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The heterologous immunity of live pathogens leads to the emergence of this approach as a pivotal component in cancer immunotherapy. However, virulence, inflammatory‐related toxicity, and the induction of Treg cells after treatment hinder their clinical translation. Here, to exploit the heterologous immunity of live pathogens without risks, a virulence‐free reconstituted synthetic nanopathogen (RSnP) is developed by the cell wall skeleton of disrupted Mycobacterium bovis and the incorporation of timely‐activating Toll‐like receptor 7/8 agonists of which multifaceted activities can be promoted by endolysosomal enzymes. Immunization with RSnP, even without tumor‐specific antigens, exhibits potent antitumor efficacy against melanoma, breast cancer, and bladder cancer by promoting antitumor effector cells (CD8+ T cells, NK cells, M1 macrophages, and Th17 cells) and proinflammatory cytokines (IL‐12p70, TNF‐α, and IL‐6) while simultaneously mitigating immunosuppressive myeloid cells (MDSCs and M2 macrophages) in the tumor microenvironment, surpassing the therapeutic efficacies of approved live‐BCG drug and mRNA vaccine. The increase in CCR8+Foxp3+ Treg cells induced to counteract RSnP treatment can be attenuated by anti‐CCR8 antibody, a depletion antibody for tumor‐specific Treg cells, to synergize therapeutic efficacy with relieved autoimmunity. RSnP can be a therapeutic nanomedicine platform across heterologous cancers and emerging infectious virus variants with minimized toxicity. [ABSTRACT FROM AUTHOR]

Mucin-1 (MUC1) is a highly relevant antigen for cancer vaccination due to its overexpression and hypo-glycosylation in a high percentage of carcinomas. To enhance the immune response to MUC1, our group has developed C3-liposomes that encapsulate the MUC1 antigen along with immunostimulatory compounds for direct delivery to antigen-presenting cells (APCs). C3-liposomes bind complement C3, which interacts with C3-receptors on APCs, resulting in liposomal uptake and the delivery of tumor antigens to APCs in a manner that mimics pathogenic uptake. In this study, MUC1 and Toll-like receptor (TLR) agonists were encapsulated in C3-liposomes to provoke an immune response in transgenic mice tolerant to MUC1. The immune response to the C3-bound MUC1 liposomal vaccine was assessed by ELISA, ELISpot, and flow cytometry. Co-administering TLR 7/8 agonists with MUC1 encapsulated in C3-liposomes resulted in a significant antibody response compared to non-encapsulated MUC1. This antibody response was significantly higher in females than in males. The co-encapsulation of three TLR agonists with MUC1 in C3-liposomes significantly increased antibody responses and eliminated sex-based differences. Furthermore, this immunization strategy resulted in a significantly increased T cell-response compared to other treatment groups. In conclusion, the co-delivery of MUC1 and TLR agonists via C3-liposomes greatly enhances the immune response to MUC1, highlighting its potential for antigen-specific cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is highly aggressive and has no standard treatment. Although being considered as an alternative to conventional treatments for TNBC, immunotherapy has to deal with many challenges that hinder its efficacy, particularly the poor immunogenic condition of the tumor microenvironment (TME). Herein, we designed a liposomal nanoparticle (LN) platform that delivers simultaneously toll-like receptor 7 (imiquimod, IQ) and toll-like receptor 3 (poly(I:C), IC) agonists to take advantage of the different toll-like receptor (TLR) signaling pathways, which enhances the condition of TME from a "cold" to a "hot" immunogenic state. The optimized IQ/IC-loaded LN (IQ/IC-LN) was effectively internalized by cancer cells, macrophages, and dendritic cells, followed by the release of the delivered drugs and subsequent stimulation of the TLR3 and TLR7 signaling pathways. This stimulation encouraged the secretion of type I interferon (IFN-α, IFN-β) and CXCLl0, a T-cell and antigen-presenting cells (APCs) recruitment chemokine, from both cancer cells and macrophages and polarized macrophages to the M 1 subtype in in vitro studies. Notably, systemic administration of IQ/IC-LN allowed for the high accumulation of drug content in the tumor, followed by the effective uptake by immune cells in the TME. IQ/IC-LN treatment comprehensively enhanced the immunogenic condition in the TME, which robustly inhibited tumor growth in tumor-bearing mice. Furthermore, synergistic antitumor efficacy was obtained when the IQ/IC-LN-induced immunogenic state in TME was combined with anti-PD1 antibody therapy. Thus, our results suggest the potential of combining 2 TLR agonists to reform the TME from a "cold" to a "hot" state, supporting the therapeutic efficacy of immune checkpoint inhibitors. [Display omitted] [ABSTRACT FROM AUTHOR]

• IMQ and CpG ODN 1826 as adjuvants enhance JE DNA vaccine immunogenicity and long-term immune response. • IMQ and CpG ODN 1826 exert synergistic effects as adjuvants for the JE DNA vaccine. • Combination of selected TLR agonists may induce stronger and longer lasting immune efficacy than a single adjuvant. Vaccines represent a significant milestone in the history of human medical science and serve as the primary means for controlling infectious diseases. In recent years, the geographical distribution of Japanese encephalitis viruses (JEV) of various genotypes has become increasingly complex, which provides a rationale for the development of safer and more effective vaccines. The advent of subunit and nucleic acid vaccines, especially propelled by advancements in genetic engineering since the 1980s, has accelerated the application of novel adjuvants. These novel vaccine adjuvants have diversified into toll-like receptor (TLR) agonists, complex adjuvants, nanoparticles and so on. However, the efficacy of adjuvant combinations can vary depending on the host system, disease model, or vaccine formulation, sometimes resulting in competitive or counteractive effects. In our previous study, we constructed a pJME-LC3 chimeric DNA vaccine aimed at inducing an immune response through autophagy induction. Building on this, we investigated the impact of the TLR7/8 agonist imiquimod (IMQ) and the TLR9 agonist CpG ODN 1826 as adjuvants on the immunogenicity of the Japanese encephalitis chimeric DNA vaccine. Our findings indicate that the combination of the pJME-LC3 vaccine with IMQ and CpG ODN 1826 adjuvants enhanced the innate immune response, promoting the maturation and activation of antigen-presenting cells in the early immune response. Furthermore, it played a regulatory and optimizing role in subsequent antigen-specific immune responses, resulting in effective cellular and humoral immunity and providing prolonged immune protection. The synergistic effect of IMQ and CpG ODN 1826 as adjuvants offers a novel approach for the development of Japanese encephalitis nucleic acid vaccines. [ABSTRACT FROM AUTHOR]

Intraperitoneal (IP) administration of immunogenic mesoporous silica nanoparticles (iMSN) in a mouse model of metastatic ovarian cancer promotes the development of tumor-specific CD8 + T cells and protective immunity. IP delivery of iMSN functionalized with the Toll-like receptor (TLR) agonists polyethyleneimine (PEI), CpG oligonucleotide, and monophosphoryl lipid A (MPLA) stimulated rapid uptake by all peritoneal myeloid subsets. Myeloid cells quickly transported iMSN to milky spots and fat-associated lymphoid clusters (FALCs) present in tumor-burdened adipose tissues, leading to a reduction in suppressive T cells and an increase in activated memory T cells. Two doses of iMSN cleared or reduced ovarian and colorectal cancer and protected against future tumor engraftment. In contrast, subcutaneous (SC) and intravenous (IV) delivery of iMSN were without therapeutic effect in mice with peritoneal metastases, supporting the need for activation of regional immune cells. Remarkably, intraperitoneal delivery of iMSN cleared subcutaneously implanted ovarian cancer, supporting homing of antigen specific T cells to extraperitoneal tumor sites., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Current immune checkpoint blockade therapy (ICBT) predominantly targets T cells to harness the antitumor effects of adaptive immune system. However, the effectiveness of ICBT is reduced by immunosuppressive innate myeloid cells in tumor microenvironments (TMEs). Toll-like receptor 7/8 agonists (TLR7/8a) are often used to address this problem because they can reprogram myeloid-derived suppressor cells (MDSCs) and tumor-associated M2 macrophages, and boost dendritic cell (DC)-based T-cell generation; however, the systemic toxicity of TLR7/8a limits its clinical translation. Here, to address this limitation and utilize the effectiveness of TLR7/8a, this work suggests a programmed two-step activation strategy via Antibody-Trojan Immune Converter Conjugates (ATICC) that specifically targets myeloid cells by anti-SIRPα followed by reactivation of transiently inactivated Trojan TLR7/8a after antibody-mediated endocytosis. ATICC blocks the CD47-SIRPα ("don't eat me" signal), enhances phagocytosis, reprograms M2 macrophages and MDSCs, and increases cross-presentation by DCs, resulting in antigen-specific CD8 + T-cell generation in tumor-draining lymph nodes and TME while minimizing systemic toxicity. The local or systemic administration of ATICC improves ICBT responsiveness through reprogramming of the immunosuppressive TME, increased infiltration of antigen-specific CD8 + T cells, and antibody-dependent cellular phagocytosis. These results highlight the programmed and target immunomodulation via ATICC could enhance cancer immunotherapy with minimized systemic toxicities., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Intratumoral immunotherapy holds promise for improving cancer treatment efficacy. However, rapid clearance from the tumor upon bolus volume injections limits efficacy and impedes assessment of dose-dependent effects on the tumor immune microenvironment (TIME). To this end, we developed a drug-agnostic nanofluidic implant to deliver immunotherapy within the tumor, providing a mechanism for sustained and controlled intratumoral dosing. Diffusive drug elution from the implant reservoir is controlled by a nanofluidic membrane, which abrogates rapid drug elimination from the tumor and maximizes immunotherapy localization. Here we first achieve in vitro sustained release of agonist CD40 monoclonal antibody (mAb), anti-programmed death ligand-1 (PDL1) mAb, and immune-cell targeted polymeric prodrugs of Resiquimod (toll-like receptor 7/8,TLR 7/8) and a small molecule STING agonist. We then demonstrated in vivo sustained intratumoral drug localization of agonist CD40 Ab and anti-PDL1 Ab in the 4T1 murine model of triple-negative breast cancer (TNBC). Further, we show highly effective anti-tumor efficacy with radiation therapy and sustained intratumoral co-delivery of agonist CD40 Ab and anti-PDL1 Ab in the EMT6 TNBC murine model. Finally, we demonstrate the versatility of this implant by showing that sustained intratumoral delivery of the STING or Resiquimod polymeric prodrugs strongly inhibits 4T1 tumor growth. Collectively, these results support our nanofluidic system as a therapeutic platform technology to investigate sustained intratumoral dosing of immunotherapy. [Display omitted] • Intratumoral implant achieves tunable and sustained dosing of immunotherapeutics in the tumor. • Sustained intratumoral administration of immunotherapeutics shows high activity in rodent EMT6 and 4T1 tumor models. • Drug-agnostic implant enables powder drug payloads for higher loading efficiency and controlled intratumoral release profiles. [ABSTRACT FROM AUTHOR]

Vaccination for cancers arising from human papillomavirus (HPV) infection holds immense potential, yet clinical success has been elusive. Herein, we describe vaccination studies involving spherical nucleic acids (SNAs) incorporating a CpG adjuvant and a peptide antigen (E7 11-19 ) from the HPV-E7 oncoprotein. Administering the vaccine to humanized mice induced immunity-dependent on the oligonucleotide anchor chemistry (cholesterol vs (C12) 9 ). SNAs containing a (C12) 9 -anchor enhanced IFN-γ production >200-fold, doubled memory CD8 + T-cell formation, and delivered more than twice the amount of oligonucleotide to lymph nodes in vivo compared to a simple admixture. Importantly, the analogous construct with a weaker cholesterol anchor performed similar to admix. Moreover, (C12) 9 -SNAs activated 50% more dendritic cells and generated T-cells cytotoxic toward an HPV + cancer cell line, UM-SCC-104, with near 2-fold greater efficiency. These observations highlight the pivotal role of structural design, and specifically oligonucleotide anchoring strength (which correlates with overall construct stability), in developing efficacious therapeutic vaccines.

Activation of the innate immune system counteracts tumor-induced immunosuppression. Hence, small molecule-based toll-like receptor 7/8 agonists (TLR7/8a), which can modulate immunosuppression in the tumor microenvironment along with the activation of innate immunity, are emerging as essential components of cancer immunotherapy. However, the clinical application of synthetic TLR7/8a therapies is limited by systemic immune-associated toxicity and immune tolerance induced by uncontrolled stimulatory activities and repeated treatments. To address these limitations, a dynamic immunomodulation strategy incorporating masking and temporal recovery of the activity of TLR7/8a through prodrug-like TLR7/8a (pro-TLR7/8a) at the molecular level and a sustained and controlled release of active TLR7/8a from nanoliposome (pro-TLR7/8a) (NL(pro-TLR7/8)) in a macroscale depot are designed. Immunization with cationic NL(pro-TLR7/8) and anionic antigens triggers robust activation of innate immune cells as well as antigen-specific T cell responses, eliciting reprogramming of immunosuppressive cells into tumor-suppressive cells, with decreased systemic adverse effects and immune tolerance. Combination treatment with NL(pro-TLR7/8a) and immune checkpoint inhibitors (anti-CTLA-4 plus anti-PD-L1) or nanoliposomes (Doxorubicin) has synergistic effects on antitumor immunity in various tumor models. The concept of pro-TLR7/8a suggested herein may facilitate the advancement of small-molecule-based immunomodulators for clinical translation and safe and effective cancer immunotherapy., (© 2023 Wiley-VCH GmbH.)

Small molecule adjuvants are attractive for enhancing broad protection and durability of immune responses elicited by subunit vaccines. Covalent attachment of an adjuvant to an immunogen is particularly attractive because it simultaneously delivers both entities to antigen presenting cells resulting in more efficient immune activation. There is, however, a lack of methods to conjugate small molecule immune potentiators to viral glycoprotein immunogens without compromising epitope integrity. We describe herein a one-step enzymatic conjugation approach for the covalent attachment of small molecule adjuvants to N-linked glycans of viral glycoproteins. It involves the attachment of an immune potentiator to CMP-Neu5AcN 3 by Cu(I)-catalyzed azide-alkyne 1,3-cycloaddition followed by sialyltransferase-mediated transfer to N-glycans of a viral glycoprotein. The method was employed to modify a native-like HIV envelope trimer with a Toll-like receptor 7/8 agonist. The modification did not compromise Env-trimer recognition by several broadly neutralization antibodies. Electron microscopy confirmed structural integrity of the modified immunogen., (© 2022 The Authors. ChemBioChem published by Wiley-VCH GmbH.)