Immunosuppressive Activity Research Articles

Deciphering adenosine signaling in hepatocellular carcinoma: pathways, prognostic models, and therapeutic implications.

Hepatocellular carcinoma (HCC) is a highly lethal cancer due to its aggressive nature and poor prognosis. Adenosine, a key metabolic regulator in the tumor microenvironment (TME), plays a crucial role in cancer progression. In this review, we first described adenosine triphosphate (ATP)-adenosine metabolism in the TME and summarize its effects on tumor growth, immune suppression, angiogenesis, and metastasis in HCC. Given the limited number of clinical studies on adenosine signaling in HCC, we conducted Lasso-Cox analysis using the TCGA-LIHC cohort to develop a prognostic risk model composed of eight adenosine signaling-related genes. This model stratified the patients into low- and high-risk groups, with Kaplan‒Meier survival analysis revealing poorer overall survival in the high-risk group. Additionally, differential gene expression analysis between the two groups identified 24 enriched signaling pathways for further investigation. Immune infiltration and single cell RNA-seq analyses revealed a correlation between adenosine and immunosuppressive activity in the TME, with a particularly strong association observed in macrophages, dendritic cells, and monocytes. Finally, we provided an overview of the advancements of antagonists that target adenosine receptors progress in both preclinical research and clinical trials. In conclusion, this review aims to deepen our understanding of the biological role of adenosine and highlights emerging therapeutic strategies that may improve treatment outcomes for HCC.

Inhibiting HnRNP L-mediated alternative splicing of EIF4G1 counteracts immune checkpoint blockade resistance in Castration-resistant prostate Cancer.

Immunotherapy with checkpoint inhibitors produced significant clinical responses in a subset of cancer patients who were resistant to prior therapies. However, Castration-resistant prostate cancer (CRPC) is seriously lack of T cell infiltration, which greatly limits the clinical application of immunotherapy, but the mechanism is unclear. In the present study, in silico analyses and experimental data show that HnRNP L was significantly negatively correlated with CD4+ and CD8+ T cells infiltration in patients; besides, we found deficiency of HnRNP L recruites CD4+ and CD8+ T cells infiltration and impairs tumorigenesis. Mechanically, HnRNP L enhanced the translation of c-Myc and then promoted CXCL8 secretion via alternative splicing of EIF4G1. In vivo, inhibition of EIF4G1 by the inhibitor, SBI-0640756, attenuated HnRNP l-induced tumor progression and immunosuppressive activity. And most of all, therapeutic synergy between HnRNP L knockdown and Anti-PD-1 could significantly suppress xenograft prostate cancer growth. In summary, this study revealled the molecular mechanism of HnRNP L regulating the immune infiltration, which provides a new theoretical basis for overcoming the limitation of immunotherapy for CRPC.

Overcoming Immunotherapy Resistance in Hepatocellular Carcinoma by Targeting Myeloid IL-8/ CXCR2 Signaling.

Durable response to immune checkpoint blockade (ICB) in hepatocellular carcinoma (HCC) are limited to a minority of patients, yet reliable biomarkers are still lacking. Inflammatory cytokines such as interleukin-8 (IL-8) are associated with HCC progression, and IL-8 is known as the chemoattractant for immunosuppressive myeloid cells. Therefore, we aim to elucidate the ICB resistance mechanisms mediated by the activation of the IL-8/CXCR2 pathway. Single-cell RNA sequencing (scRNA-seq) were performed in advanced HCC patients with baseline and on-treatment biopsy after pembrolizumab in a Phase II clinical trial cohort. Our data revealed that IL-8 and its receptor, CXCR2 mainly derived from the immunosuppressive myeloid derived suppressor cells (MDSCs). Particularly, high circulating IL-8 level strongly associated with poor ICB response. This myeloid IL-8/CXCR2 pathway was further elucidated in our ICB-resistant orthotopic mouse model using AZD5069, a clinically available CXCR2 antagonist. Suppression of IL-8/CXCR2 pathway significantly abrogated MDSCs trafficking and immunosuppressive activity, which sensitized the anti-PD-L1 blockade to reduce tumor growth and prolong survival. The association between myeloid IL-8 and ICB therapeutic outcome also extended to multiple cancer types. Collectively, our study not only suggests a potential non-invasive biomarker for patient stratification and monitoring of ICB response, but also provides a proof-of-concept for combinational immunotherapy to benefit patients who are non-responsive to ICB monotherapy.

Methods of extraction, separation and identification of cyclic peptides from flaxseed (Linum usitatissimum L.): A review

Oilseed flax (Linum usitatissimum L.) is a valuable crop characterized by a high content of fats, dietary fiber, protein and various biologically active substances, in particular cyclopeptides. Cyclic peptides are a group of cyclic hydrophobic peptides consisting of eight to ten amino acids with a molecular weight in the range of 950–2300 Da. Flax oil and seeds contain from 0.1 to 0.3% cyclopeptides, which can exhibit antioxidant, anti-inflammatory, immunosuppressive, antihypertensive and antitumor activity. The aim of this review was to systematize and summarize the available literature data on methods of extraction, separation and identification of cyclopeptides from flaxseed oil. It was found that the main methods for obtaining cyclopeptides are solid-liquid, liquid-liquid or solid-phase extraction. Commonly used solvents include methanol, hexane, ethyl acetate, dichloromethane, acetonitrile and deionized water. Preparative flash chromatography on silica gel or polymer adsorbents is used to purify and concentrate cyclopeptides, and high-performance liquid chromatography (HPLC) is used to obtain individual standards. The most commonly used stationary phases are non-polar modified sorbents — octadecyl (C18) and phenylhexyl functional groups. Identification is carried out using instrumental methods of analysis: IR spectroscopy, NMR, HPLC with a diode array detector (HPLC-PDA/DAD), high-resolution tandem mass spectrometry with electrospray ionization (ESI-HR-MS/MS). For the qualitative and quantitative determination of cyclopeptides, the HPLC with a diode array detector at a wavelength of 214 nm is sufficient. In turn, mass spectral methods, including tandem mass spectrometry, make it possible to confirm the qualitative composition and establish the amino acid sequence of cyclic peptides.

HDAC1-3 inhibition triggers NEDD4-mediated CCR2 downregulation and attenuates immunosuppression in myeloid-derived suppressor cells

Myeloid-derived suppressor cells (MDSCs) play a critical role in cancer progression and resistance, thus representing promising targets for immunotherapy. Despite the established role of histone deacetylases (HDACs) in epigenetic regulation of cell fate and function, their specific impact on MDSCs remains elusive. We sought to investigate the effects and underlying mechanisms of HDAC on MDSCs using various HDAC inhibitors. Our results indicate that HDAC1-3 inhibitors reduce CCR2 expression, a chemokine receptor that mediates the migration of monocytic (M-)MDSCs to tumors and attenuated the immunosuppressive activity of MDSCs. In an orthotropic hepatocellular carcinoma (HCC) murine model, HDAC1-3 inhibitors reduced the infiltration of M-MDSCs, increased the number of natural killer cells in tumors, and suppressed tumor growth. Our results also suggest that HDAC1-3 inhibitors potentiate the antitumor effects of anti-programmed cell death protein 1 antibodies. ATAC-seq and RNA-seq analyses revealed 115 genes epigenetically upregulated by HDAC1-3 inhibitors, primarily linked to transcriptional regulation and ubiquitination. We further elucidated that HDAC1-3 inhibitors facilitate CCR2 protein degradation through ubiquitination-mediated by NEDD4 E3 ligase. Our findings reveal a novel mechanism of action of HDAC1-3 inhibitors in MDSCs and suggest a potential synergistic immunotherapy strategy for clinical benefit in HCC.

Microbial Pigments: Types, Production Methods, and Diverse Applications in Various Industries: A Review

Microbial pigments represent a class of natural pigments with significant potential across diverse industries including food, textiles, dairy, cosmetics, marine applications, and medicine. These pigments are considered valuable due to their abundant resources, high production yield, low cost, ease of cultivation, adaptability to various environments, optimization, and stability. Additionally, they are eco-friendly, biodegradable, and free of harmful side effects. Microbial pigments have shown promise in treating various diseases due to their bioactive properties, such as antibacterial, anticancer, and immunosuppressive activities. This review explores the various types of microbial pigments, their sources, characteristics, production and their applications in various fields.

Aculeanoids A-D, the second 17-nor fusicoccane diterpenoids with immunosuppressive activity from Aspergillus aculeatus.

Chemical investigation on the secondary metabolites of Aspergillus aculeatus led to the identification of ten modified fusicoccane-type diterpenoids aculeanoids A-J (1-10). Their structures and absolute configurations were characterized by comprehensive spectroscopic analysis, DP4+ analysis, Mo2(OAc)4-induced ECD, single-crystal X-ray diffractions, and ECD calculations. Compounds 1-4 belong to a rare class of 17-nor fusicoccane diterpenoids, with only one previously reported example. Biologically, compounds 6, 7, and 10 exhibited significant immunosuppressive activities against con A-induced T cell proliferation with IC50 values ranging from 2.44 to 5.26 μM and LPS-induced B cell proliferation with IC50 values ranging from 4.18 to 5.78 μM, which provided more possibilities with the treatment of organ transplantation and various autoimmune diseases.

The small molecule peroxiredoxin mimetics restore growth factor signalings and reverse vascular remodeling.

Epidithio-diketopiperazine (ETP) compound is the family of natural fungal metabolites that are known to exert diverse biological effects, such as immunosuppression and anti-cancer activity, in higher animals. However, an enzyme-like catalytic activity or function of the ETP derivatives has not been reported. Here, we report the generation of novel thiol peroxidase mimetics that possess peroxide-reducing activity through strategic derivatization of the core ETP ring structure. The ETP derivatives with small side chains are the bona fide 2-Cys peroxiredoxin (PRX) mimetics that catalyze the H2O2-reducing reaction specifically coupled to the thioredoxin/thioredoxin reductase system. In contrast, the ETP derivatives with linear chains or a heterocyclic group show H2O2-reducing activity in coupling with both thioredoxin and glutathione systems. Moreover, the ETP derivatives with bulky heterocyclic groups almost lose catalytic activity. The 2-Cys PRX mimetics regulate intracellular H2O2 levels, thereby restoring the receptor Tyr kinase signaling and cellular functions disrupted by the absence of 2-Cys PRX in vascular cells. In a rodent model, the 2-Cys PRX mimetics reverse vascular occlusion in the injured carotid arteries by inhibiting smooth muscle hyperplasia and promoting reendothelialization. Thus, this study reveals a novel chemical platform for complementing defective 2-Cys PRX enzymes in biological systems.

Interpretable adenylation domain specificity prediction using protein language models.

Natural products have long been a rich source of diverse and clinically effective drug candidates. Non-ribosomal peptides (NRPs), polyketides (PKs), and NRP-PK hybrids are three classes of natural products that display a broad range of bioactivities, including antibiotic, antifungal, anticancer, and immunosuppressant activities. However, discovering these compounds through traditional bioactivity-guided techniques is costly and time-consuming, often resulting in the rediscovery of known molecules. Consequently, genome mining has emerged as a high-throughput strategy to screen hundreds of thousands of microbial genomes to identify their potential to produce novel natural products. Adenylation domains play a key role in the biosynthesis of NRPs and NRP-PKs by recruiting substrates to incrementally build the final structure. We propose MASPR, a machine learning method that leverages protein language models for accurate and interpretable predictions of A-domain substrate specificities. MASPR demonstrates superior accuracy and generalization over existing methods and is capable of predicting substrates not present in its training data, or zero-shot classification. We use MASPR to develop Seq2Hybrid, an efficient algorithm to predict the structure of hybrid NRP-PK natural products from microbial genomes. Using Seq2Hybrid, we propose putative biosynthetic gene clusters for the orphan natural products Octaminomycin A, Dityromycin, SW-163B, and JBIR-39.

Advances in the regulation of the role of Myeloid-derived suppressor cells in the Tumor microenvironment by Tumor-derived exosomes

In the progression of malignancies, myeloid-derived suppressor cells (MDSCs) play a crucial role in modulating tumor immunology within the tumor microenvironment (TME), which is often characterized by the extensive infiltration of immune cells. These cells are abnormally activated and demonstrate strong immunosuppressive properties under pathological conditions such as cancer. Recent research highlights the importance of tumor-derived exosomes (TEXs) as key mediators of this immunosuppressive activity. TEXs, small extracellular vesicles released by tumor cells, carry a diverse array of bioactive molecules such as proteins, lipids, and RNA, which modulate the behavior of recipient cells within the TME. The assembly and release of TEXs are tightly regulated by the TME, and accumulating evidence suggests that TEXs facilitate MDSC activation, expansion, and enhancement of their immunosuppressive functions. This study aims to investigate the role of TEXs in mediating intercellular communication between tumor cells and MDSCs. By understanding these mechanisms, it is possible to develop strategies to regulate MDSC behavior, including promoting their differentiation into mature myeloid cells, reducing their expansion and accumulation, and impairing their suppressive activity. Ultimately, these insights will provide a foundation for targeting MDSCs as a therapeutic approach to inhibit tumor growth, invasion, and metastasis, offering promising directions for future clinical applications.

Transplant oncology and anti-cancer immunosuppressants.

Organ transplantation is a life-saving intervention that enhances the quality of life for patients with end-stage organ failure. However, long-term immunosuppressive therapy is required to prevent allogeneic graft rejection, which inadvertently elevates the risk of post-transplant malignancies, especially for liver transplant recipients with a prior history of liver cancer. In response, the emerging field of transplant oncology integrates principles from oncology and immunology to improve outcomes for patients at high risk of tumor occurrence or recurrence following transplantation. Therefore, it is of substantial clinical significance to develop immunosuppressants that possess both immunosuppressive and anti-tumor properties. For instance, mTOR inhibitors demonstrate anti-tumor effects among antimetabolite immunosuppressive drugs, and recent studies indicate that capecitabine, an antimetabolite chemotherapeutic, may also exhibit immunosuppressive activity in the clinic for liver transplants suffering from hepatocellular carcinoma. This review systematically explores potential immunosuppressants with dual anti-tumor and immunosuppressive effects to support the management of transplant patients at elevated risk of tumor occurrence or recurrence.

Effect of exercise training on modulating the TH17/TREG imbalance in individuals with severe COPD: A randomized controlled trial.

Chronic obstructive pulmonary disease (COPD) induces an imbalance in T helper (Th) 17/regulatory T (Treg) cells that contributes to of the dysregulation of inflammation. Exercise training can modulate the immune response in healthy subjects. We aimed to evaluate the effects of exercise training on Th17/Treg responses and the differentiation of Treg phenotypes in individuals with COPD. This randomized controlled trial included 50 individuals with severe or very severe COPD who were allocated to the Exercise or Control groups. The Exercise group underwent eight weeks of aerobic and muscle strength training, whereas the Control group received usual care. The primary outcome was the change in the phenotypic characteristics of Tregs and Th17 profile differentiation in systemic inflammation. Exercise training increased the frequency of total and activated Tregs and decreased the frequency of Th17 cells in between-group comparisons. Additionally, Th17/Treg responses were moderately correlated with improvements in the six-minute walking test, muscle strength of the upper and lower limbs, and daily life physical activity levels. Exercise training improved functional exercise capacity, muscle strength, and physical fitness, which was associated with a decrease in the Th17 inflammatory response and an increase in Treg cell phenotypes immunosuppressive activity.

Generation of Human Chimeric Antigen Receptor Regulatory T Cells.

Chimeric antigen receptor (CAR) T-cell therapy has reshaped the face of cancer treatment, leading to record remission rates in previously incurable hematological cancers. These successes have spurred interest in adapting the CAR platform to a small yet pivotal subset of CD4+ T cells primarily responsible for regulating and inhibiting the immune response, regulatory T cells (Tregs). The ability to redirect Tregs' immunosuppressive activity to any extracellular target has enormous implications for creating cell therapies for autoimmune disease, organ transplant rejection, and graft-versus-host disease. Here, we describe in detail methodologies for bona fide Treg isolation from human peripheral blood, genetic modification of human Tregs utilizing either lentivirus or CRISPR/Cas9-aided knock-in using adeno-associated virus-mediated homologous directed repair (HDR) template delivery, and ex vivo expansion of stable human CAR Tregs. Lastly, we describe the assessment of human CAR Treg phenotypic stability and in vitro suppressive function, which provides insights into how the human CAR Tregs will behave in preclinical and clinical applications.

Highly oxygenated steroids with immunosuppressive activity from Solanum undatum.

Solanum undatum is a medicinal plant used for the treatment of oedema, rheumatoid arthritis and toothache, from which seven highly oxygenated steroids (1-7), including three new ones (1-3), have been characterized. Compound 1 is a new steroidal carboxylic acid featuring a cyclohexa-2,5-dien-1-one moiety and compounds 2 and 3 are new withanolide analogs with a 1,6-dimethyl-3,7-dioxabicyclo[4.1.0]heptan-2-ol terminus. Their structures and absolute configurations were determined by a combination of spectroscopic data, quantum chemical calculations, single-crystal X-ray diffraction, and the NMR-based phenylglycine methyl ester (PGME) method. An immunosuppressive activity assay revealed that compounds 2-7 exhibited substantial activities against the proliferation of T and B lymphocytes in vitro, with IC50 values ranging from 1.60 to 7.89 μM and 0.90 to 6.90 μM, respectively. Notably, compound 6 showed selective inhibitory effect toward B cells with the highest selective index (SI = 40.5). Preliminary structure-activity relationships of compounds 1-7 suggest that the terminal 1,6-dimethyl-3,7-dioxabicyclo[4.1.0]heptan-2-ol or 5,5-spiroacetal moiety is critical for immunosuppressive activity. Our study indicated that they could be promising lead compounds for immunosuppressive agents.

Insights into the roles of exogenous phenylalanine and tyrosine in improving rapamycin production of Streptomyces rapamycinicus with transcriptome analysis

Rapamycin is an important natural macrolide antibiotic with antifungal, immunosuppressive and antitumor activities produced by Streptomyces rapamycinicus. However, their prospective applications are limited by low fermentation units. In this study, we found that the exogenous aromatic amino acids phenylalanine and tyrosine could effectively increase the yield of rapamycin in industrial microbial fermentation. To gain insight into the mechanism of rapamycin overproduction, comparative transcriptomic profiling was performed between media with and without phenylalanine and tyrosine addition. The results showed that the addition of phenylalanine and tyrosine upregulated the transcription levels of genes involved in rapamycin biosynthesis, precursor production, and transporters. In addition, the transcription levels of many carbohydrate metabolism-related genes were down-regulated, leading to a decrease in growth, suggesting that balancing cell growth and rapamycin biosynthesis may be important to promote efficient biosynthesis of rapamycin in Streptomyces rapamycinicus. These results provide a basis for understanding physiological roles of phenylalanine and tyrosine, and a new way to increase rapamycin production in Streptomyces cultures.

CXCL16/CXCR6/TGF‐β Feedback Loop Between M‐MDSCs and Treg Inhibits Anti‐Bacterial Immunity During Biofilm Infection

AbstractStaphylococcus aureus (S. aureus) is a leading cause of Periprosthetic joint infection (PJI), a severe complication after joint arthroplasty. Immunosuppression is a major factor contributing to the infection chronicity of S. aureus PJI, posing significant treatment challenges. This study investigates the relationship between the immunosuppressive biofilm milieu and S. aureus PJI outcomes in both discovery and validation cohorts. This scRNA‐seq analysis of synovium from PJI patients reveals an expansion and heightened activity of monocyte‐related myeloid‐derived suppressor cells (M‐MDSCs) and regulatory T cells (Treg). Importantly, CXCL16 is significantly upregulated in M‐MDSCs, with its corresponding CXCR6 receptor also elevated on Treg. M‐MDSCs recruit Treg and enhance its activity via CXCL16‐CXCR6 interactions, while Treg secretes TGF‐β, inducing M‐MDSCs proliferation and immunosuppressive activity. Interfering with this cross‐talk in vivo using Treg‐specific CXCR6 knockout PJI mouse model reduces M‐MDSCs/Treg‐mediated immunosuppression and alleviates bacterial burden. Immunohistochemistry and recurrence analysis show that PJI patients with CXCR6high synovium have poor prognosis. This findings highlight the critical role of CXCR6 in Treg in orchestrating an immunosuppressive microenvironment and biofilm persistence during PJI, offering potential targets for therapeutic intervention.

Enhancing oncolytic virotherapy by extracellular vesicle mediated microRNA reprograming of the tumour microenvironment

BackgroundThere has been limited success of cancer immunotherapies in the treatment of ovarian cancer (OvCa) to date, largely due to the immunosuppressive tumour microenvironment (TME). Tumour-associated macrophages (TAMs) are a major component of both the primary tumour and malignant ascites, promoting tumour growth, angiogenesis, metastasis, chemotherapy resistance and immunosuppression. Differential microRNA (miRNA) profiles have been implicated in the plasticity of TAMs. Therefore, delivering miRNA to TAMs to promote an anti-tumour phenotype is a novel approach to reverse their pro-tumour activity and enhance the efficacy of cancer immunotherapies. Oncolytic viruses (OVs) preferentially replicate in tumour cells making them ideal vehicles to deliver miRNA mimetics to the TME. Importantly, miRNA expressed by OVs get packaged within tumour-derived extracellular vesicles (TDEVs), and release of TDEV is augmented by OV infection, thus enhancing the dissemination of miRNA throughout the TME.MethodSmall RNA sequencing was used to identify differentially expressed miRNA during TAM generation and following LPS/IFNγ stimulation to induce an anti-tumour phenotype. Two differentially expressed miRNA identified, miR-155 and miR-19a, were cloned into oncolytic rhabdovirus (ORV), and anti-tumour efficacy was investigated using both in vitro and in vivo models of OvCa.ResultsThis study demonstrates that ORV infection enhances TDEV production in OvCa cell lines both in vitro and in vivo and that TDEV are preferentially taken up by myeloid cells, including TAMs. Small RNA sequencing identified 23 miRNAs that were significantly upregulated in anti-tumour TAMs, including miR-155-5p. While 101 miRNAs were downregulated during pro-tumour TAM differentiation, including miR-19a-3p. Culturing TDEV expressing miR-155 or miR-19a with TAMs reversed their immunosuppressive activity, as measured by T cell proliferation. While ORV-miR-155 enhanced the generation of anti-tumour T cells, only ORV-miR19a significantly improved survival of mice bearing ovarian tumours.ConclusionThis study demonstrates (i) that arming ORVs with immunomodulatory miRNA is an effective approach to deliver miRNA to myeloid cells within the TME and (ii) that miRNA have the capacity to reverse the tumour promoting properties of TAMs and improve the efficacy of cancer immunotherapies, such as OV.

Genetically Engineered T Cells and Recombinant Antibodies to Target Intracellular Neoantigens: Current Status and Future Directions

Recombinant antibodies and, more recently, T cell receptor (TCR)-engineered T cell therapies represent two immunological strategies that have come to the forefront of clinical interest for targeting intracellular neoantigens in benign and malignant diseases. T cell-based therapies targeting neoantigens use T cells expressing a recombinant complete TCR (TCR-T cell), a chimeric antigen receptor (CAR) with the variable domains of a neoepitope-reactive TCR as a binding domain (TCR-CAR-T cell) or a TCR-like antibody as a binding domain (TCR-like CAR-T cell). Furthermore, the synthetic T cell receptor and antigen receptor (STAR) and heterodimeric TCR-like CAR (T-CAR) are designed as a double-chain TCRαβ-based receptor with variable regions of immunoglobulin heavy and light chains (VH and VL) fused to TCR-Cα and TCR-Cβ, respectively, resulting in TCR signaling. In contrast to the use of recombinant T cells, anti-neopeptide MHC (pMHC) antibodies and intrabodies neutralizing intracellular neoantigens can be more easily applied to cancer patients. However, different limitations should be considered, such as the loss of neoantigens, the modification of antigen peptide presentation, tumor heterogenicity, and the immunosuppressive activity of the tumor environment. The simultaneous application of immune checkpoint blocking antibodies and of CRISPR/Cas9-based genome editing tools to engineer different recombinant T cells with enhanced therapeutic functions could make T cell therapies more efficient and could pave the way for its routine clinical application.

Activatable Sulfur Dioxide Nanosonosensitizer Enables Precisely Controllable Sono-Gaseous Checkpoint Trimodal Therapy for Orthotopic Hepatocellular Carcinoma.

Immune checkpoint blockade (ICB) is combined with sonodynamic therapy (SDT) to increase response rates and enhance anticancer efficacy. However, the "always on" property of most sonosensitizers in reducing tumor microenvironment (TME) compromises the therapeutic outcome of sonoimmunotherapy and exacerbates adverse side effects. Precisely controllable strategies combining sulfur dioxide (SO2) gas therapy with cancer immunotherapy can address these issues but remain lacking. Herein an "activatable SO2 nanosonosensitizer" for precise sono-gaseous checkpoint trimodal therapy of orthotopic hepatocellular carcinoma (HCC) is reported, whose full activity is initiated by ultrasound (US) irradiation in the reducing TME. This "activatable SO2 nanosonosensitizer," Aza-DNBS nanoparticles (NPs), are established by self-assembling Aza-boron-dipyrromethene based sonosensitizer molecules and 2,4-dinitrobenzenesulfonate (DNBS)-caged SO2 prodrug. The activity of Aza-DNBS NPs is initially silenced, and the sonodynamic, gaseous, and immunosuppressive TME reprogramming activities are precisely awakened under US irradiation. Due to the glutathione-responsiveness of Aza-DNBS NPs, Aza-DNBS NPs can generate large amounts of SO2 for gas therapy-enhanced SDT, which triggers robust immunogenic cell death activation and reprogramming of the immunosuppressive TME, thereby significantly suppressing orthotopic tumor growth and delaying lung metastasis. Thus, this study represents a strategy for designing a generic nanoplatform for precisely combined immunotherapy of orthotopic HCC.

The 'Treg paradox' in inflammatory arthritis.

Classic regulatory T (Treg)cells expressing CD4 and the hallmark transcription factor FOXP3 are integral to the prevention of multi-system autoimmunity. However, immune-mediated arthritis is often associated with increased numbers of Treg cells in the inflamed joints. To understand these seemingly conflicting observations, which we collectively describe as 'the Treg paradox', we provide an overview of Treg cell biology with a focus on Treg cell heterogeneity, function and dysfunction in arthritis. We discuss how the inflamed environment constrains the immunosuppressive activity of Treg cells while also promoting the differentiation of TH17-like Tregcell, exTreg cell(effector T cells that were formerly Treg cells), and osteoclastogenic Treg cell subsets that mediate tissue injury. We present a new framework to understand Treg cells in joint inflammation and define potential strategies for Treg cell-directed interventions in human inflammatory arthritis.