The natural compound Cirsitakaoside enhances antiviral innate responses against vesicular stomatitis virus in vitro and in vivo

Cirsitakaoside, isolated and purified from the stems and leaves of Premna szemaoensis and Macaranga denticulata, is a natural compound with potential anti-inflammatory effects. However, the role of Cirsitakaoside in antiviral activity and the underlying mechanism remains largely unknown. In this study, we aimed to identify whether Cirsitakaoside has antiviral activity and investigated the underlying mechanisms. Mouse peritoneal macrophages were pretreated with Cir or DMSO, and then infected by Vesicular Stomatitis Virus (VSV) for indicated hours, Q-PCR and ELISA were used to detect the expression of interferons and pro-inflammatory cytokines, immunoblot assay were employed to investigate the involved signaling pathway in the antiviral effects of Cirsitakaoside. Furthermore, mice infected with VSV were used to investigate the antiviral activities of Cirsitakaoside in vivo. Our study demonstrated that Cirsitakaoside could promote type I IFN expression and inhibit pro-inflammatory cytokines such as IL-6 and TNF-α production in mouse peritoneal macrophages infected by VSV. Suppressive viral replication effects of Cirsitakaoside were observed on VSV-infected mouse peritoneal macrophages as well. Furthermore, Cirsitakaoside significantly increased the VSV-triggered phosphorylation of TBK1, IRF3 and reduced the phosphorylation of IκBα and p65 in mouse peritoneal macrophages. in vivo, the results showed that Cirsitakaoside-treated mice were more resistant to VSV infection by producing more IFN-β and less pro-inflammatory cytokines. Our study indicates that Cirsitakaoside is a good candidate for the treatment of viral infection and inflammation-related diseases.     

Low-dose naltrexone inhibits the epithelial-mesenchymal transition of cervical cancer cells in vitro and effects indirectly on tumor-associated macrophages in vivo

The metastasis of cervical cancer has always been a clinical challenge. We investigated the effects of low-dose naltrexone (LDN) on the epithelial mesenchymal transition of cervical cancer cells in vitro as well as its influence on macrophage polarization and associated cytokines in vivo. The results suggested that LDN supressed the proliferation, migration and invasion abilities and promote their apoptosis in Hela cells, whereas the opioid growth factor receptor (OGFr) silenced significantly reversed these effects in vitro. Knockdown the expression of OGFr, the inhibitory of LDN on EMT was weakened. LDN could inhibit cervical cancer progression in nude mice. In additon, LDN indirectly reduced the number of tumor-associated macrophages (TAMs), mainly M2 macrophages, and decreased expression of anti-inflammatory factor IL-10 in the serum of nude mice. These findings demonstrate that LDN could be a potential treatment for cervical cancer.     

The role of JAK/STAT signaling pathway and its inhibitors in diseases

The JAK/STAT signaling pathway is an universally expressed intracellular signal transduction pathway and involved in many crucial biological processes, including cell proliferation, differentiation, apoptosis, and immune regulation. It provides a direct mechanism for extracellular factors-regulated gene expression. Current researches on this pathway have been focusing on the inflammatory and neoplastic diseases and related drug.The mechanism of JAK/STAT signaling is relatively simple. However, the biological consequences of the pathway are complicated due to its crosstalk with other signaling pathways. In addition, there is increasing evidence indicates that the persistent activation of JAK/STAT signaling pathway is closely related to many immune and inflammatory diseases, yet the specific mechanism remains unclear. Therefore, it is necessary to study the detailed mechanisms of JAK/STAT signaling in disease formation to provide critical reference for clinical treatments of the diseases.In this review, we focus on the structure of JAKs and STATs, the JAK/STAT signaling pathway and its negative regulators, the associated diseases, and the JAK inhibitors for the clinical therapy.     

IFN regulatory Factor-1 induced macrophage pyroptosis by modulating m6A modification of circ_0029589 in patients with acute coronary syndrome

BackgroundPyroptosis is identified as a novel form of inflammatory programmed cell death and has been recently found to be closely related to atherosclerosis (AS). We found that IFN regulatory factor-1(IRF-1) effectively promotes macrophage pyroptosis in patients with acute coronary syndrome (ACS). Subsequent studies have demonstrated that circRNAs are implicated in AS. However, the underlying mechanisms of circRNAs in macrophage pyroptosis remain elusive.MethodsWe detected the RNA expression of hsa_circ_0002984, hsa_circ_0010283 and hsa_circ_0029589 in human PBMC-derived macrophages from patients with coronary artery disease (CAD). The lentiviral recombinant vector for hsa_circ_0029589 overexpression (pLC5-GFP-circ_0029589) and small interference RNAs targeting hsa_circ_0029589 and METTL3 were constructed. Then, macrophages were transfected with pLC5-GFP-circ_0029589, si-circ_0029589 or si-METTL3 after IRF-1 was overexpressed and to explore the potential mechanism of hsa_circ_0029589 involved in IRF-1 induced macrophage pyroptosis.ResultsThe relative RNA expression level of hsa_circ_0029589 in macrophages was decreased, whereas the N6-methyladenosine (m6A) level of hsa_circ_0029589 and the expression of m6A methyltransferase METTL3 were validated to be significantly elevated in macrophages in patients with ACS. Furthermore, overexpression of IRF-1 suppressed the expression of hsa_circ_0029589, but induced its m6A level along with the expression of METTL3 in macrophages. Additionally, either overexpression of hsa_circ_0029589 or inhibition of METTL3 significantly increased the expression of hsa_circ_0029589 and attenuated macrophage pyroptosis.ConclusionOur observations suggest a novel mechanism by which IRF-1 facilitates macrophage pyroptosis and inflammation in ACS and AS by inhibiting circ_0029589 through promoting its m6A modification.     

Celastrol and Rhynchophylline in the mitigation of simulated muscle atrophy under in vitro

BackgroundMuscular atrophy (MA) is a disease of various origins, i.e., genetic or the most common, caused by mechanical injury. So far, there is no universal therapeutic model because this disease is often progressive with numerous manifested symptoms. Moreover, there is no safe and low-risk therapy dedicated to muscle atrophy. For this reason, our research focuses on finding an alternative method using natural compounds to treat MA. This study proposes implementing natural substances such as celastrol and Rhynchophylline on the cellular level, using a simulated and controlled atrophy process. Methods: Celastrol and Rhynchophylline were used as natural compounds against simulated atrophy in C2C12 cells. Skeletal muscle C2C12 cells were stimulated for the differentiation process. Atrophic conditions were obtained by the exposure to the low concertation of doxorubicin and validated by FoxO3 and MAFbx. The protective and regenerative effect of drugs on cell proliferation was determined by the MTT assay and MT-CO1, VDAC1, and prohibitin expression. Results: The obtained results revealed that both natural substances reduced atrophic symptoms. Rhynchophylline and celastrol attenuated atrophic cells in the viability studies, morphology analysis by diameter measurements, modulated prohibitin VDAC, and MT-CO1 expression. Conclusions: The obtained results revealed that celastrol and Rhynchophylline could be effectively used as a supportive treatment in atrophy-related disorders. Thus, natural drugs seem promising for muscle regeneration.     

The role of nuclear factors as “Find-Me”/alarmin signals and immunostimulation in defective efferocytosis and related disorders

Efferocytosis as an apoptotic cell (AC) clearance mechanism facilitates the removal of dangerous and damaged cells, an important process in regulating normal homeostasis. Failure to correctly execute apoptosis and efferocytosis is associated with atherosclerosis, as well as chronic inflammatory and autoimmune disorders such as systemic lupus erythematosus (SLE). Effective and timely efferocytosis involves various molecules that act as “Find-Me” signals or as alarmins to quickly allow identification by phagocytic cells. In recent years, most of these molecules have been investigated, but less attention has been paid to the nuclear molecules associated with efferocytosis of ACs and necrotic cells (NCs). These molecules have several functions including acting as alarmin signals for faster recognition of ACs, facilitating the cleanup of ACs and for maintaining self-tolerance. The same group of molecules is also implicated in several inflammatory and autoimmune diseases. Previous studies have shown that these molecules also serve as targets for pharmacological agents such as necrostatins, recombinant Fcnb, anti-histone, neutralizing antibodies, calbiochem, aminophylline, activated protein C, CD24IgG recombinant fission protein, and recombinant thrombomodulin. Thus, greater understanding of these molecules/pathways will enable developments in the treatment and/or prevention of various disorders, especially autoimmune diseases. Here, we review current knowledge about the mechanisms by which nucleic acids, histones, nucleosomes and monosodium urate microcrystals (MSU) can act as alarmins/“Find-Me” signals, how they might be stimulated in defective efferocytosis and their function and importance as biomarkers for prognosis and treatment of atherosclerosis, inflammatory disorders and autoimmune diseases.     

Recent advances in the study of progranulin and its role in sepsis

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. The mortality rate of in-hospital patients whose conditions are complicated by sepsis remains high in spite of intensive-care treatment, therefore placing a significant financial burden on the health care system. In recent years, progranulin (PGRN), a cysteine-rich secretory protein (CRISP), has been found to play a crucial role in sepsis. PGRN participates in the pathogenesis of sepsis via diverse pathways, including bacterial clearance, cell growth and survival, tissue repair, and the regulation of inflammation. PGRN knockout mice suffer from serious infectious processes, whereas therapeutic administration of recombinant PGRN to such mice enhances bacterial clearance and reduces organ injury and mortality rate. Even though PGRN plays an important role in regulating sepsis, its potential mechanisms have not been completely clarified. In this review, we summarize the most recent research advances in the study of PGRN and its role in sepsis.     

Recent insights of the role and signalling pathways of interleukin-34 in liver diseases

Liver disease is a global health problem and is a primary cause of mortality and morbidity worldwide. Specifically, it accounts for approximately two million deaths per year worldwide. The common causes of mortality are the complications of liver cirrhosis, viral hepatitis and hepatocellular carcinoma (HCC). The mechanism of immune response and infiltration of cellular immunity is essential for promoting hepatic inflammatory, especially when the liver is abundant with lymphocytes and phagocytic cells. The injured and immunity cells secret different types of interleukins (cytokines), which can directly or indirectly amplify or inhibit liver inflammation. Many types of cells can produce interleukin-34 (IL-34) that induces the release of multiple inflammatory factors in patients via interaction with various cytokines. This phenomenon leads to the enlargement of the inflammatory response to liver diseases and induces liver fibrosis. This review highlights the proposed roles of IL-34 in liver diseases and discusses the recent findings of IL-34 that support its emerging role in HCC. Specifically, the facilitating effects of these new insights on the rational development of IL-34 for targeted therapies in the future are explored.     

Crosstalk among colon cancer-derived exosomes,fibroblast-derived exosomes,and macrophage phenotypes in colon cancer metastasis

Cellular crosstalk is an important mechanism in the pathogenesis of inflammatory disorders and cancers. One significant means by which cells communicate with each other is through the release of exosomes. Exosomes are extracellular vesicles formed by the outward budding of plasma membranes, which are then released from cells into the extracellular space. Many studies have suggested that microvesicles released by colon cancer cells initiate crosstalk and modulate the fibroblast activities and macrophage phenotypes. Interestingly, crosstalk among colon cancer cells, macrophages and cancer-associated fibroblasts maximizes the mechanical composition of the stromal extracellular matrix (ECM). Exosomes contribute to cancer cell migration and invasion, which are critical for colon cancer progression to metastasis. The majority of the studies on colorectal cancers (CRCs) have focused on developing exosomal biomarkers for the early detection and prediction of CRC prognosis. This study highlights the crosstalk among colon cancer-derived exosomes, macrophage phenotypes and fibroblasts during colon cancer metastasis.     

Genistein promotes M1 macrophage apoptosis and reduces inflammatory response by disrupting miR-21/TIPE2 pathway

Cardiovascular diseases are a major cause of mortality, and vascular injury, a common pathological basis of cardiovascular disease, is deeply correlated with macrophage apoptosis and inflammatory response. Genistein, a type of phytoestrogen, exerts cardiovascular protective activities, but the underlying mechanism has not been fully elucidated. In this study, RAW264.7 cells were treated with genistein, lipopolysaccharide (LPS), nuclear factor-kappa B (NF-κB) inhibitor, and/or protein kinase B (AKT) agonist to determine the role of genistein in apoptosis and inflammation in LPS-stimulated cells. Simultaneously, high fat diet-fed C57BL/6 mice were administered genistein to evaluate the function of genistein on LPS-induced cardiovascular injury mouse model. Here, we demonstrated that LPS obviously increased apoptosis resistance and inflammatory response of macrophages by promoting miR-21 expression, and miR-21 downregulated tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) expression by targeting the coding region. Genistein reduced miR-21 expression by inhibiting NF-κB, then blocked toll-like receptor 4 (TLR4) pathway and AKT phosphorylation dependent on TIPE2, resulting in inhibition of LPS. Our research suggests that miR-21/TIPE2 pathway is involved in M1 macrophage apoptosis and inflammatory response, and genistein inhibits the progression of LPS-induced cardiovascular injury at the epigenetic level via regulating the promoter region of Vmp1 by NF-κB.     

In vitro and in vivo characterization of erythrosin B and derivatives against Zika virus

Zika virus (ZIKV) causes significant human diseases without specific therapy. Previously we found erythrosin B, an FDA-approved food additive, inhibited viral NS2B?NS3 interactions, leading to inhibition of ZIKV infection in cell culture. In this study, we performed pharmacokinetic and in vivo studies to demonstrate the efficacy of erythrosin B against ZIKV in 3D mini-brain organoid and mouse models. Our results showed that erythrosin B is very effective in abolishing ZIKV replication in the 3D organoid model. Although pharmacokinetics studies indicated that erythrosin B had a low absorption profile, mice challenged by a lethal dose of ZIKV showed a significantly improved survival rate upon oral administration of erythrosin B, compared to vehicle control. Limited structure?activity relationship studies indicated that most analogs of erythrosin B with modifications on the xanthene ring led to loss or reduction of inhibitory activities towards viral NS2B?NS3 interactions, protease activity and antiviral efficacy. In contrast, introducing chlorine substitutions on the isobenzofuran ring led to slightly increased activities, suggesting that the isobenzofuran ring is well tolerated for modifications. Cytotoxicity studies indicated that all derivatives are nontoxic to human cells. Overall, our studies demonstrated erythrosin B is an effective antiviral against ZIKV both in vitro and in vivo.     

Defining the role of CFTR channel blocker and ClC-2 activator in DNBS induced gastrointestinal inflammation

In the present study, we have investigated and/or compared the role of glibenclamide, G as cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor, and lubiprostone, L as chloride channel-2 (ClC-2) activator in the 2,4-dinitrobenzene sulfonic acid (DNBS)-induced gastrointestinal inflammation. GI inflammation was induced by intrarectal administration of DNBS. Rats were randomly allocated in 5 groups as sham control, distilled water + DNBS, sulfasalazine (S) + DNBS, G + DNBS, and L + DNBS. All the groups were pre-treated successively for five days before the induction of colitis. One day before and the first four days after DNBS administration various parameters were studied. Later, blood chemistry, colon’s gross structure, histology, and the antioxidant load was examined. Pre-treatment with G significantly protected the change induced by DNBS concerning the change in body weight, food intake, diarrhea, occult blood in the feces, wet weight of the colon, and spleen. G because of its anti-inflammatory property down-regulated the neutrophil and WBC count and up-regulated the lymphocyte number. Moreover, G efficiently ameliorates the oxidative stress in the colon and declines the level of myeloperoxidase and malondialdehyde and up-regulated the level of superoxide dismutase and glutathione. Lubiprostone has not shown any promising effects, in fact, it causes an increase in diarrheal frequency. Our findings from this study represent that G has good potential to ameliorate GI inflammation induced by DNBS by its multiple actions including CFTR blockage and reducing the release of inflammatory markers from the MCs, anti-inflammatory and free radical scavenging property.     

Design of semisynthetic derivatives of the Amaryllidaceae alkaloid ambelline and exploration of their in vitro cytotoxic activities

Ambelline, an alkaloid from the Amaryllidaceae family with a crinane-type skeleton, has not yet demonstrated any outstanding biological activity. However, its analogues prepared by derivatization of the C-11 hydroxyl group show different interesting effects. Continuing our earlier work, twelve novel aromatic esters were developed (10, 14, 16, 17, 22–25, 30–33) and studied, together with previously synthesized derivatives (2–9, 11–13, 15, 18–21, 26–29) in terms of their cytotoxic activity. The cytotoxic potential was determined on a panel of nine human cancer cell lines and one noncancerous cell line to characterize their biological activity spectrum. To describe and foresee the structure–activity relationship for further research, substances synthesized and described in our previous work were also included in this cytotoxicity study. The most significant activity was associated with analogues having methyl (10), methoxy (14–17), or ethoxy (18) substitution on the phenyl condensed to ambelline. However, the 4-chloro-3-nitrobenzoyl derivative (32) showed the most promising IC₅₀ values, ranging from 0.6 ± 0.1 µM to 9.9 ± 0.2 µM. In vitro cytotoxicity studies indicated the most potent antiproliferative activity of 32 in a dose-dependent and time-dependent manner. Besides, 32 was found to be effective in decreasing viability and triggering apoptosis of MOLT-4 T-lymphoblastic leukemia cells.     

Phyllanthus emblica (Amla) methanolic extract regulates multiple checkpoints in 15-lipoxygenase mediated inflammopathies: Computational simulation and in vitro evidence

Amla (Phyllanthus emblica) has long been used in traditional folk medicine to prevent and cure a variety of inflammatory diseases. In this study, the antioxidant activity (DPPH scavenging and reducing power), anti-inflammatory activity (RBC Membrane Stabilization and 15-LOX inhibition), and anticoagulation activity (Serin protease inhibition and Prothrombin Time assays) of the methanolic extract of amla were conducted. Amla exhibited a substantial amount of phenolic content (TPC: 663.53 mg GAE/g) and flavonoid content (TFC: 418.89 mg GAE/g). A strong DPPH scavenging effect was observed with an IC₅₀ of 311.31 µg/ml as compared to standard ascorbic acid with an IC₅₀ of 130.53 µg/ml. In reducing power assay, the EC₅₀ value of the extract was found to be 196.20 µg/ml compared to standard ascorbic acid (EC₅₀ = 33.83 µg/ml). The IC₅₀ value of the RBC membrane stabilization and 15-LOX assays was observed as 101.08 µg/ml (IC₅₀ of 58.62 µg/ml for standard aspirin) and 195.98 µg/ml (IC₅₀ of 19.62 µg/ml for standard quercetin), respectively. The extract also strongly inhibited serine protease (trypsin) activity with an IC₅₀ of 505.81 µg/ml (IC₅₀ of 295.44 µg/ml for standard quercetin). The blood coagulation time (PTT) was found to be 11.91 min for amla extract and 24.11 min for standard Warfarin. Thus, the findings of an in vitro study revealed that the methanolic extract of amla contains significant antioxidant, anti-inflammatory, and anticoagulation activity. Furthermore, in silico docking and simulation of reported phytochemicals of amla with human 15-LOXA and 15-LOXB were carried out to validate the anti-inflammatory activity of amla. In this analysis, epicatechin and catechin showed greater molecular interaction and were considerably stable throughout the 100 ns simulation with 15-lipoxygenase A (15-LOXA) and 15-lipoxygenase B (15-LOXB) respectively.     

Fraxetin inhibits interleukin-1β-induced apoptosis,inflammation, and matrix degradation in chondrocytes and protects rat cartilage in vivo

Osteoarthritis (OA) is a disease characterized by degeneration of the joint complex due to cartilage destruction. Fraxetin, a widely used and studied coumarin compound extracted from a traditional Chinese herb (Qin Pi), has shown anti-inflammatory and antioxidant properties, but its effects on OA have not been studied. In the present study, western blotting, immunofluorescence, and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) were used to evaluate the effects of fraxetin on IL-1β-induced apoptotic activity, inflammatory responses, and catabolism in rat chondrocytes. The results showed that fraxetin prevented IL-1β-induced apoptosis of chondrocytes and inhibited inflammatory mediator release by regulating the Toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor (NF)-κB pathway in chondrocytes. Additionally, fraxetin suppressed the upregulation of matrix metalloproteinase 13 (MMP13) and degradation of collagen II in the extracellular matrix (ECM). Moreover, the effects of fraxetin in vivo were assessed in a monosodium iodoacetate (MIA)-induced rat model of OA using hematoxylin and eosin (H&E) and Safranin O-fast green staining and magnetic resonance imaging (MRI). The results showed that fraxetin protected the cartilage against destruction. In conclusion, fraxetin could be a potential therapeutic for OA.     

The role of cancer-related inflammation for prediction of poor survival in postmenopausal female patients with stage II/III colon cancer

ObjectiveCancer-related inflammation (CRI) is thought to be a successful predictor of prognosis in colon cancers (CC), but opinions on how to use it are highly variable. In this study, the role of CRI cells in survival for CC patients was investigated by considering gender and menopausal status.Methods163 stage II/III CC patients who underwent curative surgery between 1995 and 2015 were included in the study. The relationship between CRI cells was examined using a standard methodology.ResultsHigh neutrophil-lymphocyte ratio (NLR) had a better relationship with prognostic factors, especially in postmenopausal women (gender, p = 0.037, positive surgical margin, p = 0.001; MSI, p < 0.001; Crohn’s-like reaction, p = 0.001, etc). Also, the reproducibility of the study was better in postmenopausal women (intra-observer agreement = 0.72, intra-class correlation = 0.722, correlation of estimates = 0.718). In univariate analysis, 5-year survival was worse in postmenopausal women with high NLR (OS, p = 0.001; RFS, p < 0.001). In multivariate analysis, high NLR was independently a worse biomarker for OS (hazard ratio [HR], 1.29; 95% CI, 1.18–2.12; p = 0.001) and RFS (HR, 1.30; 95% CI, 1.21–2.59; p < 0.001) in postmenopausal women.ConclusionsNLR had an independent poor prognostic significance in postmenopausal female patients, and the use of a standard approach for methodology improved successful results.     

LncRNA AK085865 depletion ameliorates asthmatic airway inflammation by modulating macrophage polarization

Accumulating evidence indicates that regulators of macrophages polarization may play a key role in the development of allergic asthma (AA). However, the exact role of long non-coding RNAs (lncRNAs) in regulating in macrophages polarization in the pathogenesis of dermatophagoides farinae protein 1(Der f1)-induced AA is not fully understood. The purpose of this study was to determine the function of lncRNA AK085865 in regulating macrophages in AA. Here we report that lncRNA AK085865 served as a critical regulator of macrophages polarization and reduced the pathological progress of asthmatic airway inflammation. In response to the challenge of Der f1, AK085865^−/− mice displayed attenuated allergic airway inflammation, including decreased eosinophil in BALF and reduced production of IgE, which were associated with decreased mucous glands and goblet cell hyperplasia. In addition, Der f1-treated AK085865^−/− mice show fewer M2 macrophages when compared with WT asthmatic mice. After adopting bone marrow-derived macrophages (BMDM, M0) from WT mice, Der f1-treated AK085865^−/− mice also revealed a light inflammatory reactions. We further observed that the percentage of type II innate immune lymphoid cells (ILC2s) decreased in AK085865^−/− asthmatic mice. Moreover, M2 macrophages helped promote the differentiation of ILC2s, probably through the exosomal pathway secreted by M2 macrophages. Taken together, these findings reveal that AK085865 depletion can ameliorate asthmatic airway inflammation by modulating macrophage polarization and M2 macrophages can promote the differentiation of innate lymphoid cells progenitor (ILCP) into ILC2s.     

A hybrid bacterium with tumor-associated macrophage polarization for enhanced photothermal-immunotherapy

Remodeling the tumor microenvironment through reprogramming tumor-associated macrophages (TAMs) and increasing the immunogenicity of tumors via immunogenic cell death (ICD) have been emerging as promising anticancer immunotherapy strategies. However, the heterogeneous distribution of TAMs in tumor tissues and the heterogeneity of the tumor cells make the immune activation challenging. To overcome these dilemmas, a hybrid bacterium with tumor targeting and penetration, TAM polarization, and photothermal conversion capabilities is developed for improving antitumor immunotherapy in vivo. The hybrid bacteria (B.b@QDs) are prepared by loading Ag₂S quantum dots (QDs) on the Bifidobacterium bifidum (B.b) through electrostatic interactions. The hybrid bacteria with hypoxia targeting ability can effectively accumulate and penetrate the tumor tissues, enabling the B.b to fully contact with the TAMs and mediate their polarization toward M1 phenotype to reverse the immunosuppressive tumor microenvironment. It also enables to overcome the intratumoral heterogeneity and obtain abundant tumor-associated antigens by coupling tumor penetration of the B.b with photothermal effect of the QDs, resulting in an enhanced immune effect. This strategy that combines B.b-triggered TAM polarization and QD-induced ICD achieved a remarkable inhibition of tumor growth in orthotopic breast cancer.