Comparable clinical advantages identification of three formulae on rheumatic disease using a modular-based network proximity approach.

ETHNOPHARMACOLOGICAL RELEVANCE: Herbal formulae have been used in China for thousands of years but have unclear clinical positioning and unknown characteristic indications make it difficult to determine their specific application in various diseases, which seriously hamper their clinical value. Identifying the precise clinical positioning and clinical advantages of similar formulae for related diseases is a critical issue. AIM OF THIS STUDY: To develop a methodology based on modular pharmacology to determine the clinical advantages and precise clinical position of similar formulae. MATERIALS AND METHODS: In this study, we proposed a modular-based network proximity approach to explore drug repositioning and clinical advantages of three formulae, Shirebi tablets (SRB), Yuxuebi capsules (YXB), and Wangbifukang granules (WBFK), for rheumatic disease. First, we constructed a rheumatology target network, and modules were obtained using the cluster tool molecular complex detection (MCODE). Based on the modular interaction map established by a quantitative approach for inter-module coordination and its transition (IMCC), using a targeting rate (TR) matrix to identify targeted modules of three formulae. Moreover, the network proximity Z-score and Jaccard similarity coefficient were used to identify potential optimal symptomatic indications and related diseases using three formulae. At the same time, the driver genes for SRB and gouty arthritis were identified by flow centrality and shortest distance, and the epresentative driver genes were validated by in vivo experiments. RESULTS: 32 modules were obtained using the MCODE method. 4, 4, and 14 characteristic targeted modules of SRB, YXB, and WBFK, respectively, were identified using a targeting rate (TR) matrix. Module 2, 16, and 19 were targeted by both SRB and WBFK. The common effects of SRB and WBFK focused on inflammatory response and innate immune response, YXB was found to be involved in the collagen catabolic process, transmembrane receptor protein serine/threonine kinase signaling pathway. Moreover, potential optimal symptomatic indications and representative related diseases were identified for three formulae: SRB was significantly associated with GA (Z = -20.26); YXB was significantly associated with AS (Z = -4.532), MI (Z = -29.11), RhFv (Z = -6.945), OA (Z = -39.97), and GA (Z = -13.03); and WBFK was significantly associated with MI (Z = -205.5), SLE (Z = -37.65), RhFv (Z = -42.45), and GA (Z = -17.24). Finally, 8 driver genes for SRB and gouty arthritis were identified,the representative driver genes TRAF6 and NFE2L1 were validated by in vivo experiments. CONCLUSIONS: The modular-based network proximity approach proposed in this study may provide a new perspective for the precise drug repositioning and clinical advantages of similar formulae in disease treatment.

Ingestible Artificial Urinary Biomarker Probes for Urine Test of Gastrointestinal Cancer.

Although colorectal cancer diagnosed at an early stage shows high curability, methods simultaneously possessing point-of-care testing ability and high sensitivity are limited. Here, an orally deliverable biomarker-activatable probe (termed as HATS) for early detection of orthotopic tumors via remote urinalysis is presented. To enable its oral delivery to the colon, HATS is designed to have remarkable resistance to acidity and digestive enzymes in the stomach and small intestine and negligible intestinal absorption. Upon reaction with a cancer biomarker in the colon segment, HATS releases a small fragment of tetrazine that can transverse the intestinal barrier, enter blood circulation, and ultimately undergo renal clearance to urine. Subsequently, the urinary tetrazine fragment is detected by bioorthogonal reaction with trans-cyclooctene-caged resorufin (TCO-Reso) to afford a rapid and specific fluorescence enhancement of TCO-Reso. Such signal readout is correlated with the urinary tetrazine concentration and thus measures the level of cancer biomarkers in the colon. HATS-based optical urinalysis detects orthotopic colon tumors two weeks earlier than clinical serological tests and can be developed to a point-of-care paper test. Thereby, HATS-based urinalysis provides a non-invasive and sensitive approach to cancer screening at low-resource settings.

Direct Visualization of CO Interaction on Oxygen Poisoned Co(0001).

The poisoning of catalysts has always been a vital issue in catalytic reactions. In this study, direct observation of the interaction of CO and oxygen-poisoned Co(0001) has been achieved with scanning tunneling microscopy (STM), temperature-programmed desorption (TPD), and density functional theory calculation. A two-stage adsorption process of CO on a well-prepared p(2×2)-O layer covered Co(0001) was directly visualized. With increasing annealing time at a certain temperature after the CO dosage, the ordered (2 × 2) pattern formed in the first stage can be recovered, suggesting the weak interaction of CO with the O-covered Co(0001) surface in the latter stage. Compared to the clean Co(0001) surface, on an oxygen-poisoned surface, no further reaction was observed, illustrating the poisoning of the catalyst. Moreover, TPD results are in good agreement with the STM observation; a desorption energy of 0.35 eV is evaluated with a simple but accurate scheme.

Left ventricular reverse remodeling after transcatheter aortic valve replacement for predominant aortic stenosis and mixed aortic valve disease.

BACKGROUND: Mixed aortic valve disease (MAVD) is a frequent concomitant valve disease with unique cardiac pathological changes compared to predominant aortic stenosis (PAS). The previous studies about the MAVD are contradictory. Therefore, a new perspective is needed to assess the value of TAVR for this cohort of patients. METHODS: From January 2018 to December 2021, 90 MAVD patients and 72 PAS patients who underwent TAVR in our hospital were collected. 1:1 propensity score matching analysis was used to control the bias in patient selection. The dynamic changes in left ventricular morphology and hemodynamics were compared by generalized estimating equations. Univariate or multivariate logistic regression analysis was used to screen for independent risk factors for the non-occurrence of left ventricular reverse remodeling (non-LVRR). RESULTS: After the matching procedure, 112 patients were included in the analysis (56 in each group). Baseline characteristics were similar between the two groups. LVRR occurred in both groups, but MAVD had greater left ventricular end-diastolic volume index and left ventricular mass index, a higher incidence of mitral regurgitation (MR), and a more pronounced transformation of ventricular geometry patterns. Post-operative MR (odd ratio [OR]: 10.05; 95% confidence interval [CI]: 2.08-48.57; p < .001) and coronary artery disease (OR: 2.82; 95% CI: 1.08-7.34; p = .034) were independent risk factors for non-LVRR. CONCLUSION: LVRR also occurs in patients with MAVD, post-operative MR and coronary artery disease were independent risk factors for non-LVRR.

Astaxanthin attenuated cigarette smoke extract-induced apoptosis via decreasing oxidative DNA damage in airway epithelium.

Chronic obstructive pulmonary disease (COPD) is a lung inflammatory disease that is associated with environmental allergic component exposure. Cigarette smoke is an environmental toxicant that induces lung malfunction leading to various pulmonary diseases. Astaxanthin (AST) is a carotenoid that shows antioxidant and anti-inflammatory activities which might be a promising candidate for COPD therapy. In this study, we released that AST could attenuate cigarette smoke-induced DNA damage and apoptosis in vivo and in vitro. AST administration ameliorated cigarette smoke extract (CSE)-induced activation of Caspase-3 and apoptosis. Pretreated mice with AST significantly decrease CSE-induced DNA damage which shows lower nuclear γ-H2AX level. AST treatment also dramatically reduces the production of intracellular reactive oxygen species (ROS) by suppressing the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme 4 (NOX4) and dual oxidase 1 (DUOX1). Taken together, this study suggested that AST can decrease CSE-induced DNA damage and apoptosis by inhibiting NOX4/DUOX1 expression that promotes ROS generation. AST may be a potential protective agent against CSE-associated lung disease that is worth in-depth investigation.

Neferine Attenuates HDM-Induced Allergic Inflammation by Inhibiting the Activation of Dendritic Cell.

House dust mite (HDM) acts as an environmental antigen that might cause chronic allergic diseases. Neferine (NEF) shows anti-inflammation therapeutic effects. This study is to explore the protection role of NEF against HDM-induced allergic inflammation. HDM-induced allergic asthmatic C57BL/6J mice models were established. Differential histological staining was used to analyze lung tissue pathological scores. Flow cytometry was used to analyze subtypes and biomarker expression of immune cells. RT-PCR and ELISA were used to test cytokines-related gene and/or protein expression levels. Western blot was performed to investigate the signaling pathway that mediates allergic inflammation from mice lung tissue and bone marrow-derived dendritic cells (BMDCs). H&E and PAS staining results indicate NEF significantly attenuated inflammatory index and the percentage of goblet cells in the lung tissue induced by HDM. The HDM-elevated TH2 and TH17 cells were significantly decreased by NEF; inflammatory cytokines Il-4, Il-13 and Il-17 were dramatically downregulated in the NEF plus HDM group compared with HDM alone. CD40+ and CD86+ DCs, eosinophils and mast cells, and ILC2 cells were decreased by NEF which was elevated under HDM stimulation. In vivo and ex vivo investigations indicated NEF can attenuate the activated NF-κB signaling induced by HDM is involved in allergic inflammatory immune response and regulates cytokines-related gene expression. HDM-activated DCs promoted differentiation of TH2 and TH17 cells but were attenuated by NEF. This study suggests NEF interrupts the overexpression of some cytokines released by DCs, TH2, and TH17 cells; NEF attenuates HDM-induced allergic inflammation via inhibiting NF-κB signaling of DCs.

A Polymeric Extracellular Matrix Nanoremodeler for Activatable Cancer Photo-Immunotherapy.

Cancer immunotherapy has shown tremendous potential to train the intrinsic immune system against malignancy in the clinic. However, the extracellular matrix (ECM) in tumor microenvironment is a formidable barrier that not only restricts the penetration of therapeutic drugs but also prevents the infiltration of antitumor immune cells. We herein report a semiconducting polymer-based ECM nanoremodeler (SPNcb) to combine photodynamic antitumor activity with cancer-specific inhibition of collagen-crosslinking enzymes (lysyl oxidase (LOX) family) for activatable cancer photo-immunotherapy. SPNcb is self-assembled from an amphiphilic semiconducting polymer conjugated with a LOX inhibitor (ß-aminopropionitrile, BAPN) via a cancer biomarker (cathepsin B, CatB)-cleavable segment. BAPN can be exclusively activated to inhibit LOX activity in the presence of the tumor-overexpressed CatB, thus blocking collagen crosslinking and decreasing ECM stiffness. Such an ECM nanoremodeler synergizes immunogenic phototherapy and checkpoint blockade immunotherapy to improve the tumor infiltration of cytotoxic T cells, inhibiting tumor growth and metastasis.

[Discussion on discipline of herbalism].

Since the emergence of the term "materia medica", scholars have proposed different opinions on its concept. This term has been used to refer to traditional Chinese medicines, or medical books, or traditional pharmacology. Due to the differences in the concept of materia medica, scholars also have controversies about the concept of herbalism. Herbalism is usually understood as traditional Chinese pharmacology. After years of evolution, the term "herbalism" has now possessed the characteristics of an independent discipline, which can be defined as an applied basic discipline that comprehensively utilizes traditional and modern technological methods to study the formation, development, and changes of traditional pharmacology and reveal the basic theories and application laws of traditional medicine. At present, the research content of herbalism mainly includes three aspects: materia medica history, materia medica literature, and traditional pharmacology. This study explores the disciplinary concepts and main research content of herbalism based on a systematic review of the literature about the concepts of materia medica and herbalism, with the aim of attracting more attention to promote the establishment and development of the discipline of herbalism.

State-of-the-art self-luminescence: a win-win situation.

Self-luminescence, which eliminates the real-time external optical excitation, can effectively avoid background autofluorescence in photoluminescence, endowing with ultrahigh signal-to-noise ratio and sensitivity in bioassay. Furthermore, in situ generated and emitted photons have been applied to develop excitation-free diagnostics and therapeutic agents against deeply seated diseases. "Enhanced" self-luminescence, referring to the aggregation-induced emission (AIE)-integrated self-luminescence systems, is endowed with not only the above merits but also other superiorities including stronger luminous brightness and longer half-life compared with "traditional" self-luminescence platforms. As an emerging and booming hotspot, the "enhanced" self-luminescence facilitated by the win-win cooperation of the aggregation-induced emission and self-luminescent techniques has become a powerful tool for interdisciplinary research. This tutorial review summarizes the advancements of AIE-assisted self-luminescence including chemiluminescence and afterglow imaging, starting from the discussion on the design and working principles, luminescent mechanisms of self-luminescence fuels, versatile integrated approaches and advantages, and a broad range of representative examples in biosensors and oncotherapy. Finally, the current challenges and perspectives are discussed to further actuate the development of "enhanced" self-luminescence agents for biomedical diagnosis and treatment.

Precision cancer sono-immunotherapy using deep-tissue activatable semiconducting polymer immunomodulatory nanoparticles.

Nanomedicine holds promise to enhance cancer immunotherapy; however, its potential to elicit highly specific anti-tumor immunity without compromising immune tolerance has yet to be fully unlocked. This study develops deep-tissue activatable cancer sono-immunotherapy based on the discovery of a semiconducting polymer that generates sonodynamic singlet oxygen (1O2) substantially higher than other sonosensitizers. Conjugation of two immunomodulators via 1O2-cleavable linkers onto this polymer affords semiconducting polymer immunomodulatory nanoparticles (SPINs) whose immunotherapeutic actions are largely inhibited. Under ultrasound irradiation, SPINs generate 1O2 not only to directly debulk tumors and reprogram tumor microenvironment to enhance tumor immunogenicity, but also to remotely release the immunomodulators specifically at tumor site. Such a precision sono-immunotherapy eliminates tumors and prevents relapse in pancreatic mouse tumor model. SPINs show effective antitumor efficacy even in a rabbit tumor model. Moreover, the sonodynamic activation of SPINs confines immunotherapeutic action primarily to tumors, reducing the sign of immune-related adverse events.

Atomic-Scale Observation of Sequential Oxidation Process on Co(0001).

Oxygen dissociation and activation on surfaces play a crucial role in heterogeneous catalysis and oxidation processes. In this study, we have conducted a series of scanning tunneling microscopy (STM) experiments combined with density functional theory calculation to investigate the oxidation process in a single crystal Co(0001) surface. For the first time, we show a comprehensive in situ STM study of the oxidation process of Co(0001) from an atomic point of view. With low O2 exposure at 90 K, chemisorbed oxygen pairs are observed showing a dumbbell-like STM feature. At a relatively higher temperature range of 160-250 K, a large-scale p(2 × 2)-O adlayer forms and the O adatoms show surprisingly high mobility. With the temperature of Co(0001) kept at ≥300 K, adsorption of oxygen leads to fast oxidation of the surface to amorphous cotton-like protrusions, which occur initially at the step/edge sites and interstitial defect sites.

Catalytical nano-immunocomplexes for remote-controlled sono-metabolic checkpoint trimodal cancer therapy.

Checkpoint immunotherapies have been combined with other therapeutic modalities to increase patient response rate and improve therapeutic outcome, which however exacerbates immune-related adverse events and requires to be carefully implemented in a narrowed therapeutic window. Strategies for precisely controlled combinational cancer immunotherapy can tackle this issue but remain lacking. We herein report a catalytical nano-immunocomplex for precise and persistent sono-metabolic checkpoint trimodal cancer therapy, whose full activities are only triggered by sono-irradiation in tumor microenvironment (TME). This nano-immunocomplex comprises three FDA-approved components, wherein checkpoint blockade inhibitor (anti-programmed death-ligand 1 antibody), immunometabolic reprogramming enzyme (adenosine deaminase, ADA), and sonosensitizer (hematoporphyrin) are covalently immobilized into one entity via acid-cleavable and singlet oxygen-activatable linkers. Thus, the activities of the nano-immunocomplex are initially silenced, and only under sono-irradiation in the acidic TME, the sonodynamic, checkpoint blockade, and immunometabolic reprogramming activities are remotely awakened. Due to the enzymatic conversion of adenosine to inosine by ADA, the nano-immunocomplex can reduce levels of intratumoral adenosine and inhibit A2A/A2B adenosine receptors-adenosinergic signaling, leading to efficient activation of immune effector cells and inhibition of immune suppressor cells in vivo. Thus, this study presents a generic and translatable nanoplatform towards precision combinational cancer immunotherapy.

Efficacy and Safety of Low-Dose Rituximab in Anti-MuSK Myasthenia Gravis Patients: A Retrospective Study.

Purpose: To evaluate the efficacy and safety of low dosages of rituximab (RTX) in the treatment of MuSK-antibody-positive MG patients. Patients and Methods: We retrospectively analyzed the data of MuSK-antibody-positive MG patients who were treated with low dosages of RTX from January 2018 to October 2021. The long-term treatment response to RTX was assessed by Myasthenia Gravis Foundation of America (MGFA) post-interventional status (PIS), Myasthenia Gravis Status and Treatment Intensity (MGSTI), dosage of steroid, MG-related activities of daily living (MG-ADL) and myasthenic muscle score (MMS) at the end of follow-up. Results: Clinical improvement was observed in all eight patients with follow-up for 8 to 29 months after treatment. At the last visit, complete stable remission had been achieved in one patient, pharmacologic remission in three patients, minimal manifestations status in three patients and improved in one patient based on the MGFA-PIS criteria. MGSTI level 2 or better had been reached in six (75%) patients at the last visit. The steroid dosage decreased from 60 mg at baseline to 15 mg at the last follow-up (p = 0.011). The average MG-ADL score decreased from 11 (range 7 to 15) to 0 (range 0 to 3; p = 0.011), and the MMS improved from 38.5 (range 24 to 60) to 100 (range 90 to 100; p = 0.012). These differences were all statistically significant. During RTX treatment and subsequent follow-up, 1 patient reported minor post-infusion malaise. Conclusion: Low-dose RTX is effective and safe for treating anti-MuSK antibody positive MG patients. A long-term response is observed after treatment. Larger prospective studies are required to provide further evidence.

Activatable Cancer Sono-Immunotherapy using Semiconducting Polymer Nanobodies.

Despite the great promises of sonodynamic therapy (SDT) in combination cancer therapy, its clinical applications are hindered by the "always-on" pharmacological activities of therapeutic agents and the lack of efficient sonosensitizers. Herein, the development of semiconducting polymers as efficient sonosensitizers and further development of sono-immunotherapeutic nanobodies (SPNAb ) for activatable cancer sono-immunotherapy are reported. Conjugation of anti-CTLA-4 antibodies onto the polymer nanoparticles through a 1 O2 -cleavable linker affords SPNAb with relatively low CTLA-4 binding affinity. Upon sono-irradiation, SPNAb generates 1 O2 not only to elicit a sonodynamic effect to induce immunogenic cell death, but also to release anti-CTLA-4 antibodies and trigger in situ checkpoint blockade. Such a synergistic therapeutic action mediated by SPNAb modulates the tumoricidal function of T-cell immunity by promoting the proliferation of cytotoxic T lymphocytes and depleting immunosuppressive regulatory T cells, resulting in effective tumor regression, metastasis inhibition, durable immunological memory, and prevention of relapse. Therefore, this study represents a proof-of-concept sonodynamic strategy using semiconducting polymers for precise spatiotemporal control over immunotherapy.

A Dual-Locked Activatable Phototheranostic Probe for Biomarker-Regulated Photodynamic and Photothermal Cancer Therapy.

Activatable phototheranostics holds promise for precision cancer treatment owing to the "turn-on" signals and therapeutic effects. However, most activatable phototheranostic probes only possess photodynamic therapy (PDT) or photothermal therapy (PTT), which suffer from poor therapeutic efficacy due to deficient cellular oxygen and complex tumor microenvironment. We herein report a dual-locked activatable phototheranostic probe that activates near-infrared fluorescence (NIRF) signals in tumor, triggers PDT in response to a tumor-periphery biomarker, and switches from PDT to PTT upon detecting a tumor-core-hypoxia biomarker. This PDT-PTT auto-regulated probe exhibits complete tumor ablation under the photoirradiation of a single laser source by producing cytotoxic singlet oxygen at the tumor periphery and generating hyperthermia at tumor-core where is too hypoxic for PDT. This dual-locked probe represents a promising molecular design approach toward precise cancer phototheranostics.

Smart Nano-PROTACs Reprogram Tumor Microenvironment for Activatable Photo-metabolic Cancer Immunotherapy.

Protease inhibitors can modulate intratumoral metabolic processes to reprogram the immunosuppressive tumor microenvironment (TME), which however suffer from the limited efficacy and off-targeted side effects. We report smart nano-proteolysis targeting chimeras (nano-PROTACs) with phototherapeutic ablation and cancer-specific protein degradation to reprogram the TME for photo-metabolic cancer immunotherapy. This nano-PROTAC has a semiconducting polymer backbone linked with a cyclooxygenase 1/2 (COX-1/2)-targeting PROTAC peptide (CPP) via a cathepsin B (CatB)-cleavable segment. CPP can be activated by the tumor-overexpressed CatB to induce the degradation of COX-1/2 via the ubiquitin-proteasome system. The persistent degradation of COX-1/2 depletes their metabolite prostaglandin E2 which is responsible for activation of immune suppressor cells. Such a smart PROTAC strategy synergized with phototherapy specifically reprograms the immunosuppressive TME and reinvigorates antitumor immunity.

Activatable molecular probes for fluorescence-guided surgery, endoscopy and tissue biopsy.

The real-time, dynamic optical visualization of lesions and margins ensures not only complete resection of the malignant tissues but also better preservation of the vital organs/tissues during surgical procedures. Most imaging probes with an "always-on" signal encounter high background noise due to their non-specific accumulation in normal tissues. By contrast, activatable molecular probes only "turn on" their signals upon reaction with the targeted biomolecules that are overexpressed in malignant cells, offering high target-to-background ratios with high specificity and sensitivity. This review summarizes the recent progress of activatable molecular probes in surgical imaging and diagnosis. The design principle and mechanism of activatable molecular probes are discussed, followed by specific emphasis on applications ranging from fluorescence-guided surgery to endoscopy and tissue biopsy. Finally, potential challenges and perspectives in the field of activatable molecular probe-enabled surgical imaging are discussed.

Renal-Clearable Molecular Probe for Near-Infrared Fluorescence Imaging and Urinalysis of SARS-CoV-2.

Despite the importance of rapid and accurate detection of SARS-CoV-2 in controlling the COVID-19 pandemic, current diagnostic methods are static and unable to distinguish between viable/nonviable virus or directly reflect viral replication activity. Real-time imaging of protease activity specific to SARS-CoV-2 can overcome these issues but remains lacking. Herein, we report a near-infrared fluorescence (NIRF) activatable molecular probe (SARS-CyCD) for detection of SARS-CoV-2 protease in living mice. The probe comprises a hemicyanine fluorophore caged with a protease peptide substrate and a cyclodextrin unit, which function as an NIRF signaling moiety and a renal-clearable enabler, respectively. The peptide substrate of SARS-CyCD can be specifically cleaved by SARS-CoV-2 main protease (Mpro), resulting in NIRF signal activation and liberation of the renal-clearable fluorescent fragment (CyCD). Such a design not only allows sensitive detection of Mpro in the lungs of living mice after intratracheal administration but also permits optical urinalysis of SARS-CoV-2 infection. Thus, this study presents an in vivo sensor that holds potential in preclinical high-throughput drug screening and clinical diagnostics for respiratory viral infections.

Hemicyanine-Based Near-Infrared Activatable Probes for Imaging and Diagnosis of Diseases.

Molecular activatable probes with near-infrared (NIR) fluorescence play a critical role in in vivo imaging of biomarkers for drug screening and disease diagnosis. With structural diversity and high fluorescence quantum yields, hemicyanine dyes have emerged as a versatile scaffold for the construction of activatable optical probes. This Review presents a survey of hemicyanine-based NIR activatable probes (HNAPs) for in vivo imaging and early diagnosis of diseases. The molecular design principles of HNAPs towards activatable optical signaling against various biomarkers are discussed with a focus on their broad applications in the detection of diseases including inflammation, acute organ failure, skin diseases, intestinal diseases, and cancer. This progress not only proves the unique value of HNAPs in preclinical research but also highlights their high translational potential in clinical diagnosis.

Charge-Reversal Polymer Nano-modulators for Photodynamic Immunotherapy of Cancer.

Nanomedicine can regulate the balance between cytotoxic T lymphocytes (CTLs) and suppressive regulatory T lymphocytes (Tregs), which however has been rarely exploited for cancer immunotherapy. We report a charge-reversal polymer nano-modulator (SPDMC N) activated by tumor microenvironment (TME) for photodynamic immunotherapy of cancer. SPDMC N is constructed by conjugating an immunomodulator (demethylcantharidin, DMC) to the side chains of a photodynamic polymer via an acid-liable linker. The negative charge of SPDMC N ensures its high stability in blood circulation and ideal tumor accumulation; exposure to acidic TME reverses its surface charge to positive, enhancing tumor penetration and locally releasing DMC. Upon near-infrared photoirradiation, SPDMC N generates singlet oxygen to ablate tumors and promote maturation of dendritic cells. Released DMC inhibits protein phosphatase 2 (PP2A) activity and decreases Tregs differentiation. Such combinational action induces a sharp increase in CTL/Treg ratio in TME and effectively inhibits both primary and distant tumors in living mice.