ß-Mangostin targets and suppresses glioma via STING activation and tumor-associated microglia polarization.

Glioma, a common and highly malignant central nervous system tumor, markedly influences patient prognosis via interactions with glioma-associated macrophages. Previous research has revealed the anticancer potential of ß-mangostin, a xanthone derivative obtained from the mangosteen fruit. This research investigated the role of ß-mangostin on microglia in the glioma microenvironment and evaluated the efficacy of ß-mangostin combined with anti-PD-1 antibody (αPD-1) in glioma-bearing mice. The results showed that, ß-mangostin attenuated M2 polarization in BV2 cells and promoted M1-related interleukin (IL)-1ß and IL-6 secretion, thereby inhibiting glioma invasion. In addition, ß-mangostin improved the anti-glioma effects of αPD-1 and increased CD8+T cell and M1-type microglia infiltration. Mechanistically, ß-mangostin bound to the stimulator of interferon genes (STING) protein, which is crucial for the anti-tumor innate immune response, and promoted STING phosphorylation in microglia, both in vivo and in vitro. These results provide insights into its mode of action and supporting further investigation into ß-mangostin as a therapeutic agent.

Dihydroartemisinin breaks the immunosuppressive tumor niche during cisplatin treatment in Hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma, characterized by high mortality rates, often exhibits limited responsiveness to conventional treatments such as surgery, radiotherapy, and chemotherapy. Therefore, identifying a sensitizer for cisplatin has become crucial. Dihydroartemisinin, known for its potent role of tumor treatment, arises as a prospective candidate for cisplatin sensitization in clinical settings. METHODS: A mouse model of liver tumor was established through chemical induction of DEN/TCPOBOP. Upon successful model establishment, ultrasound was employed to detect tumors, Hematoxylin and eosin staining was conducted for observation of liver tissue pathology, and ELISA was utilized to assess cytokine changes (IFN-γ, IL-2, IL-4, IL-10, TGF-ß, IL-1ß, CCL2, and CCL21) in peripheral blood, para-tumor tissues, and tumor tissues. The infiltration of CD8+T cells and macrophages in tumor tissue sections was detected by immunofluorescence. RESULTS: Dihydroartemisinin combined with cisplatin obviously restrained the growth of liver tumors in mice and improved the weight and spleen loss caused by cisplatin. Cisplatin treatment of liver tumor mice increased the content of CCL2 and the number of macrophages in tumor tissues and promoted the formation of an immunosuppressive microenvironment. The combination therapy decreased the content of TGF-ß in tumor tissues while increasing CCL2 levels in para-tumor tissues. Both combination therapy and cisplatin alone increased the number of CD8+T cells in tumor tissue, but there was no difference between them. CONCLUSION: Dihydroartemisinin combined with cisplatin obviously prevented the deterioration of liver tumor in hepatocellular carcinoma mice and improve the therapeutic effect of cisplatin by improving the immunosuppressive microenvironment induced by cisplatin. Our findings provide a theoretical basis for considering dihydroartemisinin as an adjuvant drug for cisplatin in the treatment of hepatocellular carcinoma in the future.

Potentiating dual-directional immunometabolic regulation with nanomedicine to enhance anti-tumor immunotherapy following incomplete photothermal ablation.

Photothermal therapy (PTT) is a promising cancer treatment method due to its ability to induce tumor-specific T cell responses and enhance therapeutic outcomes. However, incomplete PTT can leave residual tumors that often lead to new metastases and decreased patient survival in clinical scenarios. This is primarily due to the release of ATP, a damage-associated molecular pattern that quickly transforms into the immunosuppressive metabolite adenosine by CD39, prevalent in the tumor microenvironment, thus promoting tumor immune evasion. This study presents a photothermal nanomedicine fabricated by electrostatic adsorption among the Fe-doped polydiaminopyridine (Fe-PDAP), indocyanine green (ICG), and CD39 inhibitor sodium polyoxotungstate (POM-1). The constructed Fe-PDAP@ICG@POM-1 (FIP) can induce tumor PTT and immunogenic cell death when exposed to a near-infrared laser. Significantly, it can inhibit the ATP-adenosine pathway by dual-directional immunometabolic regulation, resulting in increased ATP levels and decreased adenosine synthesis, which ultimately reverses the immunosuppressive microenvironment and increases the susceptibility of immune checkpoint blockade (aPD-1) therapy. With the aid of aPD-1, the dual-directional immunometabolic regulation strategy mediated by FIP can effectively suppress/eradicate primary and distant tumors and evoke long-term solid immunological memory. This study presents an immunometabolic control strategy to offer a salvage option for treating residual tumors following incomplete PTT.

A dual-enzyme-like photosensitive nanozyme for remodeling the tumor immunosuppressive microenvironment to enhance immunotherapy.

In "immune-cold" tumors, the upregulation of immunosuppressive cells and insufficient infiltration of lymphocytes contribute to the resistance against immune therapy. Herein, we have developed a dual-enzyme-like photosensitive nanozyme (PBAF) to remodel the tumor immunosuppressive microenvironment (TIME) and induce the tumor infiltration of cytotoxic T lymphocytes (CTLs). Specifically, PBAF exhibits peroxidase (POD)-like activity and glutathione oxidase (GSHOx)-like activity and can be stimulated by 750 nm laser, promoting oxidative stress at the tumor site. Consequently, this process further leads to the reconstruction of TIME in animal experiments, inducing tumor-associated macrophages (TAMs) toward the immunostimulatory M1 phenotype, eliminating myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). Simultaneously, PBAF also promotes dendritic cells (DCs) maturation to enhance CTLs infiltration into the tumor. The remodeled TIME and enhanced immune responses by PBAF demonstrate significant post-administration inhibition of recurrence and metastasis in the treatment of malignant tumors.

Pan-cancer dissection of vasculogenic mimicry characteristic to provide potential therapeutic targets.

Introduction: Vasculogenic mimicry (VM) represents a novel form of tumor angiogenesis that is associated with tumor invasiveness and drug resistance. However, the VM landscape across cancer types remains poorly understood. In this study, we elucidate the characterizations of VM across cancers based on multi-omics data and provide potential targeted therapeutic strategies. Methods: Multi-omics data from The Cancer Genome Atlas was used to conduct comprehensive analyses of the characteristics of VM related genes (VRGs) across cancer types. Pan-cancer vasculogenic mimicry score was established to provide a depiction of the VM landscape across cancer types. The correlation between VM and cancer phenotypes was conducted to explore potential regulatory mechanisms of VM. We further systematically examined the relationship between VM and both tumor immunity and tumor microenvironment (TME). In addition, cell communication analysis based on single-cell transcriptome data was used to investigate the interactions between VM cells and TME. Finally, transcriptional and drug response data from the Genomics of Drug Sensitivity in Cancer database were utilized to identify potential therapeutic targets and drugs. The impact of VM on immunotherapy was also further clarified. Results: Our study revealed that VRGs were dysregulated in tumor and regulated by multiple mechanisms. Then, VM level was found to be heterogeneous among different tumors and correlated with tumor invasiveness, metastatic potential, malignancy, and prognosis. VM was found to be strongly associated with epithelial-mesenchymal transition (EMT). Further analyses revealed cancer-associated fibroblasts can promote EMT and VM formation. Furthermore, the immune-suppressive state is associated with a microenvironment characterized by high levels of VM. VM score can be used as an indicator to predict the effect of immunotherapy. Finally, seven potential drugs targeting VM were identified. Conclusion: In conclusion, we elucidate the characteristics and key regulatory mechanisms of VM across various cancer types, underscoring the pivotal role of CAFs in VM. VM was further found to be associated with the immunosuppressive TME. We also provide clues for the research of drugs targeting VM. Our study provides an initial overview and reference point for future research on VM, opening up new avenues for therapeutic intervention.

The interplay between the tumor microenvironment and tumor-derived small extracellular vesicles in cancer development and therapeutic response.

The tumor microenvironment (TME) plays an essential role in tumor cell survival by profoundly influencing their proliferation, metastasis, immune evasion, and resistance to treatment. Extracellular vesicles (EVs) are small particles released by all cell types and often reflect the state of their parental cells and modulate other cells' functions through the various cargo they transport. Tumor-derived small EVs (TDSEVs) can transport specific proteins, nucleic acids and lipids tailored to propagate tumor signals and establish a favorable TME. Thus, the TME's biological characteristics can affect TDSEV heterogeneity, and this interplay can amplify tumor growth, dissemination, and resistance to therapy. This review discusses the interplay between TME and TDSEVs based on their biological characteristics and summarizes strategies for targeting cancer cells. Additionally, it reviews the current issues and challenges in this field to offer fresh insights into comprehending tumor development mechanisms and exploring innovative clinical applications.

Mitochondrial ribosomal protein S24 is associated with immunosuppressive microenvironment and cold tumor in lung adenocarcinoma.

Objective: MRPS24 (Mitochondrial Ribosomal Protein S24) belongs to the mitochondrial ribosomal protein family, which participates in the protein synthesis of the mitochondrion. However, the relationship of MRPS24 with lung adenocarcinoma (LUAD) remained unknown. We aimed to identify its immunological and functional mechanisms in LUAD. Methods: The analysis of MRPS24 expression, clinical features, diagnosis, prognosis, function analysis, genetic alteration, copy number variations, methylation, and tumor microenvironment was investigated by the TCGA, UCSC Xena, GEO, HPA, GEPIA, cBioPortal, MethSurv, TIMER, TIMER2.0, and TISIDB databases. Results: MRPS24 was found to be more abundant in LUAD tumor tissue than in normal tissue. High levels of MRPS24 expression were found to be an independent prognostic factor by multivariate analysis. Functional analysis revealed that MRPS24 expression was associated with the immune, cell cycle and methylation. MRPS24 methylation level was inversely linked with its expression (p < 0.001). Patients with low MRPS24 methylation had a worse prognosis than those with high methylation (p < 0.05). In addition, the result revealed that the MRPS24 expression was inversely linked to the immune cell infiltration in LUAD. Finally, the validations of the expression level, prognosis, and immune cell infiltration of MRPS24 were in accordance with our previous results. Conclusions: This study systematically explored that MRPS24 expression was significantly correlated with prognosis, tumorigenesis, genetic alteration, copy number variations, methylation, and immune cell infiltration in LUAD. MRPS24 might be a potential immune-related biomarker in the development and treatment of LUAD, thereby acting as a promising predictor of immunotherapy response in LUAD.

Targeting cellular senescence as a therapeutic vulnerability in gastric cancer.

AIMS: Cellular senescence (CS) represents an intracellular defense mechanism responding to stress signals and can be leveraged as a "vulnerability" in cancer treatment. This study aims to construct a CS atlas for gastric cancer (GC) and uncover potential therapeutics for GC patients. MATERIALS AND METHODS: 38 senescence-associated regulators with prognostic significance in GC were obtained from the CellAge database to construct Gastric cancer-specific Senescence Score (GSS). Using eXtreme Sum algorism, GSS-based drug repositioning was conducted to identify drugs that could antagonize GSS in CMap database. In vitro experiments were conducted to test the effect of combination of palbociclib and exisulind in eliminating GC cells. KEY FINDINGS: Patients with high GSS exhibited CS-related features, such as CS markers upregulation, adverse clinical outcomes and hypomethylation status. scRNA-seq data showed malignant cells with high GSS exhibited enhanced senescence state and more immunosuppressive signals such as PVR-CD96 compared with malignant cells with low GSS. In addition, the GSS-High cancer associated fibroblasts might secrete cytokines and chemokines such as IL-6, CXCL1, CXCL12, and CCL2 to from an immunosuppressive microenvironment, and GSS could serve as an indicator for immunotherapy resistance. Exisulind exhibited the greatest potential to reverse GSS. In vitro experiments demonstrated that exisulind could induce apoptosis and suppress the proliferation of palbociclib-induced senescent GC cells. SIGNIFICANCE: Overall, GSS offers a framework for better understanding of correlation between senescence and GC, which might provide new insights into the development of novel therapeutics in GC.

Effect of acute inflammatory reaction induced by biopsy on tumor microenvironment.

When it comes to the diagnosis of solid tumors, biopsy is always the gold standard. However, traumatic and inflammatory stimuli are so closely related to tumor initiation and development that the acute inflammatory response induced by biopsy can give rise to changes in the tumor microenvironment, including recruitment of immunosuppressive cells (M2 macrophages, Treg cells, Tumor-associated neutrophils) and secretion of inflammation-associated cytokines, to create immunosuppressive conditions that enable the increase of circulating tumor cells in the peripheral circulation and promote the metastatic spread of tumors after surgery. In this review, we discuss dynamic changes and inhibitory characteristics of biopsy on tumor microenvironment. By investigating its mechanism of action and summarizing the current therapeutic strategies for biopsy-induced tumor immunosuppressive microenvironment, the future of using biopsy-induced inflammation to improve the therapeutic effects and prognosis of patients is prospected.

Abnormal changes in metabolites caused by m6A methylation modification: The leading factors that induce the formation of immunosuppressive tumor microenvironment and their promising potential for clinical application.

BACKGROUND: N6-methyladenosine (m6A) RNA methylation modifications have been widely implicated in the metabolic reprogramming of various cell types within the tumor microenvironment (TME) and are essential for meeting the demands of cellular growth and maintaining tissue homeostasis, enabling cells to adapt to the specific conditions of the TME. An increasing number of research studies have focused on the role of m6A modifications in glucose, amino acid and lipid metabolism, revealing their capacity to induce aberrant changes in metabolite levels. These changes may in turn trigger oncogenic signaling pathways, leading to substantial alterations within the TME. Notably, certain metabolites, including lactate, succinate, fumarate, 2-hydroxyglutarate (2-HG), glutamate, glutamine, methionine, S-adenosylmethionine, fatty acids and cholesterol, exhibit pronounced deviations from normal levels. These deviations not only foster tumorigenesis, proliferation and angiogenesis but also give rise to an immunosuppressive TME, thereby facilitating immune evasion by the tumor. AIM OF REVIEW: The primary objective of this review is to comprehensively discuss the regulatory role of m6A modifications in the aforementioned metabolites and their potential impact on the development of an immunosuppressive TME through metabolic alterations. KEY SCIENTIFIC CONCEPTS OF REVIEW: This review aims to elaborate on the intricate networks governed by the m6A-metabolite-TME axis and underscores its pivotal role in tumor progression. Furthermore, we delve into the potential implications of the m6A-metabolite-TME axis for the development of novel and targeted therapeutic strategies in cancer research.

Light-Triggered Nanozymes Remodel the Tumor Hypoxic and Immunosuppressive Microenvironment for Ferroptosis-Enhanced Antitumor Immunity.

Cancer immunotherapy holds significant promise for addressing diverse malignancies. Nevertheless, its efficacy remains constrained by the intricate tumor immunosuppressive microenvironment. Herein, a light-triggered nanozyme Fe-TCPP-R848-PEG (Fe-MOF-RP) was designed for remodeling the immunosuppressive microenvironment. The Fe-TCPP-MOFs were utilized not only as a core catalysis component against tumor destruction but also as a biocompatible delivery vector of an immunologic agonist, improving its long circulation and tumor enrichment. Concurrently, it catalyzes the decomposition of H2O2 within the tumor, yielding oxygen to augment photodynamic therapy. The induced ferroptosis, in synergy with photodynamic therapy, prompts the liberation of tumor-associated antigens from tumor cells inducing immunogenic cell death. Phototriggered on-demand release of R848 agonists stimulated the maturation of dendritic cells and reverted the tumor-promoting M2 phenotypes into adoptive M1 macrophages, which further reshaped the tumor immunosuppressive microenvironment. Notably, the nanozyme effectively restrains well-established tumors, such as B16F10 melanoma. Moreover, it demonstrates a distal tumor-inhibiting effect upon in situ light treatment. What is more, in a lung metastasis model, it elicits robust immune memory, conferring enduring protection against tumor rechallenge. Our study presents a straightforward and broadly applicable strategy for crafting nanozymes with the potential to effectively thwart cancer recurrence and metastasis.

GPX8+ cancer-associated fibroblast, as a cancer-promoting factor in lung adenocarcinoma, is related to the immunosuppressive microenvironment.

BACKGROUND: Cancer-associated fibroblasts (CAFs) play a crucial role in the tumor microenvironment of lung adenocarcinoma (LUAD) and are often associated with poorer clinical outcomes. This study aimed to screen for CAF-specific genes that could serve as promising therapeutic targets for LUAD. METHODS: We established a single-cell transcriptional profile of LUAD, focusing on genetic changes in fibroblasts. Next, we identified key genes associated with fibroblasts through weighted gene co-expression network analysis (WGCNA) and univariate Cox analysis. Then, we evaluated the relationship between glutathione peroxidase 8 (GPX8) and clinical features in multiple independent LUAD cohorts. Furthermore, we analyzed immune infiltration to shed light on the relationship between GPX8 immune microenvironment remodeling. For clinical treatment, we used the tumor immune dysfunction and exclusion (TIDE) algorithm to assess the immunotherapy prediction efficiency of GPX8. After that, we screened potential therapeutic drugs for LUAD by the connectivity map (cMAP). Finally, we conducted a cell trajectory analysis of GPX8+ CAFs to show their unique function. RESULTS: Fibroblasts were found to be enriched in tumor tissues. Then we identified GPX8 as a key gene associated with CAFs through comprehensive bioinformatics analysis. Further analysis across multiple LUAD cohorts demonstrated the relationship between GPX8 and poor prognosis. Additionally, we found that GPX8 played a role in inducing the formation of an immunosuppressive microenvironment. The TIDE method indicated that patients with low GPX8 expression were more likely to be responsive to immunotherapy. Using the cMAP, we identified beta-CCP as a potential drug-related to GPX8. Finally, cell trajectory analysis provided insights into the dynamic process of GPX8+ CAFs formation. CONCLUSIONS: This study elucidates the association between GPX8+ CAFs and poor prognosis, as well as the induction of immunosuppressive formation in LUAD. These findings suggest that targeting GPX8+ CAFs could potentially serve as a therapeutic strategy for the treatment of LUAD.

Prognostic significance and immune escape implication of tumor-infiltrating neutrophil plasticity in human head and neck squamous cell carcinoma.

Tumor-infiltrating neutrophils play a crucial role in the progression of head and neck squamous cell carcinoma (HNSCC). Here, we aimed to statistically quantify the plasticity of HNSCC-infiltrating N2/N1 neutrophils and examine its impacts on survival and immune infiltration landscape. A retrospective study of 80 patients who underwent curative surgical resection for HNSCC between 2014 and 2017 was conducted in this study. HNSCC-infiltrating neutrophil phenotypes were classified using immunofluorescence staining, and the N2/N1 neutrophil plasticity was evaluated via the ratio of N2/N1 neutrophils. We then assessed the correlations between N2/N1 neutrophil plasticity, clinicopathological characteristics, and immune infiltration landscape using rigorous statistical methods. Infiltration variations of N1 and N2 neutrophils were observed between the tumor nest (TN) and tumor stroma (TS), with TN exhibiting higher N2 neutrophil infiltration and lower N1 neutrophil infiltration. High ratios of N2/N1 neutrophils were correlated with advanced TNM stage, large tumor size and invasion of adjacent tissue. High infiltration of N2 neutrophils was associated with decreased overall and relapse-free survival, which were opposite for N1 neutrophils. The independent prognostic role of N2/N1 neutrophil plasticity, particularly within the TN region, was confirmed by multivariate analyses. Moreover, the ratio of N2/N1 neutrophils within the TN region showed correlations with high CD8+ T cells infiltration and low FOXP3+ Tregs infiltration. We identify HNSCC-infiltrating N2/N1 neutrophil plasticity as a crucial prognostic indictor which potentially reflects the tumor microenvironment (TME) and immune escape landscape within HNSCC tissues. Further investigations and validations may provide novel therapeutic strategies for personalized immunomodulation in HNSCC patients.

Nanoparticle-mediated blockade of CXCL12/CXCR4 signaling enhances glioblastoma immunotherapy: Monitoring early responses with MRI radiomics.

The limited therapeutic efficacy of checkpoint blockade immunotherapy against glioblastoma is closely related to the blood-brain barrier (BBB) and tumor immunosuppressive microenvironment, where the latter is driven primarily by tumor-associated myeloid cells (TAMCs). Targeting the C-X-C motif chemokine ligand-12/C-X-C motif chemokine receptor-4 (CXCL12/CXCR4) signaling orchestrates the recruitment of TAMCs and has emerged as a promising approach for alleviating immunosuppression. Herein, we developed an iRGD ligand-modified polymeric nanoplatform for the co-delivery of CXCR4 antagonist AMD3100 and the small-molecule immune checkpoint inhibitor BMS-1. The iRGD peptide facilitated superior BBB crossing and tumor-targeting abilities both in vitro and in vivo. In mice bearing orthotopic GL261-Luc tumor, co-administration of AMD3100 and BMS-1 significantly inhibited tumor proliferation without adverse effects. A reprogramming of immunosuppression upon CXCL12/CXCR4 signaling blockade was observed, characterized by the reduction of TAMCs and regulatory T cells, and an increased proportion of CD8+T lymphocytes. The elevation of interferon-γ secreted from activated immune cells upregulated PD-L1 expression in tumor cells, highlighting the synergistic effect of BMS-1 in counteracting the PD-1/PD-L1 pathway. Finally, our research unveiled the ability of MRI radiomics to reveal early changes in the tumor immune microenvironment following immunotherapy, offering a powerful tool for monitoring treatment responses. STATEMENT OF SIGNIFICANCE: The insufficient BBB penetration and immunosuppressive tumor microenvironment greatly diminish the efficacy of immunotherapy for glioblastoma (GBM). In this study, we prepared iRGD-modified polymeric nanoparticles, loaded with a CXCR4 antagonist (AMD3100) and a small-molecule checkpoint inhibitor of PD-L1 (BMS-1) to overcome physical barriers and reprogram the immunosuppressive microenvironment in orthotopic GBM models. In this nanoplatform, AMD3100 converted the "cold" immune microenvironment into a "hot" one, while BMS-1 synergistically counteracted PD-L1 inhibition, enhancing GBM immunotherapy. Our findings underscore the potential of dual-blockade of CXCL12/CXCR4 and PD-1/PD-L1 pathways as a complementary approach to maximize therapeutic efficacy for GBM. Moreover, our study revealed that MRI radiomics provided a clinically translatable means to assess immunotherapeutic efficacy.

Landscape of adenosine pathway and immune checkpoint dual blockade in NSCLC: progress in basic research and clinical application.

Lung cancer poses a global threat to human health, while common cancer treatments (chemotherapy and targeted therapies) have limited efficacy. Immunotherapy offers hope of sustained remission for many patients with lung cancer, but a significant proportion of patients fail to respond to treatment owing to immune resistance. There is extensive evidence to suggest the immunosuppressive microenvironment as the cause of this treatment failure. Numerous studies have suggested that the adenosine (ADO) pathway plays an important role in the formation of an immunosuppressive microenvironment and may be a key factor in the development of immune resistance in EGFR-mutant cell lung cancer. Inhibition of this pathway may therefore be a potential target to achieve effective reversal of ADO pathway-mediated immune resistance. Recently, an increasing number of clinical trials have begun to address the broad prospects of using the ADO pathway as an immunotherapeutic strategy. However, few researchers have summarized the theoretical basis and clinical rationale of the ADO pathway and immune checkpoint dual blockade in a systematic and detailed manner, particularly in lung cancer. As such, a timely review of the potential value of the ADO pathway in combination with immunotherapy strategies for lung cancer is warranted. This comprehensive review first describes the role of ADO in the formation of a lung tumor-induced immunosuppressive microenvironment, discusses the key mechanisms of ADO inhibitors in reversing lung immunosuppression, and highlights recent evidence from preclinical and clinical studies of ADO inhibitors combined with immune checkpoint blockers to improve the lung cancer immunosuppressive microenvironment.

Chimeric Antigen Receptor T Cell and Chimeric Antigen Receptor NK Cell Therapy in Pediatric and Adult High-Grade Glioma-Recent Advances.

High-grade gliomas (HGG) account for approximately 10% of central nervous system (CNS) tumors in children and 25% of CNS tumors in adults. Despite their rare occurrence, HGG are a significant clinical problem. The standard therapeutic procedure in both pediatric and adult patients with HGG is the surgical resection of the tumor combined with chemotherapy and radiotherapy. Despite intensive treatment, the 5-year overall survival in pediatric patients is below 20-30%. This rate is even lower for the most common HGG in adults (glioblastoma), at less than 5%. It is, therefore, essential to search for new therapeutic methods that can extend the survival rate. One of the therapeutic options is the use of immune cells (T lymphocytes/natural killer (NK) cells) expressing a chimeric antigen receptor (CAR). The objective of the following review is to present the latest results of preclinical and clinical studies evaluating the efficacy of CAR-T and CAR-NK cells in HGG therapy.

Dual-responsive supramolecular photodynamic nanomedicine with activatable immunomodulation for enhanced antitumor therapy.

A major challenge facing photodynamic therapy (PDT) is that the activity of the immune-induced infiltrating CD8+ T cells is subject to the regulatory T lymphocytes (Tregs), leaving the tumor at risk of recurrence and metastasis after the initial ablation. To augment the antitumor response and reprogram the immunosuppressive tumor microenvironment (TME), a supramolecular photodynamic nanoparticle (DACss) is constructed by the host-guest interaction between demethylcantharidin-conjugated ß-cyclodextrin (DMC-CD) and amantadine-terminated disulfide-conjugated FFVLGGGC peptide with chlorin e6 decoration (Ad-ss-pep-Ce6) to achieve intelligent delivery of photosensitizer and immunomodulator for breast cancer treatment. The acid-labile ß-carboxamide bond of DMC-CD is hydrolyzed in response to the acidic TME, resulting in the localized release of DMC and subsequent inhibition of Tregs. The guest molecule Ad-ss-pep-Ce6 can be cleaved by a high level of intracellular GSH, reducing photosensitizer toxicity and increasing photosensitizer retention in the tumor. With a significant increase in the CTL/Treg ratio, the combination of Ce6-based PDT and DMC-mediated immunomodulation adequately achieved spatiotemporal regulation and remodeling of the TME, as well as improved primary tumor and in situ lung metastasis suppression with the aid of PD-1 antibody.

Mnox Nanoenzyme Armed CAR-NK Cells Enhance Solid Tumor Immunotherapy by Alleviating the Immunosuppressive Microenvironment.

Adoptively transferred cells usually suffer from exhaustion, limited expansion, and poor infiltration, partially attributing to the complicated immunosuppressive microenvironment of solid tumors. Therefore, it is necessary to explore more effective strategies to improve the poor tumor microenvironment (TME) to efficaciously deliver and support extrinsic effector cells in vivo. Herein, an intelligent biodegradable hollow manganese dioxide nanoparticle (MnOX) that possesses peroxidase activity to catalyze excess H2O2 in the TME to produce oxygen and relieve the hypoxia of solid tumors is developed. MnOX nanoenzymes modified with CD56 antibody could specifically bind CAR-NK (chimeric antigen receptor modified natural killer) cells. It is demonstrated that CAR-NK cells incorporated with MnOX nanoenzymes effectively infiltrate into tumor tissues with an improved TME, which results in superior antitumor activity in solid tumor-bearing mice. The antibody connection between MnOX nanoenzymes and CAR-NK endows the lowest efficient dosage of MnOX. This study features a smart synergistic immunotherapy approach for solid tumors using MnOX nanoenzyme-armed CAR-NK cells, which would provide a valuable tool for immunocyte therapy in solid tumors.

Nanoparticle-integrated dissolving microneedles for the co-delivery of R848/aPD-1 to synergistically reverse the immunosuppressive microenvironment of triple-negative breast cancer.

Nowadays, effective immunotherapy against triple-negative breast cancer (TNBC) remains challenging due to the immunosuppressive tumor microenvironment. Immune checkpoint inhibitor is mostly employed to restore the activity of tumor-specific immune cells, which however brings little therapeutic outcome owing to the limited number of tumor-infiltrating CD8+ T cells and the inefficient delivery of immune drugs to the tumor tissue. Aiming to solve these problems, we herein constructed a tailor-made dissolving microneedle co-encapsulating the TLR7/8 agonist R848 and the immune checkpoint inhibitor aPD-1, termed αNP-RNP@DMN, and fabricated it as a transdermal drug delivery system. This well-designed microneedle patch, endowed with efficient tumor drug delivery ability, was able to mature tumor-infiltrating dendritic cells (TIDCs) and further promote the infiltration of CD8+ T cells into the tumor tissue with the aid of R848. Moreover, the introduction of aPD-1 blocked the programmed cell death protein 1/programmed cell death ligand 1(PD-1/PD-L1) immune checkpoints, synergistically reversing the immunosuppressive microenvironment of TNBC. In vivo therapeutic results demonstrated that αNP-RNP@DMN not only significantly prolonged the survival time of 4T1 tumor-bearing mice, but also inhibited tumor recurrence and lung metastasis after surgery, implying the great potential of this effective drug delivery system for enhanced immunotherapy of superficial tumors. STATEMENT OF SIGNIFICANCE: The limited number of tumor-infiltrating CD8+ T cells and the inefficient delivery of immune drugs to the tumor tissue hinder the effective immunotherapy of triple-negative breast cancer (TNBC). Herein, a dissolving microneedle co-encapsulating TLR7/8 agonist R848 and immune checkpoint inhibitor aPD-1 was developed and fabricated as a transdermal drug delivery system. This tailor-made microneedle patch not only promoted drug accumulation in tumor sites in a safe and painless manner, but also lifted the immune-suppressive state of tumor-infiltrating dendritic cells (TIDCs). The activated TIDCs further enhanced T-cell infiltration into the tumor tissue, thus successfully boosting the therapeutic efficacy of aPD-1. This study demonstrated that this well-designed microneedle patch could be served as an effective drug delivery system for enhanced immunotherapy of TNBC.

An Adjuvant Micelle-Based Multifunctional Nanosystem for Tumor Immunotherapy by Remodeling Three Types of Immunosuppressive Cells.

Immunotherapy is restricted by a complex tumor immunosuppressive microenvironment (TIM) and low drug delivery efficiency. Herein, a multifunctional adjuvant micelle nanosystem (PPD/MPC) integrated with broken barriers and re-education of three classes of immune-tolerant cells is constructed for cancer immunotherapy. The nanosystem significantly conquers the penetration barrier via the weakly acidic tumor microenvironment-responsive size reduction and charge reversal strategy. The detached core micelle MPC could effectively be internalized by tumor-associated macrophages (TAMs), tumor-infiltrating dendritic cells (TIDCs), and myeloid-derived suppressor cells (MDSCs) via mannose-mediated targeting endocytosis and electrostatic adsorption pathways, promoting the re-education of immunosuppressive cells for allowing them to reverse from pro-tumor to antitumor phenotypes by activating TLR4/9 pathways. This process in turn leads to the remodeling of TIM. In vitro and in vivo studies collectively indicate that the adjuvant micelle-based nanosystem not only relieves the intricate immune tolerance and remodels TIM via reprogramming the three types of immunosuppressive cells and regulating the secretion of relevant cytokines/immunity factors but also strengthens immune response and evokes immune memory, consequently suppressing the tumor growth and metastasis.