Mature Dendritic Cells Research Articles

Biomimetic Metallacage Nanoparticles with Aggregation-Induced Emission for NIR-II Fluorescence Imaging-Guided Synergistic Immuno-Phototherapy of Tumors.

The integration of theranostics, which combines diagnostics with therapeutics, has markedly improved the early detection of diseases, precise medication management, and assessment of treatment outcomes. In the realm of oncology, organoplatinum-based supramolecular coordination complexes (SCCs) that can coload therapeutic agents and imaging molecules have emerged as promising candidates for multimodal theranostics of tumors. To address the challenges of tumor-targeted delivery and multimodal theranostics for SCCs, this study employs a cell membrane cloaking strategy to fabricate biomimetic metallacage nanoparticles (MCNPs) with multimodal imaging capabilities and homologous targeting capabilities. Specifically, a photosensitizer molecule (BTTP) containing AIE-active groups was assembled into a metallacage of C-BTTP through Pt-N coordination. This process endows the metallacage with strong NIR-II fluorescence in the aggregated state and significantly superior ROS generation compared to that of the precursor ligand. After being encapsulated with F127, the MCNPs were further cloaked with U87 cancer cell membranes, creating biomimetic MCNPs that achieve tumor-targeting capabilities. Verified by in vitro and in vivo experiments, MCNPs enable multimodal imaging and initiate immunotherapy under photothermal and photodynamic stimulation, leading to synergistic antitumor effects. Furthermore, the evaluation of immunogenic cell death and dendritic cell maturation rate in U87 tumor-bearing mice confirmed the mechanism of photothermal and photodynamic synergistic immunotherapy. This study provides an innovative strategy for enhancing the tumor-targeting and therapeutic efficiency of SCCs, offering a versatile strategy for efficient and minimally invasive theranostics of tumors. The development of such biomimetic nanoparticles represents a significant advancement in the field of nanomedicine, potentially transforming cancer treatment through personalized and targeted therapies.

Configuration-Mediated Efficient Non-Radiative Transition for R848-Assisted Photothermal Immunotherapy to Inhibit Tumor Growth andMetastasis by AnIn Situ Tumor Vaccine Strategy.

Cancer metastasis remains a critical factor contributing to the current limitations in cancer treatment. Photothermal immunotherapy has emerged as a safe and potent therapeutic approach, demonstrating the capability to suppress tumor growth and metastasis. While researchers have extensively investigated various structural modifications to enhance photothermal conversion performance, the influence of molecular configuration has received comparatively limited attention. In this study, we synthesized two isomers, CZTBT and LVTBT, which possessed distinct configurations. LVTBT, characterized by a flatter molecular configuration, exhibited an extended absorption wavelength and a higher molar extinction coefficient. Its excited state facilitated stronger rotation for non-radiative transitions, leading to a high photothermal conversion efficiency (PCE) of 36.3%. When combined with R848, LVTBT@R848 nanoparticles (NPs)-mediated photothermal immunotherapy functioned as an in situ tumor vaccine, promoting the maturation of dendritic cells (DCs), T cell infiltration, and the differentiation of natural killer (NK) cells and memory T cells, thereby activating the strong immune response. Consequently, it significantly inhibited the growth of both primary and distant tumors, while also limiting lung metastasis. In summary, this study proposed a configuration-mediated non-radiative transition strategy for efficient photothermal immunotherapy, advancing the frontiers of organic photothermal agents (OPTAs) design and synthesis.

Configuration‐Mediated Efficient Non‐Radiative Transition for R848‐Assisted Photothermal Immunotherapy to Inhibit Tumor Growth and Metastasis by An In Situ Tumor Vaccine Strategy

Cancer metastasis remains a critical factor contributing to the current limitations in cancer treatment. Photothermal immunotherapy has emerged as a safe and potent therapeutic approach, demonstrating the capability to suppress tumor growth and metastasis. While researchers have extensively investigated various structural modifications to enhance photothermal conversion performance, the influence of molecular configuration has received comparatively limited attention. In this study, we synthesized two isomers, CZTBT and LVTBT, which possessed distinct configurations. LVTBT, characterized by a flatter molecular configuration, exhibited an extended absorption wavelength and a higher molar extinction coefficient. Its excited state facilitated stronger rotation for non‐radiative transitions, leading to a high photothermal conversion efficiency (PCE) of 36.3%. When combined with R848, LVTBT@R848 nanoparticles (NPs)‐mediated photothermal immunotherapy functioned as an in situ tumor vaccine, promoting the maturation of dendritic cells (DCs), T cell infiltration, and the differentiation of natural killer (NK) cells and memory T cells, thereby activating the strong immune response. Consequently, it significantly inhibited the growth of both primary and distant tumors, while also limiting lung metastasis. In summary, this study proposed a configuration‐mediated non‐radiative transition strategy for efficient photothermal immunotherapy, advancing the frontiers of organic photothermal agents (OPTAs) design and synthesis.

Bicalutamide Reveals Immunomodulatory Effects in Prostate Cancer by Regulating Immunogenic Dendritic Cell Maturation

Prostate cancer poses a significant global health challenge, ranking as the second most prevalent and fifth most lethal malignancy among males. The intricate interplay between androgen signaling and the immune microenvironment underscores the complexity of prostate cancer progression. Notably, androgen receptor (AR) signaling has been shown to affect immune response mediated by tumor antigen-presenting dendritic cells (DCs). Therefore, this study aimed to explore the potential of Bicalutamide, a nonsteroidal anti-androgen, in modulating DCs-mediated immune responses. Peripheral blood mononuclear cells (PBMCs) were isolated, and monocytes were extracted, followed by their differentiation into immature dendritic cells (iDCs) using GM-CSF and IL-4. Harvested tumor cell lysates from human prostate cancer cells were then utilized to induce the transformation of iDCs into mature dendritic cells (mDCs). Then, mDCs were treated with non-toxic concentration of Bicalutamide determined by annexin V/PI assay. The morphological characteristics of mDCs were investigated using an inverted light microscope. Flow cytometry was used to determine the cell surface expression of molecular markers of DC maturation, and qRT-PCR was employed to evaluate expression levels of proinflammatory genes involved in DC maturation. The obtained results indicated that Bicalutamide treatment of monocyte-derived mDCs induces an immunogenic and matured phenotype, marked by increased expression of CD86 and HLA-DR. Besides, qRT-PCR results evidenced that Bicalutamide decreased the expression of anti-inflammatory genes, including Interleukin-10 (IL-10) and TGF-beta, as an indication of immunogenic DCs. These findings suggest that beyond its established anti-androgen role, Bicalutamide may exert anti-tumor effects through the modulation of DCs-mediated immune responses. This novel immunomodulatory feature holds promise for the development of novel therapies, including combination therapies, in prostate cancer treatment.

066 ANB032, an Investigational BTLA Checkpoint Agonist Antibody, Attenuates Dendritic Cell (DC) Maturation and Function: A Novel Mechanism Addressing Atopic Dermatitis (AD) Pathophysiology

066 ANB032, an Investigational BTLA Checkpoint Agonist Antibody, Attenuates Dendritic Cell (DC) Maturation and Function: A Novel Mechanism Addressing Atopic Dermatitis (AD) Pathophysiology

Bioengineering human heavy-chain nanoferritin for glioblastoma multiforme-specific delivery and efficient immunotherapy

The blood–brain barrier (BBB) caused limited drug accumulation and programmed death-ligand 1 (PD-L1) compromised immunosuppressive microenvironment are bottlenecks in glioblastoma multiforme (GBM) treatment. Herein, we bioengineered a human heavy chain nanoferritin (HTE NPs) for GBM-specific delivery and efficient immunotherapy. To achieve targeted mitochondrial metabolic regulation, we connected triphenylphosphonium (TPP) with the photosensitive agent IR780 to form T780, which self-assembles with esomeprazole magnesium (EM) and human H-ferritin (HFn) to obtain HTE NPs. HFn endows HTE NPs with BBB penetration and specific site-targeting capabilities, thereby enhancing tumor accumulation and pH-responsive release within GBM cells. T780 subsequently induces mitochondrial damage, activating the AMP-dependent protein kinase (AMPK) pathway and blocking the transmission of T-cell inhibitory signals through the phosphorylation of PD-L1, thereby promoting T-cell activation. Moreover, EM inhibits the release of extracellular vesicles (EVs), reducing the inhibitory effect of PD-L1 on circulating T cells. Furthermore, mitochondrial impairment-induced mitochondrial DNA (mtDNA) leakage activates the cGAS-STING signaling pathway, inducing the maturation of dendritic cells (DCs), recruiting supportive immune cells to clear GBM cells, and improving the immunosuppressive microenvironment. Therefore, HTE NPs not only achieve efficient tumor accumulation but also facilitate the activation immune response, providing a promising strategy for the clinical treatment of GBM.

Antimonene and bacterial outer membrane vesicle modification nanoplatform enhanced photothermal immunotherapy

Photothermal therapy and immunotherapy have attracted widespread attention because of their great advantages for enhancing the effectiveness of cancer treatment and reducing side effects. However, they also have their own shortcomings. Based on the characteristics of photothermal therapy and immunotherapy, functionalized nanoparticle-mediated photothermal-immune synergistic therapy can effectively compensate for their respective deficiencies and produce synergistic effects. Herein, we designed a bioengineering strategy to construct a novel anticancer nanoplatform (AM@DSPE-PEG/OMV) for photothermal-immunotherapy of cancer by coating bacterial outer membrane vesicles onto polyethylene glycolized antimony alkene nanosheets (AM@DSPE-PEG). Bacterial outer membrane vesicles (OMV) have emerged as potent activators of the host immune response in the realm of cancer immunotherapy. In conjunction with near-infrared light irradiation, antimonene nanosheets demonstrate remarkable photothermal properties, thereby instigating immunogenic cell death and facilitating the release of both antigens and "danger signals". This dual mechanism facilitates the thermal ablation of primary tumors, thereby eliciting an immune response. Additionally, these processes further stimulate the maturation of dendritic cells, consequently augmenting antigen presentation and fortifying the immune response. Thus, the synergistic utilization of OMV and antimonene nanosheets holds promise in enhancing the efficacy of immunotherapeutic interventions for cancer. We demonstrated that AM@DSPE-PEG/OMV can passively target tumors, exhibit excellent biocompatibility and superior photothermal conversion efficiency, significantly upregulate the secretion levels of cellular pro-inflammatory factors, and display outstanding cytotoxic effects against cancer cells in vitro. In summary, this bioengineering strategy displayed a broader prospect for photothermal-immunotherapy synergy.

Chitosan-coated PLA/poloxamer nanoparticles stimulate immunologic cancer cell death and synergistic chemo-immunotherapeutic efficacy

Cancer, a key factor in declining global life expectancy, has driven the integration of chemotherapy and immunotherapy to address multidrug resistance and influence the tumor microenvironment. We developed a novel vaccine delivery carrier, a chitosan-coated polylactic acid/poloxamer nanoparticle (CPP NP), designed to co-encapsulate an anticancer drug and antigen without any chemical conjugation process, enabling effective and synergistic cancer chemo-immunotherapy. The CPP NP achieved synergistic efficacy through paclitaxel (PTX), an immunogenic cell death-inducing chemotherapeutic agent; ovalbumin (OVA), which promotes dendritic cell maturation; and enhanced cellular uptake facilitated by chitosan. The PTX and OVA-loaded CPP NPs (PTX/OVA@CPP NPs) were stable in PBS for four weeks and resuspended well after lyophilization without any cryoprotectants. Moreover, PTX and OVA from the NPs exhibited a sustained release rate and pH-responsive release pattern within different cellular microenvironments. Importantly, PTX@CPP NPs exhibited much higher anticancer efficacy across various cancer cell lines, even multidrug-resistant cells, compared to free PTX and PTX@PP NPs without the chitosan coating. In antigen-presenting cells, OVA@CPP NPs led to higher IL-2 secretion and cellular uptake compared to free OVA and OVA@PP NPs. Furthermore, in a tumor-bearing mouse model, PTX/OVA@CPP NPs exhibited strong synergistic tumor suppression and triggered OVA antigen-specific responses, promoting an antitumor immune response. These findings demonstrate that PTX/OVA@CPP NPs show potential as new chemo-immunotherapeutic agents for effective cancer treatment.

Respiratory delivery of single low-dose nebulized PFCE-C25 NEs for lymphatic transport and durable stimulation of antitumor immunity in lung cancer.

The currently available immune checkpoint inhibitors (ICIs) often fail to achieve the desired clinical outcomes due to inadequate immune activation, particularly in patients with lung cancer. To reverse this situation, we synthesized inhalable PFCE-C25 nanoemulsions (NEs), which target lymphocyte activation genes (LAG-3) on immune cells within tumor microenvironment and tumor-draining lymph nodes (TDLNs). By combining in vivo 19F-MR molecular imaging, we investigate the immunological effects of a single low-dose PFCE-C25 NEs in multiple murine lung cancer models, including human immune system (HIS) mouse models, and validated its immunological effects in human TDLNs. The nebulization therapy with PFCE-C25 NEs demonstrated a notable and enduring maturation of dendritic cells (DCs) in TDLNs, leading to systemic immune responses, prolonged survival, the establishment of immune memory, and resistance to tumor rechallenge. Thus, PFCE-C25 NEs successfully demonstrate a promising and efficient approach for enhancing lymphatic transport and sustained activation of antitumor immune responses in lung cancer.

Manganese improves anti-PD-L1 immunotherapy via eliciting type I interferon signaling in melanoma.

The immune checkpoint inhibitor therapy represented by blocking programmed cell death protein 1/ programmed cell death-ligand 1 (PD-1/PD-L1) has made significant progress in melanoma treatment. However, the response rate and therapeutic effect of immunotherapy alone are still not ideal for melanoma. In this study, we aimed to evaluate the defects of treating anti-PD-L1 alone and the therapeutic effect and molecular mechanism of combined therapy with anti-PD-L1 and MnCl2. We detected the changes of immune cell populations after anti-PD-L1 treatment in melanoma xenograft mouse model. Further, we evaluated the regulatory effect of MnCl2 on dendritic cells (DCs) maturation in vitro. Next, we tested the therapeutic effect and regulatory effect on the tumor microenvironment with anti-PD-L1 and MnCl2 via combining treatment with anti-PD-L1 and MnCl2. Anti-PD-L1 therapy has a certain tumor suppressive function, but the effect is not ideal. The results of flow cytometry showed that the number of CD4+ T cells and CD8+ T cells significantly increased after anti-PD-L1 treatment. However, the number of DCs remained basically unchanged after anti-PD-L1 treatment. In vitro, we confirmed that MnCl2 significantly promoted DCs maturation vis activating cGAS-STING signaling pathway. The combination of anti-PD-L1 and MnCl2 displayed the best tumor suppression effect in melanoma xenograft mouse model. In tumor microenvironment, the infiltration of T cells and the maturation of DCs were significantly promoted, demonstrating a strong anti-tumor immune response. In summary, we conclude that combining anti-PD-L1 with MnCl2 is a promising therapeutic strategy for melanoma.

Engineering Autologous Cell-Derived Exosomes to Boost Melanoma-Targeted Radio-Immunotherapy by Cascade cGAS-STING Pathway Activation.

Radio-immunotherapy has offered emerging opportunities to treat invasive melanoma due to its immunostimulatory performances to activate antitumor immune responses. However, the immunosuppressive microenvironment and insufficient response rate significantly limit the practical efficacy. This study presents an autologous cell-derived exosomes (Exo)-engineered nanoagonist (MnExo@cGAMP) containing with metalloimmunotherapeutic agent (Mn2+ ions) and nucleotidyltransferase (2',3'-cGAMP, a STING agonist) for boosting melanoma-targeted radio-immunotherapy by cascade cGAS-STING pathway activation. The MnExo@cGAMP can efficiently accumulate in tumor cells due to the autologous targeting performance. Once internalized by tumor cells, the released Mn2+ ions will enhance stimulator of interferon gene (STING) binding and sensitize cyclic GMP-AMP (cGAS) to radiotherapy-induced double-straned DNA (dsNDA), resulting in amplification of cGAS-STING pathway activation together with X-ray irradiation. Meanwhile, loaded 2',3'-cGAMP can directly augment pathway activity acting as a secondary messenger. These cascade activations of cGAS-STING pathway trigger the overexpression of type I interferon, promote dendritic cells (DCs) maturation, antigen presentation, and increase CD8+ T cell activation, resulting effective radio-immunotherapeutic outcome by overcoming immune-suppression in melanoma. This study demonstrates a targeted therapeutic modality involving metalloimmunotherapy and agonist for efficient melanoma radio-immunotherapy by cascade cGAS-STING pathway activation.

Photothermal-Triggered Extracellular Matrix Clearance and Dendritic Cell Maturation for Enhanced Osteosarcoma Immunotherapy.

Osteosarcoma, a predominant malignant tumor among adolescents, exhibits high mortality and suboptimal immunotherapy efficacy due to a collagen-dense extracellular matrix (ECM) that hinders cytotoxic T lymphocyte (CTL) infiltration. Herein, we developed mesoporous polydopamine (MPDA) nanoparticles encapsulating bromelain and the immune adjuvant R848 (M@B/R), aimed at enhancing photothermal immunotherapy. These nanoparticles efficiently accumulate at the tumor site following injection. Upon near-infrared (NIR) light irradiation, photothermal therapy (PTT) induces immunogenic cell death in tumor cells and, with the aid of R848, efficiently promotes dendritic cell maturation, activating antitumor immunity and leading to CTL infiltration into the tumor. Concurrently, NIR-induced heating activates bromelain, resulting in ECM degradation and improved CTL penetration into the tumor. Our in vivo evaluations demonstrate potent antitumor effects in osteosarcoma-bearing mice. This integrated approach offers a promising strategy for overcoming physical barriers in ECM-rich tumors, marking a significant advancement in the treatment of osteosarcoma.

A hyaluronic acid-based dual-functional hydrogel microneedle system for sequential melanoma ablation and skin regeneration

Melanoma treatment remains a challenge due to the inadequacy of existing clinical approaches and the difficulty of tissue regeneration. Recently, microneedles have been widely studied in tumor therapy and skin repair. Hence, a hyaluronic acid (HA)-based dual-functional hydrogel microneedle (MN) system was constructed to sequentially achieve tumor ablation and skin regeneration. Carbon nanotubes@calcium peroxide@tannic acid-Fe/chlorin e6 (CCa@TF/Ce6) nanomaterial was encapsulated in dissolvable polyvinyl alcohol/polyvinylpyrrolidone tips and accurately released to the tumor site to suppress melanoma via the photothermal and photodynamic therapies under the dual laser irradiation due to the generation of reactive oxygen species (ROS) and heat. Particularly, ROS and heat triggered immunogenic cell death, promoted dendritic cells maturation and reshaped the tumor-associated macrophage phenotype from the protumor M2 phenotype to the anti-tumor M1 phenotype, ultimately activating autoimmunity to eliminate the tumor. Following tumor ablation, the MN base accelerated skin regeneration owing to HB-PVA hydrogel through reducing oxidative stress, promoting cell proliferation and facilitating cell migration. Overall, the dual-functional hydrogel MN designed in this study, offers a new avenue for sequential melanoma combination treatment and skin regeneration.

Dual-Targeted Assembled Nanodrugs for Near-Infrared Photothermal Immunotherapy of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is known for its poor prognosis and aggressive behavior, being highly prone to recurrence and metastasis, and currently has limited effective treatment options. Photothermal therapy (PTT) is an emerging, minimally invasive, low-drug-resistance, and precisely controllable therapeutic method for cancer treatment, offering hope to break through the bottleneck in TNBC therapy. The antitumor efficiency of PTT is predominantly contingent upon the performance of the photothermal drugs. Therefore, there is an urgent need to develop photothermal drugs that not only have excellent photothermal conversion efficiency but also possess strong tumor-targeting capabilities and good biosafety. Here, we have developed a tumor-targeted photothermal agent with near-infrared (NIR) absorption capability based on the strategy of biomolecular assembly, utilizing biliverdin manganese complexes (MnBV) and amphiphilic phospholipid-polymer conjugates (DSPE-PEG and DSPE-PEG-cKNGRE). This photothermal assembled drug exhibits a uniform size, good stability, and ideal photothermal conversion efficiency. In the 4T1 tumor-bearing mouse model of TNBC, it shows good tumor dual-targeting capabilities and a significant drug enrichment performance. While ablating the primary tumor, PTT further stimulates the maturation of dendritic cells (DCs), enhancing the infiltration of T lymphocytes into the spleen and tumor, thus reshaping the immune microenvironment of TNBC and thereby effectively inhibiting tumor metastasis and recurrence. The developed photothermal assembled drug provides an innovative candidate treatment paradigm for TNBC, offering the potential to advance precise, targeted, and safe therapy for highly invasive and aggressive malignancies.

Cascade Bilateral Regulation of Ferroptosis and Immune Activation Conducted by the Electron-Accepting-Inspired Glycopolymer-Based Nanoreactor.

The immunosuppressive tumor environment, characterized by elevated redox levels, significantly impairs the effectiveness of oxidation and the immune response. Here, an electron-accepting-inspired glycopolymer-based nanoreactor (chitosan-grafted nitrobenzene nanoparticles) CNP employing hypoxia-activated group nitrobenzene was constructed to realize cascade bilateral regulation of ferroptosis and immune activation by intervening antioxidant systems. The as-prepared CNP could consume nicotinamide adenine dinucleotide phosphate (NADPH) in the hypoxia-response process, allowing it to be involved in the recycling of glutathione (GSH) and thioredoxin (Trx). This ultimately affects redox homeostasis, leading to reduced GSH levels, increased reactive oxygen species (ROS), and inhibition of (glutathione peroxidase 4) Gpx4. By taking advantage of the sensitivity difference between tumor cells and dendritic cells (DCs) to the ferroptosis inducer erastin (Er) based on varying xCT expression levels, we developed Er-loaded nanoparticles CNP/Er. These nanoparticles not only enhance ferroptosis in 4T1 cells through Gpx4 inhibition by CNP but also promote DC maturation by utilizing CNP's hypoxia-responsive mechanism to increase ROS levels. The CNP/Er was believed to be an ideal candidate for bilateral regulation of ferroptosis and immune activation in one nanoreactor.

A trinity STING-activating nanoparticle harnesses cancer cell STING machinery for enhanced immunotherapy

The cGAS-STING axis is a promising therapeutic target against cancer. However, most activators require STING signaling in the host, especially within antigen-presenting cells, which are rare in a cold tumor microenvironment. The cGAS-STING cascade is also present within cancer cells but with suppressed activity. Such a paradoxical situation may account for the clinical failures. Herein, we develop a trinity STING-activating nanoparticle (CMTP) coordinated with cGAMP, Mn3+, and porphyrin to awaken autologous STING signaling in cancer cells. CMTP disintegrates into Mn2+ and TCPP upon elevated glutathione in cancer cells, where TCPP triggers mitochondrial DNA leakage, enhancing cGAS enzymatic activity in coordination with Mn2+, while concurrent cGAMP release from framework synergizes to amply STING activity. Consequently, CMTP exploits cancer cells as reservoirs for cGAS-STING signaling to promote DC maturation and T cell priming. A single administration of CMTP demonstrates robust efficacy in both hot MC38 and cold 4 T1 murine tumors. Genetic knockout studies confirm that STING in cancer cells, rather than in the host, is critical for antitumor performance. The feasibility of immune modulation is further validated in resected human patient tissues. This work presents a potent STING-activating nanomedicine based on coordination chemistry and underscores the potential of harnessing cancer cells' autologous cGAS-STING machinery in immunotherapy.

Autophagy-activating aluminum hydroxide nanovaccine for enhanced antigen presentation and anti-tumor immunity

Lymph node (LN) targeting and antigen presentation by antigen-presenting cells (APCs) are critical factors affecting the immune responses induced by tumor vaccines. Autophagy activation promotes MHC class I and II antigen presentation in APCs. To enhance antigen presentation in LNs, we developed an aluminum hydroxide nanovaccine that simultaneously incorporates the autophagy-activating peptide Beclin-1 and the antigenic protein OVA (B/O@AN nanovaccine) through layer-by-layer electrostatic interaction. B/O@AN has a particle size of approximately 80 nm and efficiently targets lymph nodes following subcutaneous administration. The combination of the Beclin-1 peptide with the aluminum hydroxide nanovaccine promotes dendritic cell (DC) maturation. More importantly, B/O@AN facilitates antigen cross-presentation by promoting lysosomal escape and autophagy induction. After immunization, compared to O/@AN without Beclin-1, B/O@AN significantly augments antigen-specific cellular immune responses, leading to substantial increases in cytotoxic T lymphocytes (CTLs), T-helper 1 (Th1) cells, as well as serum antibody levels, thereby impeding melanoma development and progression in both prophylactic and therapeutic settings. These results provide evidence that autophagy activation strengthens antigen presentation and augments the antigen-specific immune responses of the aluminum hydroxide nanovaccine.

An inducible RIPK3-driven necroptotic system enhances cancer cell-based immunotherapy and ensures safety.

Recent progress in cancer cell-based therapies has led to effective targeting and robust immune responses against cancer. However, the inherent safety risks of using live cancer cells necessitate the creation of an optimized safety switch without hindering the efficacy of immunotherapy. The existing safety switches typically induce tolerogenic cell death, potentially leading to an immunosuppressive tumor immune microenvironment (TIME), which is counterproductive to the goals of immunotherapy. Here, we developed and characterized an inducible RIPK3-driven necroptotic system that serves as a dual function of safety switch as well as inducing immunogenic cell death which in turn stimulates antitumor immune responses. We showed that activating RIPK3 safety switch triggered immunogenic responses marked by an increased release of adenosine triphosphate (ATP) and damage-associated molecular patterns (DAMPs). Compared to other existing safety switches, incorporating RIPK3 system inhibited tumor growth, improved survival outcomes in tumor-bearing mice, and fostered long-term antitumor immunity. Moreover, RIPK3 system reinvigorated the TIME by promoting dendritic cell (DC) maturation, polarizing the macrophages towards the M1 phenotype, and reducing the exhaustion of CD4+ and CD8+ T lymphocytes. Our study highlights the dual role of RIPK3-driven necroptotic system in improving the safety and efficacy of cancer cell-based therapy, with broader implications for cellular therapies.

STING-activating photo-vaccination with glutamine metabolism reprogramming and cascade mitochondrial dysfunction for robust immune landscape remodeling

Autologous tumor cells hold great promise as personalized therapeutic vaccines. Nevertheless, the metabolic competition between tumor cells and the functional immune cells limits patient responses to autologous vaccine via fostering immunosuppressive microenvironment and facilitating immune escape. Herein, the STING-activating Photo-vaccination Inducer (BMA) is developed which can shift in immunological state from “cold” to “hot” by tumor metabolic reprogramming and the release of autologous tumor vaccines. BMA can form into peroxidase mimics in situ upon external energy stimulation,enabling continuous production of reactive oxygen species (ROS) through photodynamic effects and photosensitizer recycling. Tumor metabolic reprogramming with continually ROS generation facilitates maturation of dendritic cells (DCs) and reeducation of tumor immune landscapedue tospatiotemporallycascading mitochondrial and nucleus dysfunction, leading to in situ nucleic acid vaccine release and stimulator of the interferon genes (STING) pathway activation. As anticipated, results from Cytometry by Time-Of-Flight (CyTOF) results indicate that the tumor landscape has been altered, effectively eradicating primary tumors and inducing beneficial “Abscopal Effects” that counteract checkpoint blockade (ICB) resistance. Our work for the first time leverages a universal and novel strategy of free radical therapy and personalized therapeutic vaccine for tumor immunoscape re-education thereby enhancing αPD-L1 blockade, presenting a rational way to surmount immunotherapy barriers to available clinical treatments.

Discovery of Active Ingredient of Yinchenhao Decoction Targeting TLR4 for Hepatic Inflammatory Diseases Based on Deep Learning Approach.

Yinchenhao Decoction (YCHD), a classic formula in traditional Chinese medicine, is believed to have the potential to treat liver diseases by modulating the Toll-like receptor 4 (TLR4) target. Therefore, a thorough exploration of the effective components and therapeutic mechanisms targeting TLR4 in YCHD is a promising strategy for liver diseases. In this study, the AIGO-DTI deep learning framework was proposed to predict the targeting probability of major components in YCHD for TLR4. Comparative evaluations with four machine learning models (RF, SVM, KNN, XGBoost) and two deep learning models (GCN, GAT) demonstrated that the AIGO-DTI framework exhibited the best overall performance, with Recall and AUC reaching 0.968 and 0.991, respectively.This study further utilized the AIGO-DTI model to identify the potential impact of Isoscopoletin, a major component of YCHD, on TLR4. Subsequent wet experiments revealed that Isoscopoletin could influence the maturation of Dendritic Cells (DCs) induced by Lipopolysaccharide (LPS) through TLR4, suggesting its therapeutic potential for liver diseases, especially hepatitis. Additionally, based on the AIGO-DTI framework, this study established an online platform named TLR4-Predict to facilitate domain experts in discovering more compounds related to TLR4. Overall, the proposed AIGO-DTI framework accurately predicts unique compounds in YCHD that interact with TLR4, providing new insights for identifying and screening lead compounds targeting TLR4.