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Due to its unique physical structure and chemical properties, graphene family nanomaterials (GFNs) and derived commodities have been widely used in commercial products, particularly biomedical applications, which has significantly increased the risk of human exposure. There exists significant evidence that GFNs are accumulated in a number of tissues and organs through different exposure pathways, and further cause toxicity manifested as lesions or functional impairment. Moreover, GFNs can be internalized by varing cell types and induce cytoskeletal disorders, organelle dysfunction, and interact directly with biological macromolecules such as DNA, mRNA and proteins, ultimately resulting in greater rates of cell apoptosis, necrosis and autophagic cell death. The toxicological effect of GFN is closely related to its lateral size, surface structure, functionalization, and propensity to adsorb proteins. Using major data published over the past four years, this review presents and summarizes state of current understanding of GFN toxicology and identifies current deficiencies and challenges. This review aims to help improve evaluation of the biocompatibility of GFNs and provides theoretical guidance for their safe application.

Titanium dioxide nanoparticles (TiO 2 NPs) possess unique characteristics and are widely used in many fields. Numerous in vivo studies, exposing experimental animals to these NPs through systematic administration, have suggested that TiO 2 NPs can accumulate in the brain and induce brain dysfunction. Nevertheless, the exact mechanisms underlying the neurotoxicity of TiO 2 NPs remain unclear. However, we have concluded from previous studies that these mechanisms mainly consist of oxidative stress (OS), apoptosis, inflammatory response, genotoxicity, and direct impairment of cell components. Meanwhile, other factors such as disturbed distributions of trace elements, disrupted signaling pathways, dysregulated neurotransmitters and synaptic plasticity have also been shown to contribute to neurotoxicity of TiO 2 NPs. Recently, studies on autophagy and DNA methylation have shed some light on possible mechanisms of nanotoxicity. Therefore, we offer a new perspective that autophagy and DNA methylation could contribute to neurotoxicity of TiO 2 NPs. Undoubtedly, more studies are needed to test this idea in the future. In short, to fully understand the health threats posed by TiO 2 NPs and to improve the bio-safety of TiO 2 NPs-based products, the neurotoxicity of TiO 2 NPs must be investigated comprehensively through studying every possible molecular mechanism.

Due to their unique physicochemical properties, graphene-family nanomaterials (GFNs) are widely used in many fields, especially in biomedical applications. Currently, many studies have investigated the biocompatibility and toxicity of GFNs in vivo and in intro. Generally, GFNs may exert different degrees of toxicity in animals or cell models by following with different administration routes and penetrating through physiological barriers, subsequently being distributed in tissues or located in cells, eventually being excreted out of the bodies. This review collects studies on the toxic effects of GFNs in several organs and cell models. We also point out that various factors determine the toxicity of GFNs including the lateral size, surface structure, functionalization, charge, impurities, aggregations, and corona effect ect. In addition, several typical mechanisms underlying GFN toxicity have been revealed, for instance, physical destruction, oxidative stress, DNA damage, inflammatory response, apoptosis, autophagy, and necrosis. In these mechanisms, (toll-like receptors-) TLR-, transforming growth factor β- (TGF-β-) and tumor necrosis factor-alpha (TNF-α) dependent-pathways are involved in the signalling pathway network, and oxidative stress plays a crucial role in these pathways. In this review, we summarize the available information on regulating factors and the mechanisms of GFNs toxicity, and propose some challenges and suggestions for further investigations of GFNs, with the aim of completing the toxicology mechanisms, and providing suggestions to improve the biological safety of GFNs and facilitate their wide application.

Breast cancer is a major global health burden with the highest incidence in women, and triple-negative breast cancer (TNBC) stands out as the most malignant subtype. Effective therapeutic targets are urgently needed to develop new therapies for TNBC. Nicotinic acetylcholine receptor is a ligand-gated ion channel receptor that is associated with the advancement of multiple cancers. Notably, α9 nicotinic acetylcholine receptor (α9 nAChR) is less investigated towards its role in cancer. This study sought to clarify the significance of α9 nAChR in TNBC. Firstly, our results uncovered that the expression of CHRNA9 was notably elevated in TNBC tissues and was associated with poor prognosis of TNBC patients. Further, our data indicated that overexpression of α9 nAChR facilitated the growth of TNBC cells, via mechanisms of simultaneously activating AKT-, ERK- and STAT3-mediated proliferation and negatively regulating ferroptosis through promoting SLC7A11/GSH/GPX4 and Keap1/Nrf2/HO1 signaling. Conversely, CHRNA9 knockdown would completely reverse all this signaling, ultimately inhibiting TNBC tumor growth both in vitro and in vivo. Finally, we reported a specific polypeptide antagonist of α9 nAChR, GeXIVA[1,2] and exerted good anti-tumor effects in tumor-bearing mice of TNBC, which indicated a great potential of GeXIVA[1,2] to be further studied as a novel targeted therapy for TNBC. This study provides a scientific basis for establishing α9 nAChR as a novel therapeutic target for TNBC, which is worthy of further development in the future.

Background: As the most lethal neuroendocrine tumor, small cell lung cancer (SCLC) can drive its progression by hijacking neuronal mechanisms. At the core of this neural integration is the N-methyl-D-aspartate receptor (NMDAR) complex. However, its pan-cancer expression and clinical significance in SCLC remain poorly understood. Methods: We characterized NMDAR transcriptomic profiles across human cancers to develop the NMDAscore, and analyzed three independent European and Asian SCLC cohorts to identify prognostic biomarkers. Furthermore, we investigated the molecular mechanisms of GRIN2A and evaluated the efficacy of GluN2 inhibitors. Results: The developed NMDAscore exhibited significant prognostic correlations in ACC, COAD, KIRC, UVM, KIRP, OV, PCPG, UCS, THCA, THYM, HNSC, KICH, LGG, and PAAD. Focusing on the SCLC cohorts, we identified GRIN2A (encoding the GluN2A subunit) as a statistically relevant prognostic biomarker associated with poor survival. Mechanistically, GRIN2A upregulation correlates with the activation of neuro-synaptic signaling, metabolic reprogramming, genomic instability, and an immune-cold microenvironment characterized by CD8+ T cell exclusion. Pharmacological inhibition of GluN2 using dizocilpine and the FDA-approved antagonist memantine suppressed SCLC proliferation and tumorigenicity in vitro, in 3D tumor spheroids and in vivo xenograft models. Conclusions: Collectively, these findings establish GRIN2A as a prognostic biomarker, linking synaptic hijacking, metabolic plasticity, immune evasion, and drug resistance, and identify the therapeutic potentials of the GluN2 inhibitors dizocilpine and memantine for SCLC.

Silicon-based materials and their oxides are widely used in drug delivery, dietary supplements, implants and dental fillers. Silica nanoparticles (SiNPs) interact with immunocompetent cells and induce immunotoxicity. However, the toxic effects of SiNPs on the immune system have been inadequately reviewed. The toxicity of SiNPs to the immune system depends on their physicochemical properties and the cell type. Assessments of immunotoxicity include determining cell dysfunctions, cytotoxicity and genotoxicity. This review focuses on the immunotoxicity of SiNPs and investigates the underlying mechanisms. The main mechanisms were proinflammatory responses, oxidative stress and autophagy. Considering the toxicity of SiNPs, surface and shape modifications may mitigate the toxic effects of SiNPs, providing a new way to produce these nanomaterials with less toxic impaction.

Digestive tract-related cancers account for four of the top ten high-risk cancers worldwide. In recent years, cancer immunotherapy, which exploits the innate immune system to attack tumors, has led to a paradigm shifts in cancer treatment. Gut microbiota modification has been widely used to regulate cancer immunotherapy. Dietary compounds and traditional Chinese medicine (TCM) can alter the gut microbiota and its influence on toxic metabolite production, such as the effect of iprindole on lipopolysaccharide (LPS), and involvement in various metabolic pathways that are closely associated with immune reactions. Therefore, it is an effective strategy to explore new immunotherapies for gastrointestinal cancer to clarify the immunoregulatory effects of different dietary compounds/TCMs on intestinal microbiota. In this review, we have summarized recent progress regarding the effects of dietary compounds/TCMs on gut microbiota and their metabolites, as well as the relationship between digestive cancer immunotherapy and gut microbiota. We hope that this review will act as reference, providing a theoretical basis for the clinical immunotherapy of digestive cancer via gut microbiota modulation.

Background: EGFR mutation is a common oncogene driver in East Asians with lung adenocarcinoma (LUAD), conferring a favorable prognosis with effective targeted therapy. However, the EGFR mutation is a weak predictor of long-term survival. Therefore, a powerful predictive tool is urgently needed to estimate disease prognosis and patient survival for East-Asian patients with LUAD. Methods: In this first systematic analysis of the relationships among EGFR mutation, immunophenotype, and prognosis in LUAD samples from East-Asian patients, we constructed a prognostic signature consisting of EGFR-associated immune-related gene pairs (EIGPs). The predictive performance for overall survival (OS) and the clinical significance of this signature were then comprehensively investigated. Results: Based on transcriptome data analysis of a training set, we proposed the EIGP index (EIGPI), represented by five EIGPs, which was significantly associated with the OS of East-Asian patients with LUAD. It was also well validated in a test set. Furthermore, the prognostic performance of the EIGPI was further verified using protein levels in an additional independent set. Stratification analysis and multivariate Cox regression analysis revealed that the EIGPI was an independent prognostic factor. When combined with stage, the composite immune-clinical prognostic model index (ICPMI) showed improved prognostic accuracy in all datasets. Conclusion: This study was the first to systematically investigate the relationships among EGFR mutation, immunophenotype, and prognosis in East Asians with LUAD and develop a composite clinical and immune model associated with EGFR mutation. This model may be a reliable and promising prognostic tool and help further personalize patient management.

Background Although immune checkpoint inhibitors (ICIs) against programmed cell death protein 1 (PD‐1) and its ligand PD‐L1 have demonstrated potency towards treating patients with non‐small cell lung carcinoma (NSCLC), the potential association between Kirsten rat sarcoma viral oncogene homolog (KRAS) oncogene substitutions and the efficacy of ICIs remains unclear. In this study, we aimed to find point mutations in the KRAS gene resistant to ICIs and elucidate resistance mechanism. Methods The association between KRAS variant status and the efficacy of ICIs was explored with a clinical cohort (n = 74), and confirmed with a mouse model. In addition, the tumor immune microenvironment (TIME) of KRAS‐mutant NSCLC, such as CD8+ tumor‐infiltrating lymphocytes (TILs) and PD‐L1 level, was investigated. Cell lines expressing classic KRAS substitutions were used to explore signaling pathway activation involved in the formation of TIME. Furthermore, interventions that improved TIME were developed to increase responsiveness to ICIs. Results We observed the inferior efficacy of ICIs in KRAS‐G12D‐mutant NSCLC. Based upon transcriptome data and immunostaining results from KRAS‐mutant NSCLC, KRAS‐G12D point mutation negatively correlated with PD‐L1 level and secretion of chemokines CXCL10/CXCL11 that led to a decrease in CD8+ TILs, which in turn yielded an immunosuppressive TIME. The analysis of cell lines overexpressing classic KRAS substitutions further revealed that KRAS‐G12D mutation suppressed PD‐L1 level via the P70S6K/PI3K/AKT axis and reduced CXCL10/CXCL11 levels by down‐regulating high mobility group protein A2 (HMGA2) level. Notably, paclitaxel, a chemotherapeutic agent, upregulated HMGA2 level, and in turn, stimulated the secretion of CXCL10/CXCL11. Moreover, PD‐L1 blockade combined with paclitaxel significantly suppressed tumor growth compared with PD‐L1 inhibitor monotherapy in a mouse model with KRAS‐G12D‐mutant lung adenocarcinoma. Further analyses revealed that the combined treatment significantly enhanced the recruitment of CD8+ TILs via the up‐regulation of CXCL10/CXCL11 levels. Results of clinical study also revealed the superior efficacy of chemo‐immunotherapy in patients with KRAS‐G12D‐mutant NSCLC compared with ICI monotherapy. Conclusions Our study elucidated the molecular mechanism by which KRAS‐G12D mutation drives immunosuppression and enhances resistance of ICIs in NSCLC. Importantly, our findings demonstrate that ICIs in combination with chemotherapy may be more effective in patients with KRAS‐G12D‐mutant NSCLC.

Background Cytokines have been reported to alter the response to immune checkpoint inhibitors (ICIs) in patients with the tumor in accordance with their plasma concentrations. Here, we aimed to identify the key cytokines which influenced the responses and stimulated resistance to ICIs and tried to improve immunological response and develop novel clinical treatments in non-small cell lung cancer (NSCLC). Methods The promising predictive cytokines were analyzed via the multi-analyte flow assay. Next, we explored the correlation baseline level of plasma cytokines and clinical outcomes in 45 NSCLC patients treated with ICIs. The mechanism of the potential candidate cytokine in predicting response and inducing resistance to ICIs was then investigated. Results We found NSCLC with a low baseline concentration of IL-6 in plasma specimens or tumor tissues could derive more benefit from ICIs based on the patient cohort. Further analyses revealed that a favorable relationship between PD-L1 and IL-6 expression was seen in NSCLC specimens. Results in vitro showed that PD-L1 expression in the tumor was enhanced by IL-6 via the JAK1/Stat3 pathway, which induced immune evasion. Notably, an adverse correlation was found between IL-6 levels and CD8 + T cells. And a positive association between IL-6 levels and myeloid-derived suppressor cells, M2 macrophages and regulator T cells was also seen in tumor samples, which may result in an inferior response to ICIs. Results of murine models of NSCLC suggested that the dual blockade of IL-6 and PD-L1 attenuated tumor growth. Further analyses detected that the inhibitor of IL-6 stimulated the infiltration of CD8 + T cells and yielded the inflammatory phenotype. Conclusions This study elucidated the role of baseline IL-6 levels in predicting the responses and promoting resistance to immunotherapy in patients with NSCLC. Our results indicated that the treatment targeting IL-6 may be beneficial for ICIs in NSCLC. Graphical Abstract