Biodegradable copper-iodide clusters modulate mitochondrial function and suppress tumor growth under ultralow-dose X-ray irradiation.

Both copper (Cu2+/+) and iodine (I-) are essential elements in all living organisms. Increasing the intracellular concentrations of Cu or I ions may efficiently inhibit tumor growth. However, efficient delivery of Cu and I ions into tumor cells is still a challenge, as Cu chelation and iodide salts are highly water-soluble and can release in untargeted tissue. Here we report mitochondria-targeted Cu-I cluster nanoparticles using the reaction of Cu+ and I- to form stable bovine serum albumin (BSA) radiation-induced phosphors (Cu-I@BSA). These solve the stability issues of Cu+ and I- ions. Cu-I@BSA exhibit bright radioluminescence, and easily conjugate with the emission-matched photosensitizer and targeting molecule using functional groups on the surface of BSA. Investigations in vitro and in vivo demonstrate that radioluminescence under low-dose X-ray irradiation excites the conjugated photosensitizer to generate singlet oxygen, and combines with the radiosensitization mechanism of the heavy atom of iodine, resulting in efficient tumor inhibition in female mice. Furthermore, our study reveals that BSA protection causes the biodegradable Cu-I clusters to release free Cu and I ions and induce cell death by modulating mitochondrial function, damaging DNA, disrupting the tricarboxylic acid cycle, decreasing ATP generation, amplifying oxidative stress, and boosting the Bcl-2 pathway.

An acid-activatable fluorouracil prodrug for colorectal cancer synergistic therapy.

5-Fluorouracil has demonstrated certain efficiency in patients with colorectal cancer. However, significant side effects of use by injection are common. To address this issue defects, a reengineered 5'-deoxy-5-fluorocytidine (DFCR) based drug delivery system (POACa) is developed as a prominent tumor-selective nano-activator. Investigations demonstrate that the constructed nano-activator exhibits good biocompatibility and high therapeutic efficiency in mice with subcutaneous and orthotopic SW-480 colorectal tumors, as its activity is strictly dependent on the tumor-associated acid environment and thymidine phosphorylase. These strategies diminish the off-target toxicity and improve the specificity and sensitivity of human colorectal cancer cells to 5-Fu, obtaining potent efficiency by the combination of H2O2 mediated oxidative stress, calcium overload and 5-Fu-induced chemotherapy (the combination index is 0.11). Overall, the engineered nano-activator exhibits a high therapeutic index in vitro and in vivo. STATEMENT OF SIGNIFICANCE: In this study, we designed and prepared a pH-responsive polymer to synchronously deliver DFCR (5'-deoxy-5-fluorocytidine, a prodrug of 5-Fu), Ca2+ and H2O2. The constructed nano-activator was denoted as POACa. (1) To address the problem of premature leakage of cargo by physical embedding, our research modified the inactive prodrug DFCR through chemical bonding. (2) The activation of the prepared nano-activator was strictly dependent on the tumor-associated acid environment and thymidine phosphorylase, providing the drug delivery system with inherent safety. (3) A distinctly low combination index value (0.11) of CaO2 and DFCR indicated that POACa has a prominent tumor suppression effect by tumor calcium overload sensitized chemotherapy and H2O2 mediated cytotoxicity.

Cuproptosis and Cuproptosis-Based Synergistic Therapy for Cancer Treatment.

Copper, as an essential trace nutrient for human, plays a crucial role in numerous cellular activities, and is vital for maintaining homeostasis in organisms. Deviations from normal intracellular copper concentration range can disrupt the cellular homeostasis and lead to cell death. Cell death is the process in which cells lose their vitality and cannot sustain normal metabolism, which has various forms. The recently discovered cuproptosis mechanism differs from the previously recognized forms, which is triggered by intracellular copper accumulation. The discovery of cuproptosis has sparked interest among researchers, and this mechanism has been applied in the treatment of various intractable diseases, including different types of cancer. However, the developed cuproptosis-based therapies have revealed certain limitations, such as low immunostimulatory efficiency, poor tumor targeting, and inhibition by the tumor microenvironment. Therefore, researchers are devoted to combining cuproptosis with existing cancer therapies to develop more effective synergistic cancer therapies. This review summarizes the latest research advancements in the cuproptosis-based therapies for various types of cancer, with a focus on the synergistic cancer therapies. Finally, it provides an outlook on the future development of cuproptosis in anti-tumor therapy.

Integrated anti-vascular and immune-chemotherapy for colorectal carcinoma using a pH-responsive polymeric delivery system.

Colorectal carcinoma (CRC) has become one of the most prevalent malignant tumors and exploring a potential therapeutic strategy with diminished drug-associated adverse effects to combat CRC is urgent. Herein, we designed a pH-responsive polymer to efficiently encapsulate a stimulator of interferon genes (STING) agonist (5,6- dimethylxanthenone-4-acetic acid, termed ASA404) and a common clinically used chemotherapeutic agent (1-hexylcarbamoyl-5-fluorouracil, termed HCFU). Investigations in vitro demonstrated that polymer encapsulation endowed the system with a pH-dependent disassembly behavior (pHt 6.37), which preferentially selected cancerous cells with a favorable dose reduction (dose reduction index (DRI) of HCFU was 4.09). Moreover, the growth of CRC in tumor-bearing mice was effectively suppressed, with tumor suppression rates up to 94.74%, and a combination index (CI) value of less than one (CI = 0.41 for CT26 cell lines), indicating a significant synergistic therapeutic effect. Histological analysis of the tumor micro-vessel density and enzyme-linked immunosorbent assay (ELISA) tests indicated that the system increased TNF-α and IFN-ß levels in serum. Therefore, this research introduces a pH-responsive polymer-based theranostic platform with great potential for immune-chemotherapeutic and anti-vascular combination therapy of CRC.

Extracellular-vesicle-packaged S100A11 from osteosarcoma cells mediates lung premetastatic niche formation by recruiting gMDSCs.

The premetastatic niche (PMN) contributes to lung-specific metastatic tropism in osteosarcoma. However, the crosstalk between primary tumor cells and lung stromal cells is not clearly defined. Here, we dissect the composition of immune cells in the lung PMN and identify granulocytic myeloid-derived suppressor cell (gMDSC) infiltration as positively associated with immunosuppressive PMN formation and tumor cell colonization. Osteosarcoma-cell-derived extracellular vesicles (EVs) activate lung interstitial macrophages to initiate the influx of gMDSCs via secretion of the chemokine CXCL2. Proteomic profiling of EVs reveals that EV-packaged S100A11 stimulates the Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway in macrophages by interacting with USP9X. High level of S100A11 expression or circulating gMDSCs correlates with the presentation of lung metastasis and poor prognosis in osteosarcoma patients. In summary, we identify a key role of tumor-derived EVs in lung PMN formation, providing potential strategies for monitoring or preventing lung metastasis in osteosarcoma.

Mass Spectrometry-Based Proteomics Identifies Serpin B9 as a Key Protein in Promoting Bone Metastases in Lung Cancer.

Bone metastasis (BM) is one of the most common complications of advanced cancer. Immunotherapy for bone metastasis of lung cancer (LCBM) is not so promising and the immune mechanisms are still unknown. Here, we utilized a model of BM by injecting cancer cells through caudal artery (CA) to screen out a highly bone metastatic derivative (LLC1-BM3) from a murine lung cancer cell line LLC1. Mass spectrometry-based proteomics was performed in LLC1-parental and LLC1-BM3 cells. Combining with prognostic survival information from patients with lung cancer, we identified serpin B9 (SB9) as a key factor in BM. Molecular characterization showed that SB9 overexpression was associated with poor prognosis and high bone metastatic burden in lung cancer. Moreover, SB9 could increase the ability of lung cancer cells to metastasize to the bone. The mechanistic studies revealed that tumor-derived SB9 promoted BM through an immune cell-dependent way by inactivating granzyme B, manifesting with the decreased infiltration of cytotoxic T cells and increased expression level of exhausted markers. A specific SB9-targeting inhibitor [1,3-benzoxazole-6-carboxylic acid (BTCA)] significantly suppressed LCBM in the CA mouse model. This study reveals that SB9 may serve as a therapeutic target and potential prognostic marker for patients with LCBM. IMPLICATIONS: SB9 as a therapeutic target for LCBM.

Extracellular vesicles released by cancer-associated fibroblast-induced myeloid-derived suppressor cells inhibit T-cell function.

Myeloid cells are known to play a crucial role in creating a tumor-promoting and immune suppressive microenvironment. Our previous study demonstrated that primary human monocytes can be polarized into immunosuppressive myeloid-derived suppressor cells (MDSCs) by cancer-associated fibroblasts (CAFs) in a 3D co-culture system. However, the molecular mechanisms underlying the immunosuppressive function of MDSCs, especially CAF-induced MDSCs, remain poorly understood. Using mass spectrometry-based proteomics, we compared cell surface protein changes among monocytes, in vitro differentiated CAF-induced MDSCs, M1/M2 macrophages, and dendritic cells, and identified an extracellular vesicle (EV)-mediated secretory phenotype of MDSCs. Functional assays using an MDSC/T-cell co-culture system revealed that blocking EV generation in CAF-induced MDSCs reversed their ability to suppress T-cell proliferation, while EVs isolated from CAF-induced MDSCs directly inhibited T-cell function. Furthermore, we identified fructose bisphosphatase 1 (FBP1) as a cargo protein that is highly enriched in EVs isolated from CAF-induced MDSCs, and pharmacological inhibition of FBP1 partially reversed the suppressive phenotype of MDSCs. Our findings provide valuable insights into the cell surface proteome of different monocyte-derived myeloid subsets and uncover a novel mechanism underlying the interplay between CAFs and myeloid cells in shaping a tumor-permissive microenvironment.

Osteosarcoma Cells Secrete CXCL14 That Activates Integrin α11ß1 on Fibroblasts to Form a Lung Metastatic Niche.

Cooperation between primary malignant cells and stromal cells can mediate the establishment of lung metastatic niches. Here, we characterized the landscape of cell populations in the tumor microenvironment in treatment-naïve osteosarcoma using single-cell RNA sequencing and identified a stem cell-like cluster with tumor cell-initiating properties and prometastatic traits. CXCL14 was specifically enriched in the stem cell-like cluster and was also significantly upregulated in lung metastases compared with primary tumors. CXCL14 induced stromal reprogramming and evoked a malignant phenotype in fibroblasts to form a supportive lung metastatic niche. Binding of CXCL14 to heterodimeric integrin α11ß1 on fibroblasts activated actomyosin contractility and matrix remodeling properties. CXCL14-stimulated fibroblasts produced TGFß and increased osteosarcoma invasion and migration. mAbs targeting the CXCL14-integrin α11ß1 axis inhibited fibroblast TGFß production, enhanced CD8+ T cell-mediated antitumor immunity, and suppressed osteosarcoma lung metastasis. Taken together, these findings identify cross-talk between osteosarcoma cells and fibroblasts that promotes metastasis and demonstrate that targeting the CXCL14-integrin α11ß1 axis is a potential strategy to inhibit osteosarcoma lung metastasis. SIGNIFICANCE: Cooperation between stem-like osteosarcoma cells and fibroblasts mediated by a CXCL14-integrin α11ß1 axis creates a tumor-supportive lung metastatic niche and represents a therapeutic target to suppress osteosarcoma metastasis.

Surgical outcomes and risk factors for surgical complications after en bloc resection following reconstruction with 3D-printed artificial vertebral body for thoracolumbar tumors.

BACKGROUND: The outcomes of patients with tumors of the thoracolumbar spine treated with en bloc resection (EBR) using three-dimensional (3D)-printed endoprostheses are underreported. METHODS: We retrospectively evaluated patients with thoracolumbar tumors who underwent surgery at our institution. Logistic regression analysis was performed to identify the potential risk factors for surgical complications. Nomograms to predict complications were constructed and validated. RESULTS: A total of 53 patients with spinal tumors underwent EBR at our hospital; of these, 2 were lost to follow-up, 45 underwent total en bloc spondylectomy, and 6 were treated with sagittal en bloc spondylectomy. The anterior reconstruction materials included a customized 3D-printed artificial vertebral body (AVB) in 10 cases and an off-the-shelf 3D-printed AVB in 41 cases, and prosthesis mismatch occurred in 2 patients reconstructed with the off-the-shelf 3D-printed AVB. The median follow-up period was 21 months (range, 7-57 months). Three patients experienced local recurrence, and 5 patients died at the final follow-up. A total of 50 perioperative complications were encountered in 29 patients, including 25 major and 25 minor complications. Instrumentation failure occurred in 1 patient, and no prosthesis subsidence was observed. Using a combined surgical approach was a dependent predictor of overall complications, while Karnofsky performance status score, lumbar spine lesion, and intraoperative blood loss ≥ 2000 mL were predictors of major complications. Nomograms for the overall and major complications were constructed using these factors, with C-indices of 0.850 and 0.891, respectively. CONCLUSIONS: EBR is essential for the management of thoracolumbar tumors; however, EBR has a steep learning curve and a high complication rate. A 3D-printed AVB is an effective and feasible reconstruction option for patients treated with EBR.

Cu2+ -Anchored Carbon Nano-Photocatalysts for Visible Water Splitting to Boost Hydrogen Cuproptosis.

Both hydrogen (H2 ) and copper ions (Cu+ ) can be used as anti-cancer treatments. However, the continuous generation of H2 molecules and Cu+ in specific sites of tumors is challenging. Here we anchored Cu2+ on carbon photocatalyst (Cu@CDCN) to allow the continuous generation of H2 and hydrogen peroxide (H2 O2 ) in tumors using the two-electron process of visible water splitting. The photocatalytic process also generated redox-active Cu-carbon centers. Meanwhile, the Cu2+ residues reacted with H2 O2 (the obstacle to the photocatalytic process) to accelerate the two-electron process of water splitting and cuprous ion (Cu+ ) generation, in which the Cu2+ residue promoted a pro-oxidant effect with glutathione through metal-reducing actions. Both H2 and Cu+ induced mitochondrial dysfunction and intracellular redox homeostasis destruction, which enabled hydrogen therapy and cuproptosis to inhibit cancer cell growth and suppress tumor growth. Our research is the first attempt to integrate hydrogen therapy and cuproptosis using metal-enhanced visible solar water splitting in nanomedicine, which may provide a safe and effective cancer treatment.

Mumia quercus sp. nov., isolated from the root of Quercus variabilis.

A novel endophytic actinomycete, designated strain NEAU-365T, was isolated from the root of Quercus variabilis collected from Nanjing, Jiangsu, PR China. Comparative 16S rRNA gene sequencing showed that strain NEAU-365T belonged to the genus Mumia but clearly differs from the currently recognized species Mumia zhuanghuii Z350T (99.31 %), Mumia xiangluensis NEAU-KD1T (98.82 %) and Mumia flava MUSC 201T (97.78 %). Phylogenetic tree analysis revealed that strain NEAU-365T clustered with the type strains of the genus Mumia. The genome size was 4.1 Mbp with a DNA G+C content of 71.2 mol%. Digital DNA-DNA hybridization and average nucleotide identity values between the genome sequence of strain NEAU-365T and those of M. zhuanghuii Z350T(27.5 and 84.0 %), M. xiangluensis NEAU-KD1T(23.4 and 80.9 %) and M. flava MUSC 201T(20.9 and 77.7 %) were below the recommended thresholds for species delineation. Cells were observed to be irregular cocci shaped. The cell wall contained ll-diaminopimelic acid and the whole-cell sugars were galactose and rhamnose. The polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphoglycolipid and three unidentified phospholipids. The predominant menaquinone was detected as MK-9(H4). The major fatty acids were C16 : 0, C18 : 0, C18 : 1 ω9c and 10-methyl C18 : 0. On the basis of genotypic and phenotypic differences from members of the genus Mumia, a novel species, Mumia quercus sp. nov. is proposed. The type strain is NEAU-365T (=CCTCC AA 2021033T=JCM 35005T).

Sphaerisporangium perillae sp. nov., isolated from the root of Perilla frutescens (Linn.) Britt.

A novel protease-producing actinomycete, designated strain NEAU-ZS1T, was isolated from the root of Perilla frutescens (Linn.) Britt collected from Jiamusi, Heilongjiang, PR China. Comparative 16S rRNA gene sequencing showed that strain NEAU-ZS1T belonged to the genus Sphaerisporangium and was most closely related to 'Sphaerisporangium corydalis' NEAU-YHS15T (99.2%) and Sphaerisporangium cinnabarinum JCM 3291T (99.0%). Phylogenetic tree analysis revealed that strain NEAU-ZS1T formed a monophyletic clade with 'S. corydalis' NEAU-YHS15T. The genome size was 9.3 Mbp with a DNA G+C content of 70.3 mol%. Digital DNA-DNA hybridization, average nucleotide identity and average amino acid identity values between the genome sequence of strain NEAU-ZS1T and those of 'S. corydalis' NEAU-YHS15T (28.6, 83.9 and 79.1 %) and S. cinnabarinum JCM 3291T (18.5, 70.6 and 50.2 %) were below the recommended thresholds for species delineation. The strain formed spherical spore vesicles produced on the aerial hyphae. The cell wall contained meso-diaminopimelic acid and the whole-cell sugars were glucose and madurose. The polar lipids consisted of diphosphatidylglycerol, phosphatidylmethylethanolamine, phosphatidylethanolamine, phosphatidylinositol, an unidentified phospholipid and an unidentified glycolipid. The menaquinones were MK-9(H4), MK-9(H6) and MK-9(H2). The major fatty acids were iso-C16 : 0, C16 : 1 ω5c, 10-methy C17 : 0 and C17 : 1 ω7c. On the basis of the results of a polyphasic taxonomic study, it is concluded that strain NEAU-ZS1T represents a novel species of the genus Sphaerisporangium, for which the name Sphaerisporangium perillae sp. nov. is proposed. The type strain is NEAU-ZS1T (=CCTCC AA 2021019T= JCM 35655T).

Screening of core genes and prediction of ceRNA regulation mechanism of circRNAs in nasopharyngeal carcinoma by bioinformatics analysis.

Background: Nasopharyngeal carcinoma (NPC) represents a highly aggressive malignant tumor. Competing endogenous RNAs (ceRNA) regulation is a common regulatory mechanism in tumors. The ceRNA network links the functions between mRNAs and ncRNAs, thus playing an important regulatory role in diseases. This study screened the potential key genes in NPC and predicted regulatory mechanisms using bioinformatics analysis. Methods: The merged microarray data of three NPC-related mRNA expression microarrays from the Gene Expression Omnibus (GEO) database and the expression data of tumor samples or normal samples from the nasopharynx and tonsil in The Cancer Genome Atlas (TCGA) database were both subjected to differential analysis and Weighted Gene Co-expression Network Analysis (WGCNA). The results from two different databases were intersected with WGCNA results to obtain potential regulatory genes in NPC, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses. The hub-gene in candidate genes was discerned through Protein-Protein Interaction (PPI) analysis and its upstream regulatory mechanism was predicted by miRwalk and circbank databases. Results: Totally 68 upregulated genes and 96 downregulated genes in NPC were screened through GEO and TCGA. According to WGCNA, the NPC-related modules were screened from GEO and TCGA analysis results, and the genes in the modules were obtained. After the results of differential analysis and WGCNA were intersected, 74 differentially expressed candidate genes associated with NPC were discerned. Finally, fibronectin 1 (FN1) was identified as a hub-gene in NPC. Prediction of upstream regulatory mechanisms of FN1 suggested that FN1 may be regulated by ceRNA mechanisms involving multiple circRNAs, thereby influencing NPC progression through ceRNA regulation. Conclusion: FN1 is identified as a key regulator in NPC development and is likely to be regulated by numerous circRNA-mediated ceRNA mechanisms.

NIR-II-absorbing diimmonium polymer agent achieves excellent photothermal therapy with induction of tumor immunogenic cell death.

Photothermal therapy has shown great promise for cancer treatment and second near-infrared (NIR-II) -absorbing particles could further improve its precision and applicability due to its superior penetration depth and new imaging ability. Herein, high NIR-II-absorbing polymer particles were prepared by using soluble isobutyl-substituted diammonium borates (P-IDI). The P-IDI showed stronger absorption at 1000-1100 nm, which exhibited excellent photostability, strong photoacoustic imaging ability and high photothermal conversion efficiency (34.7%). The investigations in vitro and in vivo demonstrated that the excellent photothermal effect facilitated complete tumor ablation and also triggered immunogenic cell death in activation of the immune response. The high solubility and excellent photothermal conversion ability demonstrated that polymer IDI particles were promising theranostic agents for treatment of tumors with minor side effects.

Nanosensitizer-mediated unique dynamic therapy tactics for effective inhibition of deep tumors.

X-ray and ultrasound waves are widely employed for diagnostic and therapeutic purposes in clinic. Recently, they have been demonstrated to be ideal excitation sources that activate sensitizers for the dynamic therapy of deep-seated tumors due to their excellent tissue penetration. Here, we focused on the recent progress in five years in the unique dynamic therapy strategies for the effective inhibition of deep tumors that activated by X-ray and ultrasound waves. The concepts, mechanisms, and typical nanosensitizers used as energy transducers are described as well as their applications in oncology. The future developments and potential challenges are also discussed. These unique therapeutic methods are expected to be developed as depth-independent, minimally invasive, and multifunctional strategies for the clinic treatment of various deep malignancies.

Identification of the miRNA-mRNA regulatory network associated with radiosensitivity in esophageal cancer based on integrative analysis of the TCGA and GEO data.

BACKGROUND: The current study set out to identify the miRNA-mRNA regulatory networks that influence the radiosensitivity in esophageal cancer based on the The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. METHODS: Firstly, esophageal cancer-related miRNA-seq and mRNA-seq data were retrieved from the TCGA database, and the mRNA dataset of esophageal cancer radiotherapy was downloaded from the GEO database to analyze the differential expressed miRNAs (DEmiRNAs) and mRNAs (DEmRNAs) in radiosensitive and radioresistant samples, followed by the construction of the miRNA-mRNA regulatory network and Gene Ontology and KEGG enrichment analysis. Additionally, a prognostic risk model was constructed, and its accuracy was evaluated by means of receiver operating characteristic analysis. RESULTS: A total of 125 DEmiRNAs and 42 DEmRNAs were closely related to the radiosensitivity in patients with esophageal cancer. Based on 47 miRNA-mRNA interactions, including 21 miRNAs and 21 mRNAs, the miRNA-mRNA regulatory network was constructed. The prognostic risk model based on 2 miRNAs (miR-132-3p and miR-576-5p) and 4 mRNAs (CAND1, ZDHHC23, AHR, and MTMR4) could accurately predict the prognosis of esophageal cancer patients. Finally, it was verified that miR-132-3p/CAND1/ZDHHC23 and miR-576-5p/AHR could affect the radiosensitivity in esophageal cancer. CONCLUSION: Our study demonstrated that miR-132-3p/CAND1/ZDHHC23 and miR-576-5p/AHR were critical molecular pathways related to the radiosensitivity of esophageal cancer.

Organic phosphorescent nanoscintillator for low-dose X-ray-induced photodynamic therapy.

X-ray-induced photodynamic therapy utilizes penetrating X-rays to activate reactive oxygen species in deep tissues for cancer treatment, which combines the advantages of photodynamic therapy and radiotherapy. Conventional therapy usually requires heavy-metal-containing inorganic scintillators and organic photosensitizers to generate singlet oxygen. Here, we report a more convenient strategy for X-ray-induced photodynamic therapy based on a class of organic phosphorescence nanoscintillators, that act in a dual capacity as scintillators and photosensitizers. The resulting low dose of 0.4 Gy and negligible adverse effects demonstrate the great potential for the treatment of deep tumours. These findings provide an optional route that leverages the optical properties of purely organic scintillators for deep-tissue photodynamic therapy. Furthermore, these organic nanoscintillators offer an opportunity to expand applications in the fields of biomaterials and nanobiotechnology.