory T cells protected mice from tumor cell rechallenge. Combining the vaccine with immune checkpoint inhibitor further boosted the antitumor activity. Of note, LPP-based personalized cancer vaccine was administered in two cancer patients and induced meaningful neoantigen-specific T cell and clinical responses. In conclusion, we demonstrated that the LPP-based mRNA vaccine can elicit strong antitumor immune responses, and the results support further clinical evaluation of the therapeutic mRNA cancer vaccine.

Introduction: Self-antigens abnormally expressed on tumors, such as MUC1, have been targeted by therapeutic cancer vaccines. We recently assessed in two clinical trials in a preventative setting whether immunity induced with a MUC1 peptide vaccine could reduce high colon cancer risk in individuals with a history of premalignant colon adenomas. In both trials, there were immune responders and non-responders to the vaccine., Methods: Here we used PBMC pre-vaccination and 2 weeks after the first vaccine of responders and non-responders selected from both trials to identify early biomarkers of immune response involved in long-term memory generation and prevention of adenoma recurrence. We performed flow cytometry, phosflow, and differential gene expression analyses on PBMCs collected from MUC1 vaccine responders and non-responders pre-vaccination and two weeks after the first of three vaccine doses., Results: MUC1 vaccine responders had higher frequencies of CD4 cells pre-vaccination, increased expression of CD40L on CD8 and CD4 T-cells, and a greater increase in ICOS expression on CD8 T-cells. Differential gene expression analysis revealed that iCOSL, PI3K AKT MTOR, and B-cell signaling pathways are activated early in response to the MUC1 vaccine. We identified six specific transcripts involved in elevated antigen presentation, B-cell activation, and NF-κB1 activation that were directly linked to finding antibody response at week 12. Finally, a model using these transcripts was able to predict non-responders with accuracy., Discussion: These findings suggest that individuals who can be predicted to respond to the MUC1 vaccine, and potentially other vaccines, have greater readiness in all immune compartments to present and respond to antigens. Predictive biomarkers of MUC1 vaccine response may lead to more effective vaccines tailored to individuals with high risk for cancer but with varying immune fitness., Competing Interests: Author RS reports support from Freenome, Exact Sciences, and Immunovia during the conduct of the study. Author OF reports personal fees from PDS Biotech, Invectys, Immodulon, and Ardigen outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Cameron, Raghu, Richardson, Zagore, Tamilselvan, Golden, Cartwright, Schoen, Finn, Benos and Cameron.)

The Thomsen-Friedenreich (TF) antigen has proven to be a promising target for developing novel therapeutic cancer vaccines. Here, a new strategy that TF antigen covalently coupled with KRN7000 and vizantin was developed. The resulting three-component vaccine KRN7000-TF-vizantin simultaneously triggers invariant natural killer T (iNKT) cells and macrophage-inducible C-type lectin (Mincle) signaling pathways, eliciting much stronger TF-specific immune responses than glycoprotein vaccine TF-KLH/alum and the corresponding two-component conjugate vaccines TF-KRN7000 and TF-vizantin. The analysis of IgG isotypes and the secretion of cytokines revealed that KRN7000-TF-vizantin induced Th1/Th2 mixed immune responses, where Th1 was dominant. In vivo experiments demonstrated that KRN7000-TF-vizantin increased the survival rate and survival time of tumor-challenged mice, and surviving mice rejected further tumor attacks without any additional treatment. This work demonstrates that covalently coupled KRN7000 and vizantin could serve as a promising TF-based vaccine carrier for antitumor immune therapy, and KRN7000-TF-vizantin features great potential to be a vaccine candidate.

Despite the transformative impact of anti-PD-1/PD-L1 therapies, challenges such as low response rates persist. The stimulator of interferon genes (STING) pathway, a crucial element of innate immunity, emerges as a strategic target to overcome these limitations. Understanding its multifaceted functions in cancer, including antigen presentation and response to DNA damage, provides valuable insights. STING agonists, categorized into cyclic dinucleotides (CDNs) and non-CDNs, exhibit promising safety and efficacy profiles. Innovative delivery systems, including antibody-drug conjugates, nanocarriers, and exosome-based therapies, address challenges associated with systemic administration and enhance targeted tumor delivery. Personalized vaccines, such as DT-Exo-STING, showcase the adaptability of STING agonists for individualized treatment. These advancements not only offer new prospects for combination therapies but also pave the way for overcoming resistance mechanisms. This review focuses on the potential of targeting STING pathway to enhance cancer immunotherapy. The integration of STING agonists into cancer immunotherapy holds promise for more effective, personalized, and successful approaches against malignancies, presenting a beacon of hope for the future of cancer treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xu and Xiong.)

Dendritic cells (DCs) are critical players at the intersection of innate and adaptive immunity, making them ideal candidates for anticancer vaccine development. DC-based immunotherapies typically involve isolating patient-derived DCs, pulsing them with tumor-associated antigens (TAAs) or tumor-specific antigens (TSAs), and utilizing maturation cocktails to ensure their effective activation. These matured DCs are then reinfused to elicit tumor-specific T-cell responses. While this approach has demonstrated the ability to generate potent immune responses, its clinical efficacy has been limited due to the immunosuppressive tumor microenvironment. Recent efforts have focused on enhancing the immunogenicity of DC-based vaccines, particularly through combination therapies with T cell-targeting immunotherapies. This Trial Watch summarizes recent advances in DC-based cancer treatments, including the development of new preclinical and clinical strategies, and discusses the future potential of DC-based vaccines in the evolving landscape of immuno-oncology., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Compared to other types of tumor vaccines, RNA vaccines have emerged as promising alternatives to conventional vaccine therapy due to their high efficiency, rapid development capability, and potential for low-cost manufacturing and safe drug delivery. RNA vaccines mainly include mRNA, circular RNA (circRNA), and Self-amplifying mRNA(SAM). Different RNA vaccine platforms for different tumors have shown encouraging results in animal and human models. This review comprehensively describes the advances and applications of RNA vaccines in antitumor therapy. Future directions for extending this promising vaccine platform to a wide range of therapeutic uses are also discussed., (© 2024. The Author(s).)