STING-targeted PET tracer for early assessment of tumor immunogenicity in colorectal cancer after chemotherapy.

PURPOSE: To optimize chemotherapy regimens and improve the effectiveness of chemotherapy combined with immunotherapy, a PET tracer specifically targeting the stimulator of interferon genes (STING), denoted as [18F]FBTA was used to monitor the early changes in tumor immunogenicity after chemotherapy in colorectal cancer (CRC) mice. METHODS: The toluene sulfonate precursor was labeled with 18F to produce the STING targeted probe-[18F]FBTA. [18F]FBTA-PET imaging and biodistribution were performed using CRC mice treated with oxaliplatin (OXA) or cisplatin (CDDP). CRC mice were also treated with low (CDDP-LD: 1 mg/kg) or medium (CDDP-MD: 2.5 mg/kg) doses of CDDP, and subjected to PET imaging and biodistribution. The effects of different chemotherapeutic agents and different doses of CDDP on tumor innate immunity were verified by flow cytometry and immunohistochemistry. RESULTS: PET imaging of CRC mice exhibited notably enhanced tumor uptake in the early phase of chemotherapy with treatment with OXA (3.09 ± 0.25%ID/g) and CDDP (4.01 ± 0.18%ID/g), especially in the CDDP group. The PET-derived tumor uptake values have strong correlations with STING immunohistochemical score. Flow cytometry showed both agents led to DCs and macrophages infiltration in tumors. Compared with OXA, CDDP treatment recruits more DCs and macrophages in CRC tumors. Both CDDP-LD and CDDP-MD treatment elevated uptake in CRC tumors, especially in CDDP-MD group. Immunohistochemistry and flow cytometry confirmed CDDP-MD treatment recruits more DCs and macrophages than CDDP-LD treatment. CONCLUSION: Overall, the STING-targeted tracer-[18F]FBTA was demonstrated to monitor early changes in tumor immunogenicity in CRC mice after chemotherapy. Besides, the STING-targeted strategy may help to select the appropriate chemotherapy regimen, including chemotherapeutic agents and doses, which further improve clinical decision making for combination immunotherapy after chemotherapy for CRC.

Tetrandrine activates STING/TBK1/IRF3 pathway to potentiate anti-PD-1 immunotherapy efficacy in non-small cell lung cancer.

The efficacy of PD-1 therapy in non-small cell lung cancer (NSCLC) patients remains unsatisfactory. Activating the STING pathway is a promising strategy to improve PD-1 inhibitor efficacy. Here, we found tetrandrine (TET), an anti-tumor compound extracted from a medicinal plant commonly used in traditional Chinese medicine, has the ability to inhibit NSCLC tumor growth. Mechanistically, TET induces nuclear DNA damage and increases cytosolic dsDNA, thereby activating the STING/TBK1/IRF3 pathway, which in turn promotes the tumor infiltration of dendritic cells (DCs), macrophages, as well as CD8+ T cells in mice. In vivo imaging dynamically monitored the increased activity of the STING pathway after TET treatment and predicted the activation of the tumor immune microenvironment. We further revealed that the combination of TET with αPD-1 monoclonal antibody (αPD-1 mAb) yields significant anti-cancer effects by promoting CD8+ T cell infiltration and enhancing its cell-killing effect, which in turn reduced the growth of tumors and prolonged survival of NSCLC mice. Therefore, TET effectively eliminates NSCLC cells and enhances immunotherapy efficacy through the activation of the STING pathway, and combining TET with anti-PD-1 immunotherapy deserves further exploration for applications.

pH-sensitive molybdenum (Mo)-based polyoxometalate nanoclusters have therapeutic efficacy in inflammatory bowel disease by counteracting ferroptosis.

Current therapeutic drugs for ulcerative colitis (UC) remained inadequate due to drug dependence and unacceptable adverse events. Reactive oxygen species (ROS) played a critical role in the occurrence and development of UC, which most likely benefited from treatment in scavenging ROS. In this study, we developed a pH-sensitive molybdenum-based polyoxometalate (POM) nanocluster, which might contribute to site specific colonic delivery and enhance systemic efficacy of UC treatment. Our results demonstrated that POM displayed robust ROS scavenging ability in vitro. POM could significantly alleviate the enteric symptoms and inflammatory indicators in DSS-induced UC mouse models. Flow cytometry showed an effective diminishment of macrophages, neutrophils and T cells infiltration after POM administration in UC models. Also, for the first time, we demonstrated that POM interfered with metabolic pathway associated to oxidative stress and partially improved the abnormal production of intestinal metabolites in UC to some extent. Benefiting from the ROS scavenging ability, POM attenuated ferroptosis in DSS induced UC, as evidenced by increase of GSH, down-expression of GPX4 and improvement in mitochondrial morphological changes. Meanwhile, there were no side effects on normal tissues. Thus, our powerful therapeutic effects pioneered the application of POM for safer and more effective POM-based UC therapy.

ß-Elemene enhances erlotinib sensitivity through induction of ferroptosis by upregulating lncRNA H19 in EGFR-mutant non-small cell lung cancer.

Nearly half of all Asian non-small cell lung cancer (NSCLC) patients harbour epidermal growth factor receptor (EGFR) mutations, and first-generation EGFR tyrosine kinase inhibitors (TKIs) are one of the first-line treatments that have improved the outcomes of these patients. Unfortunately, 20% of these patients can not benefit from the treatment. The basis of this primary resistance is poorly understood. Therefore, overcoming EGFR-TKI primary resistance and maintaining the efficacy of TKIs has become a key issue. ß-Elemene, a sesquiterpene compound extracted from Curcuma aromatica Salisb. (wenyujing), has shown potent antitumor effects. In this research, we found that ß-elemene combined with erlotinib enhanced the cytotoxicity of erlotinib to primary EGFR-TKI-resistant NSCLC cells with EGFR mutations and that ferroptosis was involved in the antitumor effect of the combination treatment. We found that lncRNA H19 was significantly downregulated in primary EGFR-TKI-resistant NSCLC cell lines and was upregulated by the combination treatment. Overexpression or knockdown of H19 conferred sensitivity or resistance to erlotinib, respectively, in both in vitro and in vivo studies. The high level of H19 enhanced the cytotoxicity of erlotinib by inducing ferroptosis. In conclusion, our data showed that ß-elemene combined with erlotinib could enhance sensitivity to EGFR-TKIs through induction of ferroptosis via H19 in primary EGFR-TKI-resistant lung cancer, providing a promising strategy to overcome EGFR-TKI resistance in NSCLC patients.

Ginseng polysaccharides alter the gut microbiota and kynurenine/tryptophan ratio, potentiating the antitumour effect of antiprogrammed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) immunotherapy.

OBJECTIVE: Programmed death 1 and its ligand 1 (PD-1/PD-L1) immunotherapy is promising for late-stage lung cancer treatment, however, the response rate needs to be improved. Gut microbiota plays a crucial role in immunotherapy sensitisation and Panax ginseng has been shown to possess immunomodulatory potential. In this study, we aimed to investigate whether the combination treatment of ginseng polysaccharides (GPs) and αPD-1 monoclonal antibody (mAb) could sensitise the response by modulating gut microbiota. DESIGN: Syngeneic mouse models were administered GPs and αPD-1 mAb, the sensitising antitumour effects of the combination therapy on gut microbiota were assessed by faecal microbiota transplantation (FMT) and 16S PacBio single-molecule real-time (SMRT) sequencing. To assess the immune-related metabolites, metabolomics analysis of the plasma samples was performed. RESULTS: We found GPs increased the antitumour response to αPD-1 mAb by increasing the microbial metabolites valeric acid and decreasing L-kynurenine, as well as the ratio of Kyn/Trp, which contributed to the suppression of regulatory T cells and induction of Teff cells after combination treatment. Besides, the microbial analysis indicated that the abundance of Parabacteroides distasonis and Bacteroides vulgatus was higher in responders to anti-PD-1 blockade than non-responders in the clinic. Furthermore, the combination therapy sensitised the response to PD-1 inhibitor in the mice receiving microbes by FMT from six non-responders by reshaping the gut microbiota from non-responders towards that of responders. CONCLUSION: Our results demonstrate that GPs combined with αPD-1 mAb may be a new strategy to sensitise non-small cell lung cancer patients to anti-PD-1 immunotherapy. The gut microbiota can be used as a novel biomarker to predict the response to anti-PD-1 immunotherapy.

Andrographolide suppresses non-small-cell lung cancer progression through induction of autophagy and antitumor immune response.

Despite recent advances in diagnosis and therapeutic strategies, treatment of non-small-cell lung cancer (NSCLC) remains unsatisfactory in terms of prognosis. Andrographolide (AD), a principal active component of Andrographis paniculata (Burm.f.) Nees, exerts anti-cancer therapeutic properties. AD has been used for centuries in China for clinical treatment of viral infections. However, the pharmacological biology of AD in NSCLC remains unknown. In this study, AD regulated autophagy and PD-L1 expression in NSCLC. Molecular dynamics simulations indicated that AD bound directly to signal transducer and activator of transcription-3 (STAT3) with high affinity. Proteomics analysis indicated that AD reduced the expression of tumour PD-L1 in NSCLC by suppressing JAK2/STAT3 signalling. AD modulated the P62-dependent selective autophagic degradation of PD-L1 by inhibiting STAT3 phosphorylation. In vivo study revealed that AD suppressed tumour growth in H1975 xenograft mice and Lewis lung carcinoma cell models, and better efficacy was obtained at higher concentrations. AD prolonged the survival time of the mice and enhanced the treatment efficacy of anti-PD-1 mAb immunotherapy by stimulating CD8+ T cell infiltration and function. This work elucidated the specific mechanism by which AD inhibited NSCLC. Treatment with the combination of AD and anti-PD-1 mAb immunotherapy could be a potential strategy for patients with NSCLC.

Plumbagin suppresses non-small cell lung cancer progression through downregulating ARF1 and by elevating CD8+ T cells.

Non-small cell lung cancer (NSCLC) is one of the most frequently diagnosed cancers and the leading causes of cancer death worldwide. Therefore, new therapeutic agents are urgently needed to improve patient outcomes. Plumbagin (PLB), a natural sesquiterpene present in many Chinese herbal medicines, has been reported for its anti-cancer activity in various cancer cells. In this study, the effects and underlying mechanisms of PLB on the tumorigenesis of NSCLC were investigated. PLB dose-dependently inhibited the growth of NSCLC cell lines. PLB promoted ROS production, activated the endoplasmic reticulum (ER) stress pathway, and induced cell apoptosis, accompanied by the decreased expression level of ADP-ribosylation factor 1 (ARF1) in NSCLC cancer cells, and those effects of PLB could be reversed by the pretreatment with N-acetyl-L-cysteine (NAC). More importantly, the calcium chelator (BM) significantly reversed PLB-induced cell apoptosis. Furthermore, PLB significantly inhibited the growth of both H1975 xenograft and LLC1 tumors and exhibited antitumor activity by enhancing the number and the effector function of CD8+ T cells in KRASLA2 mice model and the LLC1 xenograft. Our findings suggest that PLB exerts potent antitumor activity against NSCLC in vitro and in vivo through ARF1 downregulation and induction of antitumor immune response, indicating that PLB is a new novel therapeutic candidate for the treatment of patients with NSCLC.

Metabolomics and integrated network pharmacology analysis reveal Tricin as the active anti-cancer component of Weijing decoction by suppression of PRKCA and sphingolipid signaling.

Currently, conventional methods of treating non-small cell lung cancer (NSCLC) have many disadvantages. An alternative effective therapy with minimal adverse reactions is urgently needed. Weijing decoction (WJD), which is a classic ancient Chinese herbal prescription, has been used successfully to treat pulmonary system diseases containing lung cancer in the clinic. However, the key active component and target of Weijing decoction are still unexplored. Therefore, for the first time, our study aims to investigate the pharmacological treatment mechanism of Weijing decoction in treating NSCLC via an integrated model of network pharmacology, metabolomics and biological methods. Network pharmacology results conjectured that Tricin is a main bioactive component in this formula which targets PRKCA to suppress cancer cell growth. Metabolomics analysis demonstrated that sphingosine-1-phosphate, which is regulated by sphingosine kinase 1 and sphingosine kinase 2, is a differential metabolite in plasma between the WJD-treated group and the control group, participating in the sphingolipid signaling. In vitro experiments demonstrated that Tricin had vital effects on the proliferation, pro-apoptosis, migration and colony formation of Lewis lung carcinoma cells. Through a series of validation assays, Tricin inhibited the tumor growth mainly by suppressing PRKCA/SPHK/S1P signaling and antiapoptotic signaling. On the other hand, Weijing formula could inhibit the tumor growth and prolong the survival time. A high dosage of Tricin was much more potent in animal experiments. In conclusion, we confirmed that Weijing formula and its primary active compound Tricin are promising alternative treatments for NSCLC patients.

Artificial intelligence-based collaborative filtering method with ensemble learning for personalized lung cancer medicine without genetic sequencing.

In personalized medicine, many factors influence the choice of compounds. Hence, the selection of suitable medicine for patients with non-small-cell lung cancer (NSCLC) is expensive. To shorten the decision-making process for compounds, we propose a computationally efficient and cost-effective collaborative filtering method with ensemble learning. The ensemble learning is used to handle small-sample sizes in drug response datasets as the typical number of patients in a cancer dataset is very small. Moreover, the proposed method can be used to identify the most suitable compounds for patients without genetic data. To the best of our knowledge, this is the first method to provide effective recommendations without genetic data. We also constructed a reliable dataset that includes eight NSCLC cell lines and ten compounds that have been approved by the Food and Drug Administration. With the new dataset, the experimental results demonstrated that the dataset shift phenomenon that commonly occurs in practical biomedical data does not occur in this problem. The experimental results demonstrated that our proposed method can outperform two state-of-the-art recommender system techniques on both the NCI60 dataset and our new dataset. Our model can be applied to the prediction of drug sensitivity with less labor-intensive experiments in the future.

Dolutegravir derivative inhibits proliferation and induces apoptosis of non-small cell lung cancer cells via calcium signaling pathway.

Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer. However, there has been little improvement in its cure rate in the last 30 years, due to its intricate heterogeneity and drug resistance. Accumulating evidences have demonstrated that dysregulation of calcium (Ca2+) homeostasis contributes to oncogenesis and promotes tumor development. Inhibitors of Ca2+ channels/transporters to restore intracellular Ca2+ level were found to arrest tumor cell division, induce apoptosis, and suppress tumor growth both in vitro and in vivo. Dolutegravir (DTG), which is a first-line drug for Acquired Immune Deficiency Syndrome (AIDs) treatment, has been shown to increase intracellular Ca2+ levels and Reactive oxygen species (ROS) levels in human erythrocytes, leading to suicidal erythrocyte death or eryptosis. To explore the potential of DTG as an antitumor agent, we have designed and synthesized a panel of compounds based on the principle of biologically active substructure splicing of DTG. Our data demonstrated that 7-methoxy-4-methyl-6,8-dioxo-N-(3-(1-(2-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide (DTHP), a novel derivative of DTG, strongly inhibited the colony-forming ability and proliferation of NSCLC cells, but displayed no cytotoxicity to normal lung cells. DTHP treatment also induced apoptosis and upregulate intracellular Ca2+ level in NSCLC cells significantly. Inhibiting Ca2+ signaling alleviated DTHP-induced apoptosis, suggesting the perturbation of intracellular Ca2+ is responsible for DTHP-induced apoptosis. We further discovered that DTHP activates AMPK signaling pathway through binding to SERCA, a Ca2+-ATPase. On the other hand, DTHP treatment promoted mitochondrial ROS production, causing mitochondrial dysfunction and cell death. Finally, DTHP effectively inhibited tumor growth in the mouse xenograft model of lung cancer with low toxicity to normal organs. Taken together, our work identified DTHP as a superior antitumor agent, which will provide a novel strategy for the treatment of NSCLC with potential clinical application.

Chelidonine selectively inhibits the growth of gefitinib-resistant non-small cell lung cancer cells through the EGFR-AMPK pathway.

Tyrosine kinase inhibitors (TKIs) have been widely used for the clinical treatment of patients with non-small cell lung cancer (NSCLC) harboring mutations in the EGFR. Unfortunately, due to the secondary mutation in EGFR, eventual drug-resistance is inevitable. Therefore, to overcome the resistance, new agent is urgently required. Chelidonine, extracted from the roots of Chelidonium majus, was proved to effectively suppress the growth of NSCLC cells with EGFR double mutation. Proteomics analysis indicated that mitochondrial respiratory chain was significantly inhibited by chelidonine, and inhibitor of AMPK effectively blocked the apoptosis induced by chelidonine. Molecular dynamics simulations indicated that chelidonine could directly bind to EGFR and showed a much higher binding affinity to EGFRL858R/T790M than EGFRWT, which demonstrated that chelidonine could selectively inhibit the phosphorylation of EGFR in cells with EGFR double-mutation. In vivo study revealed that chelidonine has a similar inhibitory effect like second generation TKI Afatinib. In conclusion, targeting EGFR and inhibition of mitochondrial function is a promising anti-cancer therapeutic strategy for inhibiting NSCLC with EGFR mutation and TKI resistance.

Cordycepin Inhibits Drug-resistance Non-small Cell Lung Cancer Progression by Activating AMPK Signaling Pathway.

Lung cancer is the most commonly diagnosed cancer worldwide and it is also the most leading cause of cancer-related deaths. Although multiple generations of targeted therapeutic drugs such as gefitinib and afatinib specifically targeting the epidermal growth factor receptor (EGFR) pathway are currently available for lung cancer treatment, none of them can escape their eventual drug-resistance. As a key component of Cordyceps Sinensis and widely used in traditional Chinese medicines (TCM), cordycepin (CD) has attracted increasing attention to both scientists and clinicians. We aimed to explore the potential in developing cordycepin (CD) as an anti-lung cancer drug. A systematic analysis was conducted on a panel of non-small cell lung cancer (NSCLC) cell lines to identify the cells sensitive to CD. We found that CD can affect different aspects of lung cancer development including proliferation, migration, invasion, cell cycle, and apoptosis. We then explored the underlying molecular mechanisms of CD-mediated NSCLC cell apoptosis by conducting a series of in vitro and in vivo experiments. We found that in addition to affecting different stages of NSCLC development including tumor growth, migration, and invasion, the CD is capable of inhibiting NSCLC cell cycle progression and inducing cancer cell apoptosis without apparent adverse effect on normal lung cells. Furthermore, we found that the cells containing EGFR mutations are more sensitive to CD treatment than those without. Mechanistically, CD induces NSCLC cell apoptosis by interacting with and activating AMP-activated protein kinase (AMPK). More importantly, we found that the potency of CD's anticancer effect both in vitro and in vivo is comparable to afatinib and even better than gefitinib. Our findings suggest that CD either by itself or in combination with the currently available targeted therapeutic drugs might be additional therapeutic options for drug-resistance NSCLC treatment.

Shikonin inhibits gefitinib-resistant non-small cell lung cancer by inhibiting TrxR and activating the EGFR proteasomal degradation pathway.

Non-small cell lung cancer (NSCLC) is the dominant type of lung cancer. Molecular targeting has highly improved the treatment efficacy of lung cancer, but new challenges have emerged, such as gefitinib-resistance and cancer recurrence. Therefore, new chemotherapeutic agents and treatment strategies are urgently needed. Shikonin is the main active component of a Chinese medicinal plant 'Zi Cao', which has been shown to exhibit powerful anti-cancer activity in certain types of cancer; however, its activity in gefitinib-resistant lung cancer has never been addressed. In this study, we used a high-throughput screening assay for epidermal growth factor receptor (EGFR) inhibitors and discovered that Shikonin is a potent inhibitor of EGFR. The cytotoxicity of Shikonin and its anti-cancer mechanism in NSCLC was deeply explored. Shikonin exhibited selective cytotoxicity among two NSCLC cell lines (H1975 and H1650) and one normal lung fibroblast cell line (CCD-19LU). Shikonin significantly increased the activity of caspases and poly (ADP-ribosyl) polymerase (PARP), which are indicators of apoptosis, and the intensity of ROS by greater than 10-fold. NAC, an inhibitor of ROS, completely blocked apoptosis, caspase and PARP activation induced by Shikonin. Shikonin remarkably suppressed the phosphorylation of EGFR and led to EGFR degradation. The enhancement of ROS generation in H1650 and H1975 gefitinib-resistant NSCLC cells leads to impairment of growth and induction of apoptosis, whereas modulation of EGFR degradation and its downstream signalling pathways by Shikonin contributes to its anti-tumour properties in H1975 gefitinib-resistant NSCLC cells (with T790M and L858R activating mutations). Shikonin-induced cell apoptosis is closely associated with ROS elevation in the cells. These findings indicate that Shikonin can be an effective small molecule treating gefitinib-resistant NSCLC.

[Effect of Glycyrrhizae Radix et Rhizoma combined with Atractylodis Macrocephalae Rhizoma on p53 and p21 gene expression of IEC-6 cells].

To study the effect of the combined administration of different doses of Glycyrrhizae Radix et Rhizoma and Atractylodis Macrocephalae Rhizoma on the proliferation of DFMO-treated intestinal epithelial cells (IEC-6) and p53, p21 mRNA and protein expressions, in order to define the molecular basis for the effect of the combined administration of different doses of Glycyrrhizae Radix et Rhizoma and Atractylodis Macrocephalae Rhizoma on the cell proliferation. The effect of the drugs on the cell division rate and cell cycle of IEC-6 cells was detected by FCM. Quantitative Real-time PCR (qRT-PCR) was used to analyze the effect of the drugs on mRNA of p2l and p53 related to IEC-6 proliferation. Western blot was used to analyze the effect of the drugs on p2l and p53 protein expressions of IEC-6 cells. Atractylodis Macrocephalae Rhizoma could increase p53, p21 mRNA and proteins expression in DFMO-treated IEC-6 cells. The combined administration of different ratios of Atractylodis Macrocephalae Rhizoma and Glycyrrhizae Radix et Rhizoma could significantly down-regulate Atractylodis Macrocephalae Rhizoma's effect on p53, p21 mRNA and proteins expression in DFMO-treated IEC-6 cells and promote the proliferation of IEC-6 cells. The combined administration of Atractylodis Macrocephalae Rhizoma and Glycyrrhizae Radix et Rhizoma could down-regulate Atractylodis Macrocephalae Rhizoma's effect on DFMO-treated intestinal epithelial cells (IEC-6).

Glycyrrhizin suppresses lung adenocarcinoma cell growth through inhibition of thromboxane synthase.

BACKGROUND/AIMS: The effects of glycyrrhizin treatment in lung cancer remain undetermined, despite extensive studies of the anti-tumor activities of glycyrrhizin. METHODS: Lung adenocarcinoma A549 and NCI-H23 cell lines were used in this study. Cell growth was examined by MTS assays, while apoptosis and cell cycle were determined by flow cytometric analysis. Both real-time PCR and western blotting were used to examine the expression levels of thromboxane synthase (TxAS), and TxAS activity was measured using EIA detection of the biosynthesis of TxA2. TxAS was overexpressed in NCI-H23 cells by transfection with TxAS cDNA, while TxAS was inhibited by transfection with TxAS siRNA in A549 cells. For the mouse model of lung adenocarcinoma, the effects of glycyrrhizin on tumor growth were analyzed by western blot evaluation of TxAS, PTEN and survivin. TxAS activity was determined by EIA assay. RESULTS: Glycyrrhizin suppressed cell growth in A549 cells, but not in NCI-H23 cells, by induction of apoptosis. TxAS was overexpressed in A549 cells, but the TxAS levels in NCI-H23 cells were minimal. Moreover, TxAS expression and activity were suppressed by glycyrrhizin. Glycyrrhizin had no additive effects with TxAS siRNA knockdown in suppressing A549 cell growth, whereas it completely suppressed cell growth of NCI-H23 cells transfected with TxAS cDNA. These results were further confirmed by the in vivo study. CONCLUSION: Our study suggests that the anti-tumor effect of glycyrrhizin in lung adenocarcinoma is, at least in part, TxAS-dependent. Therefore, glycyrrhizin is a promising anti-cancer agent for the treatment of lung adenocarcinoma.

STING agonist-based hydrogel enhances immune activation in synergy with radiofrequency ablation for hepatocellular carcinoma treatment.

Immunosuppression caused by incomplete radiofrequency ablation (iRFA) is a crucial factor affecting the effectiveness of RFA for solid tumors. However, little is known about the changes iRFA induces in the tumor immune microenvironment (TIME) of hepatocellular carcinoma (HCC), the primary application area for RFA. In this study, we found iRFA promotes a suppressive TIME in residual HCC tumors, characterized by M2 macrophage polarization, inhibited antigen presentation by dendritic cells (DCs), and reduced infiltration of cytotoxic T lymphocytes (CTLs). Interestingly, the STING agonist MSA-2 was able to reorganize M2-like tumor-promoting macrophages into M1-like anti-tumor states and enhance antigen presentation by DCs. To optimize the therapeutic effect of MSA-2, we used a calcium ion (Ca2+) responsive sodium alginate (ALG) as a carrier, forming an injectable hydrogel named ALG@MSA-2. This hydrogel can change from liquid to gel, maintaining continuous drug release in situ. Our results suggested that ALG@MSA-2 effectively activated anti-tumor immunity, as manifested by increased M1-like macrophage polarization, enhanced antigen presentation by DCs, increased CTL infiltration, and inhibited residual tumor growth. ALG@MSA-2 also resulted in a complete regression of contralateral tumors and widespread liver metastases in vivo. In addition, the excellent biosafety of ALG@MSA-2 was also proved by blood biochemical analysis and body weight changes in mice. In summary, this study demonstrated that the immune cascade of ALG@MSA-2 mediated the STING pathway activation and promoted a favorable TIME which might provide novel insights for the RFA treatment of HCC.

Tanshinone IIA induces ER stress and JNK activation to inhibit tumor growth and enhance anti-PD-1 immunotherapy in non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) remains at the forefront of new cancer cases, and there is an urgent need to find new treatments or improve the efficacy of existing therapies. In addition to the application in the field of cerebrovascular diseases, recent studies have revealed that tanshinone IIA (Tan IIA) has anticancer activity in a variety of cancers. PURPOSE: To investigate the potential anticancer mechanism of Tan IIA and its impact on immunotherapy in NSCLC. METHODS: Cytotoxicity and colony formation assays were used to detect the Tan IIA inhibitory effect on NSCLC cells. This research clarified the mechanisms of Tan IIA in anti-tumor and programmed death-ligand 1 (PD-L1) regulation by using flow cytometry, transient transfection, western blotting and immunohistochemistry (IHC) methods. Besides, IHC was also used to analyze the nuclear factor of activated T cells 1 (NFAT2) expression in NSCLC clinical samples. Two animal models including xenograft mouse model and Lewis lung cancer model were used for evaluating tumor suppressive efficacy of Tan IIA. We also tested the efficacy of Tan IIA combined with programmed cell death protein 1 (PD-1) inhibitors in Lewis lung cancer model. RESULTS: Tan IIA exhibited good NSCLC inhibitory effect which was accompanied by endoplasmic reticulum (ER) stress response and increasing Ca2+ levels. Moreover, Tan IIA could suppress the NFAT2/ Myc proto oncogene protein (c-Myc) signaling, and it also was able to control the Jun Proto-Oncogene(c-Jun)/PD-L1 axis in NSCLC cells through the c-Jun N-terminal kinase (JNK) pathway. High NFAT2 levels were potential factors for poor prognosis in NSCLC patients. Finally, animal experiments data showed a stronger immune activation phenotype, when we performed treatment of Tan IIA combined with PD-1 monoclonal antibody. CONCLUSION: The findings of our research suggested a novel mechanism for Tan IIA to inhibit NSCLC, which could exert anti-cancer effects through the JNK/NFAT2/c-Myc pathway. Furthermore, Tan IIA could regulate tumor PD-L1 levels and has the potential to improve the efficacy of PD-1 inhibitors.

Novel STING-targeted PET radiotracer for alert and therapeutic evaluation of acute lung injury.

Acute lung injury (ALI), as a common clinical emergency, is pulmonary edema and diffuse lung infiltration caused by inflammation. The lack of non-invasive alert strategy, resulting in failure to carry out preventive treatment, means high mortality and poor prognosis. Stimulator of interferon genes (STING) is a key molecular biomarker of innate immunity in response to inflammation, but there is still a lack of STING-targeted strategy. In this study, a novel STING-targeted PET tracer, [18F]FBTA, was labeled with high radiochemical yield (79.7 ± 4.3%) and molar activity (32.5 ± 2.9 GBq/µmol). We confirmed that [18F]FBTA has a strong STING binding affinity (Kd = 26.86 ± 6.79 nmol/L) and can be used for PET imaging in ALI mice to alert early lung inflammation and to assess the efficacy of drug therapy. Our STING-targeted strategy also reveals that [18F]FBTA can trace ALI before reaching the computed tomography (CT) diagnostic criteria, and demonstrates its better specificity and distribution than [18F]fluorodeoxyglucose ([18F]FDG).

Erratum: Author correction to 'Herbal formula BaWeiBaiDuSan alleviates polymicrobial sepsis-induced liver injury via increasing the gut microbiota Lactobacillus johnsonii and regulating macrophage anti-inflammatory activity in mice' [Acta Pharmaceutica Sinica B 13 (2023) 1164-1179].

[This corrects the article DOI: 10.1016/j.apsb.2022.10.016.].

Anti-breast cancer-induced cardiomyopathy: Mechanisms and future directions.

With the progression of tumor treatment, the 5-year survival rate of breast cancer is close to 90%. Cardiovascular toxicity caused by chemotherapy has become a vital factor affecting the survival of patients with breast cancer. Anthracyclines, such as doxorubicin, are still some of the most effective chemotherapeutic agents, but their resulting cardiotoxicity is generally considered to be progressive and irreversible. In addition to anthracyclines, platinum- and alkyl-based antitumor drugs also demonstrate certain cardiotoxic effects. Targeted drugs have always been considered a relatively safe option. However, in recent years, some random clinical trials have observed the occurrence of subclinical cardiotoxicity in targeted antitumor drug users, which may be related to the effects of targeted drugs on the angiotensin converting enzyme, angiotensin receptor and ß receptor. The use of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and beta-blockers may prevent clinical cardiotoxicity. This article reviews the toxicity and mechanisms of current clinical anti-breast cancer drugs and proposes strategies for preventing cardiovascular toxicity to provide recommendations for the clinical prevention and treatment of chemotherapy-related cardiomyopathy.