Nifuroxazide (NFZ) is an antimicrobial drug, which has been found to be a promising antitumor agent in recent years. In addition to being a classic STAT3 inhibitor, NFZ can also act on IL-6 and exert an anti-tumor role through inflammatory factor pathways. It can also bind to target proteins of aldehyde dehydrogenase 1, one of the families of E-twenty-six transcription factors and ubiquitin-specific protease 21 to play an anti-tumor role in different pathways. NFZ is able to act on the tumor cell microenvironment to inhibit tumor angiogenesis and tumor cell migration, enhance tumor immune cells, increase the cytotoxicity of tumor cells and enhance the anti-tumor effect of other drugs. Furthermore, it has high safety with few toxic side effects. The anti-tumor mechanisms of NFZ were described in the current review, aiming to provide insight and a reference for future studies promoting the implementation of NFZ as an anti-tumor drug in the clinic.

The identification of biomarkers that reliably forecast cervical cancer (CC) outcomes is a key area of research. Several studies have explored the link between the platelet-to-lymphocyte ratio (PLR) and cervical cancer prognosis, though the results are not entirely conclusive.

PubMed, Embase, Web of Science, and the Cochrane Library were used to search, with studies published up to May 30, 2024. The selection of studies followed predetermined inclusion and exclusion criteria. Overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS) were primary outcomes. Hazard ratios (HR) and 95% confidence intervals (CIs) were calculated. Sensitivity and subgroup analyses were performed to evaluate the stability and investigate potential heterogeneity. Review Manager version 5.4.1 and STATA version 15.0 were conducted to analyze.

Thirty cohort studies, involving 8,597 patients, were included. The pooled data showed that a higher PLR was associated with worse OS significantly (HR = 1.77, 95% CI: 1.43-2.19; p < 0.0001), PFS (HR = 1.69, 95% CI: 1.26-2.27; p = 0.0004), and DFS (HR = 1.57, 95% CI: 1.12-2.18; p = 0.008). Subgroup analysis indicated that the prognostic relevance of PLR was most prominent in patients who underwent both surgery and radiotherapy, as well as those from Asia and the America. Furthermore, a PLR threshold above 150 was associated with improved predictive accuracy.

Increased PLR among cervical cancer patients was significantly correlated with reduced OS, PFS, and DFS, pointing to its potential role as an independent prognostic marker. Nonetheless, additional prospective research is required to verify this finding.

Immune checkpoint blockade (ICB) has transformed cancer therapy1,2. The efficacy of immunotherapy depends on dendritic cell-mediated tumour antigen presentation, T cell priming and activation3,4. However, the relationship between the key transcription factors in dendritic cells and ICB efficacy remains unknown. Here we found that ICB reprograms the interplay between the STAT3 and STAT5 transcriptional pathways in dendritic cells, thereby activating T cell immunity and enabling ICB efficacy. Mechanistically, STAT3 restrained the JAK2 and STAT5 transcriptional pathway, determining the fate of dendritic cell function. As STAT3 is often activated in the tumour microenvironment5, we developed two distinct PROTAC (proteolysis-targeting chimera) degraders of STAT3, SD-36 and SD-2301. STAT3 degraders effectively degraded STAT3 in dendritic cells and reprogrammed the dendritic cell-transcriptional network towards immunogenicity. Furthermore, STAT3 degrader monotherapy was efficacious in treatment of advanced tumours and ICB-resistant tumours without toxicity in mice. Thus, the crosstalk between STAT3 and STAT5 transcriptional pathways determines the dendritic cell phenotype in the tumour microenvironment and STAT3 degraders hold promise for cancer immunotherapy.

Psoriasis is a prevalent chronic inflammatory skin disease characterized by immune cell activation and aberrant keratinocyte proliferation. Signal transducer and activator of transcription 3 (STAT3) plays a key role in the pathology of psoriasis, positioning it as a promising target for therapeutic strategies. However, current STAT3 inhibitors often lack specificity, leading to adverse effects. Here, we present the development of dendritic lipopeptides (DLPs) designed to facilitate the transdermal delivery of small interfering RNA (siRNA) to specifically inhibit STAT3 expression in psoriatic lesions. The dendritic architecture and peptide composition of DLP are crucial for interaction with keratin of stratum corneum and gene transfection efficiency, while the lipid chain selection aims to increase lipophilicity and enhance interactions with cellular membranes. We conducted extensive in vitro and in vivo investigations to assess the therapeutic efficacy of these DLPs for siRNA delivery in psoriasis treatment. The results demonstrated that our DLPs effectively penetrated the skin barrier, delivered siRNA to target cells, and significantly reduced STAT3 expression, regulated immune cell imbalance, leading to a marked improvement in psoriasis symptoms. In conclusion, our study presents a promising non-invasive approach to psoriasis treatment by focusing on the targeted suppression of STAT3 expression. The dendritic lipopeptides offer a safe and effective platform of siRNA delivery, potentially revolutionizing the management of psoriasis and other chronic inflammatory dermatological conditions.

Non-small cell lung cancer (NSCLC) poses a significant threat to public health worldwide. Curcumae Rhizoma (CR) has potent therapeutic potential in different cancers. However, the mechanism of CR treating NSCLC remains unclear. In this study, a network pharmacology-based strategy is followed to address the issue. The targets related to CR or NSCLC were obtained from multiple online public databases. Compound-target network was constructed using Cytoscape. Protein-protein interaction (PPI) was analyzed by STRING. Key transcription factors were explored in TRRUST. Gene ontology (GO) function and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were accomplished in Metascape. The druglikeness of compounds was tested in Molinspiration Cheminformatics Software. Autodock Vina was used for molecular docking. Molecular dynamic (MD) simulation was performed using Gromacs. There were 104 overlapped targets considered as key targets of CR treating NSCLC. The key components of CR, including reynosin, (4S,5S)-13-hydroxygermacrone 4,5-epoxide, and (E)-1,7-bis(4-hydroxyphenyl)-6-hepten-3-one, were screened by topological parameters and bioactivity scores. Central clustered targets in PPI network (epidermal growth factor receptor [EGFR], SRC, JAK2, and mitogen-activated protein kinase 3 [MAPK3]) were identified as critical therapeutic targets of CR. GO and KEGG enrichment analysis suggested that therapeutic effect of CR on NSCLC involved various biological processes, cellular components, and molecular functions, and pathways in cancer, JAK-STAT signaling pathway, and p53 signaling pathway were strongly related. Molecular docking and MD simulation suggested that key compounds in CR had high binding affinity to critical NSCLC targets, like EGFR, JAK2, SRC, and MAPK3, with stable complexes formed. This study revealed key components and mechanism of CR treating NSCLC based on a network pharmacology-driven strategy, providing a reference for in-depth study on treating NSCLC.

The cytokine-driven transcription factor STAT1 (signal transducer and activator of transcription 1) executes anti-microbial and pro-apoptotic functions, and loss-of-function mutations are associated with increased susceptibility to various infections and the development of tumors. A targeted mutation in mice expressing an N-terminally truncated STAT1 protein (STAT1-ΔN) typically develops splenomegaly in animals older than 6 months due to the formation of splenic non-Hodgkin lymphomas. The expression of the STAT1-ΔN variant resulted in the disruption of normal spleen architecture by malignant CD3- and CD20-negative tumor cells, which stained positively for both tyrosine-phosphorylated STAT1 and STAT3. Immunoblotting of lysates from isolated tumor cells revealed the cytokine-independent hyperphosphorylation of both STAT proteins, whereas the expression level of NF-κB was significantly reduced. Gel-shift assays showed that the DNA-binding activity of STAT1-ΔN was increased compared to the wild-type protein. This elevated level of tyrosine-phosphorylated STAT1-ΔN did not further increase upon stimulation of isolated tumor cells with either interferon-γ (IFNγ), lipopolysaccharide (LPS), or the combination of both. Since the truncation mutant was unable to accumulate in the nucleus upon cytokine stimulation, real-time PCR data from tumor tissue as well as from isolated, IFNγ/LPS-treated lymphoma cells demonstrated significantly reduced STAT1-regulated target gene expression despite its observed hyperphosphorylation. The nuclear import defect of tyrosine-phosphorylated STAT1-ΔN was associated with an elevated tyrosine-phosphorylation level of its antagonistic homolog STAT3, which is a known oncogene. These data demonstrate that the lack of STAT1 nuclear accumulation interferes with the functional balance between the two STAT proteins and, thereby, promotes the formation of phospho-STAT3-expressing CD3-/- CD20-/- non-Hodgkin lymphomas in the spleens of the diseased animals.

Teashirt zinc finger homeobox 3 (TSHZ3) is a transcription factor implicated in the progression of certain cancers. However, its expression and function in lung adenocarcinoma (LUAD) remain unclear. Therefore, we aimed to investigate TSHZ3 expression and assess its prognostic significance in LUAD patients. First, we explored prognostic data and predicted the function of TSHZ3 in lung cancer through bioinformatics analysis. We then validated the functions using cellular and animal experiments. Our results indicated that TSHZ3 expression was significantly lower in LUAD compared to normal lung tissues. High TSHZ3 expression was positively associated with better overall survival in LUAD patients. GO and pathway analyses suggested that TSHZ3 is involved in immune responses and various cancer-related processes. Immune infiltration analysis revealed correlations between TSHZ3 and immune cell infiltration, particularly macrophages, as well as the expression of numerous immune stimulators, chemokines, and receptors. Our experiment results suggest that TSHZ3 overexpression inhibits cell migration, invasion, and epithelial-mesenchymal transition (EMT) in vivo and in vitro. LUAD cells overexpressing TSHZ3 were more prone to apoptosis due to the recruitment of CD86+ macrophages. In addition, CCL2 expression was significantly higher in LUAD cells overexpressing TSHZ3, while CCR2 expression was also significantly upregulated in co-cultured macrophages. These findings suggest that TSHZ3 is an important tumor suppressor by inhibiting EMT and metastasis while inducing apoptosis through M1 macrophage chemotaxis via the CCL2/CCR2.

Cachexia, a severe wasting syndrome characterized by tumour-induced metabolic dysregulation, is a leading cause of death in people with cancer, yet its underlying mechanisms remain poorly understood. Here we show that a longitudinal full-body single-nuclei-resolution transcriptome analysis in a Drosophila model of cancer cachexia captures interorgan dysregulations. Our study reveals that the tumour-secreted interleukin-like cytokine Upd3 induces fat-body expression of Pepck1 and Pdk, key regulators of gluconeogenesis, disrupting glucose metabolism and contributing to cachexia. Similarly, in mouse cancer cachexia models, we observe IL-6-JAK-STAT-signalling-mediated induction of Pck1 and Pdk3 expression in the liver. Increased expression of these genes in fly, mouse, and human correlates with poor prognosis, and hepatic expression of Pdk3 emerges as a previously unknown mechanism contributing to metabolic dysfunction in cancer cachexia. This study highlights the conserved nature of tumour-induced metabolic disruptions and identifies potential therapeutic targets to mitigate cachexia in people with cancer.

Nanocatalytic platforms are promising in cancer therapeutics via combining multiple treatments, which can be leveraged through the metabolic dysfunction in cancer progression. However, the lack of effective tumor delivery platforms hampers this approach. Here, a gelatin-based platform is designed that is preloaded with gold nanoparticles and photothermal polypyrrole (GNPs@AuNPs-PPy) with an acid-induced doping enhancement. Benefiting from the tumor associated overexpression of H2O2, peroxidase-like Au nanoparticles induce a burst of oxidative reactive oxygen species in the local tumor microenvironment (TME). Subsequent orchestration of redox surroundings recruits immune cells, showcasing an effective antineoplastic pathway. Under near infrared light (NIR) irradiation, nanohybrids exhibit dual pH/NIR enhanced drug release within the TME, while allowing for multimodal imaging-guided theranostics. Leveraging this modality, GNPs@AuNPs-PPy delivers quercetin (a natural antitumor mediator) in TME, boosting anti-tumor therapy. The gelatin-mediated nanomedicine provides an alternative platform for combinatorial dynamic antitumor treatment.

Signal transducer and activator of transcription 3 is a transcription factor that is essential for the survival and immune sequestration of cancer cells. We conducted a phase I study of TTI-101, a first-in-class, selective small-molecule inhibitor of signal transducer and activator of transcription 3, in patients with advanced metastatic cancer.

Patients were treated with TTI-101 orally twice daily in 28-day cycles at four dose levels (DL): 3.2 (DL1), 6.4 (DL2), 12.8 (DL3), and 25.6 (DL4) mg/kg/day ("3+3" design). Three TTI-101 formulations were used in a stepwise manner (NCT03195699).

Sixty-four patients were treated (median age, 63 years; male sex, 52%; median number of prior therapies, 3). No dose-limiting toxicities or fatal treatment-related adverse events (TRAE) were observed. Diarrhea (mostly grade 1/2) was the only TRAE observed in ≥30% of subjects. Five patients experienced grade 3 TRAEs that resolved. TTI-101 showed linear pharmacokinetics from DL1 to DL3, with the pharmacokinetics plateauing at DL3. The recommended phase II dose is 12.8 mg/kg/day (DL3). Of the 41 patients who were evaluable for response, five (12%) had confirmed partial responses (cPR) and 17 (41%) had stable disease. Three (18%) of the 17 patients with hepatocellular carcinoma had a cPR (median time to treatment failure, 10.6 months). Two other cPRs were noted in one patient with ovarian cancer and one patient with gastric cancer.

TTI-101 was well tolerated. cPRs were observed across tumor types. The antitumor activity of TTI-101 monotherapy in patients with advanced, metastatic solid tumors is promising. A phase II study of TTI-101 in hepatocellular carcinoma is currently underway.

The standard treatment for breast cancer typically includes surgery, often followed by systemic therapy and individualized treatment regimens. However, there is growing interest in identifying pre-therapeutic biomarkers that can predict tumor response to neoadjuvant chemotherapy (NACT). This study systematically evaluated various analytical parameters, including age, TNM stage, histological type, molecular subtype, and several biomarker ratios, such as the platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammatory index (SII), and prognostic nutritional index (PNI). We aimed to assess the predictive value of these parameters regarding the tumor's response rate to NACT. The analysis revealed a statistically significant association between the pathological complete response-pCR (absence of any detectable cancer cells in the tissue following neoadjuvant chemotherapy (NACT))-rate and NLR in the subgroup with values between 1 and 3 (p = 0.001). The optimal cut-off for PLR was determined to be 120.45, with 80.55% of patients achieving pCR showing PLR values below this threshold (p = 0.000). Similarly, the LMR cut-off was found to be 12.34, with 77.77% of patients with pCR having LMR values below this threshold (p = 0.002). Additionally, lower pre-therapeutic values of NLR (p < 0.001), PLR (p = 0.002), SII (p = 0.001), and LMR (p = 0.001) were significantly correlated with pCR compared to the non-pCR subgroup (p < 0.005). These findings highlight the predictive potential of these biomarkers for achieving pCR following NACT. Our study supports the hypothesis that pre-therapeutic values of NLR, PLR, SII, and LMR can serve as predictive biomarkers for pCR in breast cancer patients undergoing NACT. However, the PNI did not demonstrate predictive potential in relation to pCR. These biomarkers may provide valuable insights into patient prognosis and guide personalized treatment strategies.

Tumor hypoxia is a critical driver of cancer progression, metastasis, and therapy resistance, posing significant challenges in effective cancer treatment. Hypoxia-activable prodrugs offer a promising strategy to target tumors in low-oxygen conditions, but their efficacy is often hindered by intrinsic properties and extrinsic cues. In this study, we developed a dual-prodrug nanoassembly system (CPPA) composed of a hypoxia-triggerable camptothecin (CPT)-based dimeric prodrug (CP) and a lipid-conjugated STAT3 antisense oligonucleotide (ASO) prodrug (PA), aiming to enhance tumor-targeted chemotherapy and overcome the immune evasion within the tumor microenvironment. The CPPA self-assemble into stable nanomicelle capable of co-delivering both agents directly to the tumor site, where the hypoxia-triggered release of CPT induces immunogenic cell death (ICD) while STAT3 inhibition enhances immune response. In murine breast cancer models, CPPA demonstrated superior therapeutic efficacy by improving tumor cell killing, promoting immune cell infiltration, and modulating the immunosuppressive tumor microenvironment. This combination therapy not only reversed drug resistance but also prevented the formation of the pre-metastatic niche, significantly inhibiting tumor progression and metastasis. These findings highlight the potential of CPPA as an effective strategy for enhancing cancer immunotherapy, offering a promising approach to address the complex challenges of tumor hypoxia, immune evasion, and resistance to chemotherapy.

Dual-specificity phosphatases (DUSPs) catalyze the dephosphorylation of tyrosine and serine/threonine residues in target proteins. Atypical DUSPs (aDUSPs) lack substrate-binding motifs, suggesting their potential to target a diverse array of substrates. This study demonstrated that DUSP21, an aDUSP, is induced by leukemia inhibitory factor (LIF) in HeLa cells and acts as a negative regulator of LIF-induced signal transducer and activator of transcription 3 (STAT3) activation. Overexpressed DUSP21 co-localized and interacted with STAT3 in HeLa cells. Recombinant DUSP21 directly dephosphorylated STAT3 in vitro. Additionally, DUSP21 overexpression modulated STAT3-dependent growth of Ba/F3-G133 cells. These findings indicate that LIF-induced DUSP21 exerts an inhibitory effect on the LIF/STAT3 signaling pathway, thereby functioning as a suppressor of STAT3-mediated transcriptional activity.

Oligonucleotide therapeutics (ONTs) represent a rapidly evolving modality for cancer treatment, capitalizing on their ability to modulate gene expression with high specificity. With more than 20 nucleic acid-based therapies that gained regulatory approval, advances in chemical modifications, sequence optimization, and novel delivery systems have propelled ONTs from research tools to clinical realities. ONTs, including siRNAs, antisense oligonucleotides, saRNA, miRNA, aptamers, and decoys, offer promising solutions for targeting previously "undruggable" molecules, such as transcription factors, and enhancing cancer immunotherapy by overcoming tumor immune evasion. The promise of ONT application in cancer treatment is exemplified by the recent FDA approval of the first oligonucleotide-based treatment to myeloproliferative disease. At the same time, there are challenges in delivering ONTs to specific tissues, mitigating off-target effects, and improving cellular uptake and endosomal release. This review provides a comprehensive overview of ONTs in clinical trials, emerging delivery strategies, and innovative therapeutic approaches, emphasizing the role of ONTs in immunotherapy and addressing hurdles that hinder their clinical translation. By examining advances and remaining challenges, we highlight opportunities for ONTs to revolutionize oncology and enhance patient outcomes.

Tumor-associated macrophages (TAMs) significantly influence tumor progression and patient responses to conventional chemotherapy. However, the interplay between anti-cancer drugs, immune responses in the tumor microenvironment, and their implications for cancer treatment remains poorly understood. This study investigates the effects of vinorelbine on M2 macrophages in lung cancer and its capacity to modulate TAMs toward an M1 phenotype. Peripheral blood mononuclear cells (PBMCs) were polarized into M2 macrophages, and subsequent phenotype alterations upon vinorelbine treatment were assessed. Additionally, we evaluated vinorelbine's impact on gene and protein expression associated with cancer progression and cell invasion in non-small-cell lung cancer (NSCLC) cells indirectly co-cultured with M2 macrophages. Notably, vinorelbine, particularly at low concentrations, reprogrammed M2 macrophages to exhibit M1-like characteristics. While M2 macrophages enhanced cancer cell invasion, vinorelbine significantly mitigated this effect. M2 macrophages led to the overexpression of numerous genes linked to tumor growth, angiogenesis, invasion, and immune suppression in NSCLC cells, increasing the BCL2/BAX ratio and promoting cellular resistance to apoptosis. The anti-tumor efficacy of vinorelbine appears to be partly attributed to the reprogramming of M2 macrophages to the M1 phenotype, suggesting that low-dose vinorelbine may optimize therapeutic outcomes while minimizing toxicity in cancer patients.

Hepatocellular carcinoma (HCC) presents a formidable challenge in oncology, attributed to its association with chronic liver diseases and global prevalence. The immune microenvironment profoundly influences HCC progression, balancing immune suppression and antitumor responses. The Signal Transducer and Activator of Transcription 3 (STAT3) is central to this equilibrium, orchestrating immune dynamics and intertwining tumor progression with immune evasion mechanisms. Dysregulated STAT3 signaling, activated by various stimuli, including cytokines and growth factors, promotes an immunosuppressive milieu within HCC tumors, fostering tumor survival and proliferation while hindering immune surveillance. Non-coding RNAs and other molecules regulate this process, modulating STAT3 activity and influencing immune cell function. Moreover, therapeutic interventions targeting the STAT3 pathway, alongside advancements in radiotherapy, cancer vaccines, and diabetes-related drugs, offer promising strategies in HCC management. Integrating natural compounds with immunotherapy emerges as a novel approach, leveraging their ability to enhance antitumor immunity and counter immune evasion strategies. Understanding the multifaceted role of STAT3 and its interactions within the immune landscape of HCC is paramount for devising effective therapeutic interventions and improving patient outcomes.

Sestrin1 and Sestrin2 (SESN1&2) are evolutionarily conserved, stress-responsive proteins that regulate cell growth and viability. The primary target of Sestrins is the mTORC1 protein kinase, an activator of anabolic processes and an autophagy inhibitor. Our previous studies showed that inactivating SESN1&2 in lung adenocarcinoma A549 cells accelerates cell proliferation and confers resistance to cell death without affecting mTORC1 activity, suggesting that SESN1&2 modulate cellular processes via mTORC1-independent mechanisms. This work describes a new mechanism through which SESN1&2 regulate cell proliferation and death by suppressing the STAT3 transcription factor. Normally activated in response to stress and inflammation, STAT3 is frequently overactivated in human cancers. This overactivation promotes the expression of pro-proliferative and anti-apoptotic genes that drive carcinogenesis. We demonstrate that SESN1&2 inactivation stimulates STAT3 by downregulating the PTPRD phosphatase, a protein responsible for STAT3 dephosphorylation. Our study demonstrates that SESN1&2 deficiency may cause STAT3 activation and facilitate carcinogenesis and drug resistance, making SESN1&2 reactivation a potential cancer treatment strategy.

Cancer evades therapy by multiple mechanisms, leading to uncontrolled cell growth and metastasis. Targeted therapies have shown promise in treating cancer by focusing on pathways within cancer cells. The PEAK family, comprising PEAK1 (SgK269), PEAK2 (SgK223/Pragmin), and the latest addition, PEAK3 (C19orf35), plays a crucial role in modulating cellular processes. Dysregulation and hyperactivity of these proteins, through overexpression or mutations, are associated with a wide range of cancers. This review delves into the different roles of the PEAK family members in regulating cell signaling pathways and highlights their potential in cancer therapy.

Interferons (IFNs) are important signaling molecules in the human immune response against micro-organisms. Throughout initial Borrelia burgdorferi sensu lato (B. burgdorferi s.l.) infection in vitro, inadequate IFN-γ production results in the absence of a strong T-helper 1 cell response, potentially hampering the development of an effective antibody responses in Lyme borreliosis (LB) patients. The aim of this study is to help understand the immunomodulatory mechanisms why IFN-γ production is absent in the early onset of LB. Therefore, cytokine production and STAT activation signature, following exposure of human immune cells to B. burgdorferi s.l., was investigated in vivo and in vitro. While STAT3 phosphorylation was highly induced in T cells, B cells and NK-(T) cells, STAT1 expression and IL-12p70 production were not or only slightly increased upon B. burgdorferi s.l. exposure. In response to B. burgdorferi s.l., STAT2 phosphorylation and IFNα production remained stable. STAT2 activation only increased in NK-(T) cells. In contrast, STAT4 signaling was reduced in all B. burgdorferi s.l. exposed immune cells. Moreover, B. burgdorferi s.l. significantly increased suppressor of cytokine signaling (SOCS)1 and SOCS3 gene expression in LB patients. Absence of IFN-γ production and STAT4 activation, in combination with STAT3 phosphorylation and upregulated SOCS1 and SOCS3 gene expression, suggests the formation of a more tolerant and anti-inflammatory response to B. burgdorferi s.l., specifically in T- and B-cells. In primary human PBMCs and monocyte populations, B. burgdorferi s.l. also specifically interfered with CIITA isoforms normally expressed in antigen presenting dendritic cells. In contrast, it enhanced CIITA isoforms typically present in adaptive immune cell subsets. Restoring antigen presentation capacity of innate immune cells and early production of IFN-γ in LB patients may help re-establish immune functions during initial LB. These new insights will help to understand the immunomodulatory mechanisms of B. burgdorferi s.l. during the onset of LB.

Squamous cell carcinoma of the head and neck (SCCHN) is an aggressive disease with poor prognosis. It is known that the activation of STAT3 signaling pathways promotes the development and progression of this neoplasia and it has been described the role of PTPRT as a negative regulator of STAT3. Then, we have evaluated the impact of them as biomarkers of outcome in a series of patients with recurrent and/or metastatic SCCHN treated with weekly paclitaxel-plus-cetuximab (ERBITAX) regimen.

Between 2008 and 2017, 52 patients with recurrent/metastatic SCCHN were treated with ERBITAX at our center, 34 of whom had available tumor samples. Phosphorylated STAT3 (pSTAT3) protein expression was analyzed by immunohistochemistry, STAT3 mRNA expression by qPCR, and PTPRT promoter methylation by methylation-specific PCR. Molecular results were correlated with response rate (RR), progression-free survival (PFS), and overall survival (OS).

pSTAT3 overexpression was detected in 67% and PTPRT promoter hypermethylation in 41% of tumor samples. PTPRT promoter hypermethylation showed a trend towards an association with lower RR (21% vs. 60%; p = 0.06). A lower RR was also observed in patients with pSTAT3 overexpression (36% vs. 54%) and in those with high STAT3 mRNA levels (43% vs. 64%), but these differences did not reach statistical significance. PTPRT promoter hypermethylation correlated with pSTAT3 overexpression (p = 0.009) but not with STAT3 mRNA overexpression. OS and PFS was shorter in patients with activated STAT3, but the difference did not reach statistical significance.

Although this was a relatively small retrospective study, it provides preliminary indications of the potential role of the STAT3 pathway on outcome in SCCHN and confirms that PTPRT acts as a negative regulator of STAT3. Our findings warrant investigation in a larger patient cohort to determine if inactivating this pathway through specific targeted treatments could improve outcomes in recurrent/metastatic SCCHN patients.

This study investigates the potential treatment of breast cancer utilizing Gentiana robusta King ex Hook. f. (QJ) through an integrated approach involving network pharmacology, molecular docking, and molecular dynamics simulation. Building upon prior research on QJ's chemical constituents, we conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using the DAVID database. Network interactions and core genes were identified using Cytoscape 3.9.1. Key target genes, including Interleukin-6 (IL-6), tumour suppressor gene P53 (TP53), and epidermal growth factor receptor (EGFR), were selected for molecular docking with QJ's active components, 2'-O-β-D-glucopyranosyl-gentiopicroside and macrophylloside D, employing Schrodinger Maestro 13.5. Molecular dynamics (MD) simulations were performed using the Desmond program. A total of 270 intersection targets of active ingredients and diseases were identified, with three core targets determined through network topology screening. Enrichment analysis highlighted the involvement of QJ in breast cancer treatment, primarily through the hsa05200 cancer signaling pathway and the hsa04066 HIF-1 signaling pathway. Molecular docking and dynamics simulations demonstrated the close interaction of 2'-O-β-D-glucopyranosyl-gentiopicroside (QJ17) and macrophylloside D (QJ25) with IL6, TP53, and EGFR, and other target genes, showcasing a stabilizing effect. In conclusion, this study unveils the effective components and potential mechanisms of 2'-O-β-D-glucopyranosyl-gentiopicroside and macrophylloside D in breast cancer prevention and treatment. The identified components act on target genes such as IL6, TP53, and EGFR, regulating crucial pathways including the cancer signaling and Hypoxia-inducible factor 1 (HIF-1) signaling pathways. These findings provide valuable insights into the therapeutic potential of QJ in breast cancer management. However, further experimental research are needed to validate the computational findings of QJ.

Ferroptosis is linked to various pathological conditions; however, the specific targets and mechanisms through which traditional Chinese medicine influences ischemic stroke (IS)-induced ferroptosis remain poorly understood. In this study, data from the Gene Expression Omnibus and disease target databases (OMIM, GeneCards, DisGeNet, TTD, and DrugBank) were integrated with ferroptosis-related gene datasets. To identify key molecular targets of Chuanxiong Rhizoma (CX), drug ingredient databases, including PubChem and TCMBank, were employed to map CX-related targets (CX-DEGs-FRG and CX-IS-FRG). Gene targets and relevant signaling pathways were analyzed using weighted gene co-expression network analysis, protein-protein interaction networks, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment. The least absolute shrinkage and selection operator regression and support vector machine methods were utilized to identify intersecting genes, and the predictive accuracy of core targets was evaluated through receiver operating characteristic curve analysis. Immune cell infiltration in the IS microenvironment was assessed using CIBERSORT, followed by molecular docking of CX's active components with key targets. The JAK-STAT3 pathway was identified as a critical regulatory mechanism, and five key targets (ALOX5, PTGS2, STAT3, G6PD, and HIF1A) emerged as central to the IS-induced ferroptosis. Elevated infiltration of CD8 + T cells and neutrophils was significantly correlated with IS. Notably, the active components mandenol and myricanone demonstrated strong binding affinities with these five targets, which validated the results from network-based analysis. In conclusion, the JAK-STAT3 pathway, through its regulation of ALOX5, PTGS2, STAT3, G6PD, and HIF1A, could play a crucial role in modulating ferroptosis and immune responses in IS. These findings suggest that CX could serve as a potential therapeutic approach for IS, targeting the regulation of IS-induced ferroptosis and the immune microenvironment.

Drug resistance limits the efficacy of chemotherapy for colorectal cancer liver metastasis (CRLM). However, the evolution of CRLM during drug treatment remains poorly elucidated. Multi-omics and treatment response data from 115 samples of 49 patients with CRLM undergoing bevacizumab (BVZ)-based chemotherapy show little difference in genomic alterations in 92% of cases, while remarkable differences are observed at the transcriptomic level. By decoupling intrinsic and acquired resistance, we find that hepatocyte and myeloid cell infiltration contribute to 38.5% and 23.1% of acquired resistance, respectively. Importantly, SMAD4 mutations and chr20q copy-number gain are associated with intrinsic chemoresistance. Gene interference experiments suggest that SMAD4R361H/C mutations confer BVZ and 5-fluorouracil (5-FU) resistance through STAT3 signaling. Notably, supplementing BVZ and 5-FU with the STAT3 inhibitor GB201 restores therapeutic efficacy in SMAD4R361H/C cancer cells. Our study uncovers the evolutionary dynamics of CRLM and its microenvironment during treatment and offers strategies to overcome drug resistance.

The tumor secretome comprises the totality of protein factors secreted by various cell components within the tumor microenvironment, serving as the primary medium for signal transduction between tumor cells and between tumor cells and stromal cells. The deletion or mutation of the p53 gene leads to alterations in cellular secretion characteristics, contributing to the construction of the tumor microenvironment in a cell non-autonomous manner. This review discusses the critical roles of mutant p53 in regulating the tumor secretome to remodel the tumor microenvironment, drive tumor progression, and influence the plasticity of cancer-associated fibroblasts (CAFs) as well as the dynamics of tumor immunity by focusing on both secreted protein expression and secretion pathways. The aim is to provide new insights for targeted cancer therapies.

Immune checkpoint blockade (ICB) therapy has significantly benefited patients with several types of solid tumors and some lymphomas. However, many of the treated patients do not have a durable clinical response. It has been demonstrated that rescuing exhausted CD8+ T cells is required for ICB-mediated antitumor effects. We recently developed an immunostimulatory strategy based on silencing STAT3 while stimulating immune responses by CpG, a ligand for Toll-like receptor 9 (TLR9). The CpG-small interfering RNA (siRNA) conjugates efficiently enter immune cells, silencing STAT3 and activating innate immunity to enhance T cell-mediated antitumor immune responses. In the present study, we demonstrate that blocking STAT3 through locally delivered CpG-Stat3 siRNA enhances the efficacies of the systemic PD-1 and CTLA4 blockade against mouse A20 B cell lymphoma. In addition, locally delivered CpG-Stat3 siRNA combined with systemic administration of PD-1 antibody significantly augmented both local and systemic antitumor effects against mouse B16 melanoma tumors, with enhanced tumor-associated T cell activation. Furthermore, locally delivered CpG-Stat3 siRNA enhanced CD8+ T cell tumor infiltration and antitumor activity in a xenograft tumor model. Overall, our studies in both B cell lymphoma and melanoma mouse models demonstrate the potential of combinatory immunotherapy with CpG-Stat3 siRNA and checkpoint inhibitors as a therapeutic strategy for B cell lymphoma and melanoma.

A cyclin-dependent kinase 4/6 (CDK4/6) inhibitor combined with endocrine therapy is the standard-of-care for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. However, not all patients respond to the treatment, resistance often occurs and efficacy outcomes from early breast cancer trials have been mixed. To identify biomarkers associated with CDK4/6 inhibitor response or resistance, we combined bioinformatic-database analyses, artificial intelligence-assisted literature review, and manual literature review (Embase and OVID Medline; search window: January 2012-October 2022) to compile data to comprehensively describe the CDK4/6 inhibitor biomarker landscape. Based on these results, and validation by external experts, we identified 15 biomarkers of clinical importance (AR , AURKA, ERBB2, ESR1, CCNE1, CDKN1A/B, CDK2, CDK6, CDK7, CDK9, FGFR1/2, MYC, PIK3CA/AKT, RB1 and STAT3) that could guide future breast cancer research.

C-reactive protein (CRP) is a well-known acute-phase protein that increases remarkably under various inflammatory conditions and is elevated in patients with malignant tumors. In this study, we investigated the influence of CRP on the tumor microenvironment in clear cell renal cell carcinoma (ccRCC).

This study explored CRP's role in ccRCC by co-culturing human macrophages with ccRCC cells and employing antibody blocking, RNA sequencing and in vitro experiments for functional insights. We also analysed The Cancer Genome Atlas Program (TCGA) data to link CD64 expression with ccRCC prognosis and used immunohistochemistry to associate CD64+ macrophages with tumor severity and systemic CRP levels.

A co-culture study using human macrophages and RCC cell lines showed that CRP-stimulated macrophages secrete IL-6, which induces RCC proliferation via STAT3 activation. CRP-induced protumor activation of macrophages was suppressed by CD64 blocking antibodies. Furthermore, CRP elevates PD-L1 expression in macrophages via the CD64-STAT1 signalling pathway. Statistical analysis of TCGA data indicated that increased CD64 expression was associated with a worse clinical course in ccRCC. Immunohistochemical analysis of pathological specimens revealed that high CD64 expression in tumor-associated macrophages (TAMs), and a high density of CD64+ TAMs, was linked to high nuclear grade and stage. High CD64 expression was also correlated with increased serum CRP levels.

The CRP-CD64 signal was linked to the protumor activation of TAMs and could be a promising target for anticancer immunotherapy in ccRCC.

Hepatocellular carcinoma (HCC) is a common cancer that is fatal and has a dismal prognosis. Obovatol (Ob), a novel lignan derived from the leaf and stem bark of Magnolia obovata Thunb, has exhibited anti-tumor effect on diverse tumors. However, its effect and mechanisms on HCC remain to be further explored.

Huh7 and Hep3B cells, as well as BALB/c nude mice were used to determine the function and mechanisms of Ob on growth, invasion and immune escape by cell counting kit-8, transwell, enzyme-linked immunosorbent assay (ELISA) and western blot experiments.

Ob reduced the cell viability of Huh7 and Hep3B cells, with a IC50 value of 57.41 µM and 62.86 µM, respectively. Ob declined the invasion ability, the protein expression of N-cadherin and the concentrations of IL-10 and TGF-β, whereas increased the E-cadherin expression and the contents of IFN-γ and IL-2 in Hep3B and Huh7 cells. Mechanically, Ob decreased the protein level of p-JAK/JAK, p-STAT3/STAT3 and PD-L1, which was partly restored with the treatment of RO8191, an activator of JAK/STAT3 axis. The effect of Ob on the cell viability, the invasion ability, the protein level of N-cadherin and E-cadherin, and the concentrations of IL-10, TGF-β, IFN-γ and IL-2 in both Hep3B and Huh7 cells was reversed with the management of RO8191. In vivo, Ob reduced tumor volume and weight, the level of N-cadherin, PD-L1, p-JAK/JAK, and p-STAT3/STAT3, with an elevated expression of E-cadherin and IFN-γ.

Ob downregulated the JAK/STST3/PD-L1 pathway to attenuate the growth, invasion and immune escape of HCC.

Immunogene therapy has emerged as strategy against cancer by introducing immune-stimulating components into gene therapy. However, there is still a need for an ideal platform to achieve both immune stimulation and efficient gene delivery. Lactobacillus reuteri has potential immunomodulatory activity owing to its unique antigenicity, which is potentially relevant to cancer progression. Here, we designed a novel non-viral siRNA vector (DMPLAC) by encapsulating Lactobacillus reuteri lysate in DMP. DMPLAC can promote maturation and activation of immune cells, increase infiltration of APC and cytotoxic T cells in tumor microenvironment, and exhibit tumor suppressive effects. Loading of siRNA targeting Stat3, DMPLAC/siStat3 further inhibits tumor in multiple models. We designed a strategy that combines immune activation with Stat3 silencing, triggering an immune response and tumor killing. This dual-functional design provides a new choice in development of effective immunogene therapy.

Targeted protein degradation (TPD) represents a revolutionary therapeutic strategy in disease management, providing a stark contrast to traditional therapeutic approaches like small molecule inhibitors that primarily focus on inhibiting protein function. This advanced technology capitalizes on the cell's intrinsic proteolytic systems, including the proteasome and lysosomal pathways, to selectively eliminate disease-causing proteins. TPD not only enhances the efficacy of treatments but also expands the scope of protein degradation applications. Despite its considerable potential, TPD faces challenges related to the properties of the drugs and their rational design. This review thoroughly explores the mechanisms and clinical advancements of TPD, from its initial conceptualization to practical implementation, with a particular focus on proteolysis-targeting chimeras and molecular glues. In addition, the review delves into emerging technologies and methodologies aimed at addressing these challenges and enhancing therapeutic efficacy. We also discuss the significant clinical trials and highlight the promising therapeutic outcomes associated with TPD drugs, illustrating their potential to transform the treatment landscape. Furthermore, the review considers the benefits of combining TPD with other therapies to enhance overall treatment effectiveness and overcome drug resistance. The future directions of TPD applications are also explored, presenting an optimistic perspective on further innovations. By offering a comprehensive overview of the current innovations and the challenges faced, this review assesses the transformative potential of TPD in revolutionizing drug development and disease management, setting the stage for a new era in medical therapy.

In the colorectal cancer (CRC) niche, the transcription factors signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB (NF-κB) are hyperactivated in both malignant cells and tumor-infiltrating leukocytes (TILs) and cooperate to maintain cancer cell proliferation/survival and drive protumor inflammation. Through drug repositioning studies, the anthelmintic drug rafoxanide has recently emerged as a potent and selective antitumor molecule for different types of cancer, including CRC. Here, we investigate whether rafoxanide could negatively modulate STAT3/NF-κB and inflammation-associated CRC. The antineoplastic effect of rafoxanide was explored in a murine model of CRC resembling colitis-associated disease. Cell proliferation and/or STAT3/NF-κB activation were evaluated in colon tissues taken from mice with colitis-associated CRC, human CRC cells, and CRC patient-derived explants and organoids after treatment with rafoxanide. The STAT3/NF-κB activation and cytokine production/secretion were assessed in TILs isolated from CRC specimens and treated with rafoxanide. Finally, we investigated the effects of TIL-derived supernatants cultured with or without rafoxanide on CRC cell proliferation and STAT3/NF-κB activation. The results showed that rafoxanide restrains STAT3/NF-κB activation and inflammation-associated colon tumorigenesis in vivo without apparent effects on normal intestinal cells. Rafoxanide markedly reduces STAT3/NF-κB activation in cultured CRC cells, CRC-derived explants/organoids, and TILs. Finally, rafoxanide treatment impairs the ability of TILs to produce protumor cytokines and promote CRC cell proliferation. We report the novel observation that rafoxanide negatively affects STAT3/NF-κB oncogenic activity at multiple levels in the CRC microenvironment. Our data suggest that rafoxanide could potentially be deployed as an anticancer drug in inflammation-associated CRC.

The genesis and progression of tumors are multifaceted processes influenced by genetic mutations within the tumor cells and the dynamic interplay with their surrounding milieu, which incessantly impacts the course of cancer. The tumor microenvironment (TME) is a complex and dynamic entity that encompasses not only the tumor cells but also an array of non-cancerous cells, signaling molecules, and the extracellular matrix. This intricate network is crucial in tumor progression, metastasis, and response to treatments. The TME is populated by diverse cell types, including immune cells, fibroblasts, endothelial cells, alongside cytokines and growth factors, all of which play roles in either suppressing or fostering tumor growth. Grasping the nuances of the interactions within the TME is vital for the advancement of targeted cancer therapies. Consequently, a thorough understanding of the alterations of TME and the identification of upstream regulatory targets have emerged as a research priority. NF-κB transcription factors, central to inflammation and innate immunity, are increasingly recognized for their significant role in cancer onset and progression. This review emphasizes the crucial influence of the NF-κB signaling pathway within the TME, underscoring its roles in the development and advancement of cancer. By examining the interactions between NF-κB and various components of the TME, targeting the NF-κB pathway appears as a promising cancer treatment approach.

Monocytes and macrophages are part of innate immunity and constitute the first line of defense against pathogens. Bone marrow-derived monocytes circulate in the bloodstream for one to three days and then typically migrate into tissues, where they differentiate into macrophages. Circulatory monocytes represent 5% of the nucleated cells in normal adult blood. Following differentiation, macrophages are distributed into various tissues and organs to take residence and maintain body homeostasis. Emerging evidence has highlighted the critical role of monocytes/macrophages in oncogenic viral infections, mainly their crucial functions in viral persistence and disease progression. These findings open opportunities to target innate immunity in the context of oncogenic viruses and to explore their potential as immunotherapies.

Chrysin is a natural flavonoid with anti-cancer effects. Despite its beneficial effects, little information is available regarding its immunogenic cell death (ICD) properties. In this work, we hypothesized that chrysin can potentiate radiotherapy(RT)-induced immunogenicity in melanoma cell line (B16-F10). We examined the effects of chrysin alone and in combination with radiation on ICD induction in B16-F10 cells. Cell viability was assessed using an MTT assay. Cell apoptosis and calreticulin (CRT) exposure were determined using flow cytometry. Western blotting and ELISA assay were employed to examine changes in protein expression. Combination therapy exhibited a synergistic effect, with an optimum combination index of 0.66. The synergistic anti-cancer effect correlated with increased cell apoptosis in cancer cells. Compared to the untreated control, chrysin alone and in combination with RT induced higher levels of DAMPs, such as CRT, HSP70, HMGB1, and ATP. The protein expression of p-STAT3/STAT3 and PD-L1 was reduced in B16-F10 cells exposed to chrysin alone and in combination with RT. Conditioned media from B16-F10 cells exposed to mono-and combination treatments elicited IL-12 secretion in dendritic cells (DCs), inducing a Th1 response. Our findings revealed that chrysin could induce ICD and intensify the RT-induced immunogenicity.

Dendritic cells (DCs) are antigen-presenting cells that play a crucial role in initiating immune responses by cross-presenting relevant antigens to initial T cells. The activation of DCs is a crucial step in inducing anti-tumor immunity. Upon recognition and uptake of tumor antigens, activated DCs present these antigens to naive T cells, thereby stimulating T cell-mediated immune responses and enhancing their ability to attack tumors. It is particularly noted that DCs are able to cross-present foreign antigens to major histocompatibility complex class I (MHC-I) molecules, prompting CD8+ T cells to proliferate and differentiate into cytotoxic T cells. In the malignant progression of hepatocellular carcinoma (HCC), the inactivation of DCs plays an important role, and the activation of DCs is particularly important in anti-HCC immunotherapy. In this review, we summarize the mechanisms of DCs activation in HCC, the involved regulatory factors and strategies to activate DCs in HCC immunotherapy. It provides a basis for the study of HCC immunotherapy through DCs activation.