MIOX inhibits autophagy to regulate the ROS -driven inhibition of STAT3/c-Myc-mediated epithelial-mesenchymal transition in clear cell renal cell carcinoma.

The specific mechanism of clear cell renal cell carcinoma (ccRCC) progression, a pathological type that accounts for the highest proportion of RCC, remains unclear. In this study, bioinformatics analysis of scRNA-seq dataset in ccRCC revealed that MIOX was a gene specifically down-regulated in tumor epithelial cells of ccRCC. Analysis of the TCGA database further validated the association between decreased MIOX mRNA levels and ccRCC malignant phenotype and poor prognosis. Immunohistochemistry indicated the down-regulation of MIOX in ccRCC tissues compared to paired adjacent renal tissues, with further down-regulation of MIOX in the primary tumors of patients with primary metastasis compared to those without metastasis. Also, patients with low expression of MIOX showed shorter metastasis-free survival (MFS) compared to those with high MIOX expression. In vitro results showed that overexpression of MIOX in ccRCC cells inhibited the proliferation, migration and invasion and promoted apoptosis. Mechanistically, up-regulation of MIOX inhibited autophagy to elevate the levels of ROS, and thus suppressed STAT3/c-Myc-mediated epithelial-mesenchymal transition in ccRCC cells. In vivo data further confirmed that increased MIOX expression suppressed the growth and proliferation of RCC cells and reduced the ability of RCC cells to form metastases in the lung. This study demonstrates that MIOX is an important regulatory molecule of ccRCC, which is conducive to understanding the potential molecular mechanism of ccRCC progression.

ROS Scavenging Nanozyme Modulates Immunosuppression for Sensitized Cancer Immunotherapy.

Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), two immunosuppressive myeloid components within the tumor microenvironment (TME), represent fundamental barriers in cancer immunotherapy, whereas current nanomedicines rarely exert dual modulatory roles on these cell types simultaneously. Reactive oxygen species (ROS) not only mediates MDSC-induced immunosuppression but also triggers differentiation and polarization of M2-TAMs. Herein, an ROS scavenging nanozyme, Zr-CeO, with enhanced superoxide dismutase- and catalase-like activities for renal tumor growth inhibition is reported. Mechanistically, intracellular ROS scavenging by Zr-CeO significantly attenuates MDSC immunosuppression via dampening the unfolded protein response, hinders M2-TAM polarization through the ERK and STAT3 pathways, but barely affects neoplastic cells and cancer-associated fibroblasts. Furthermore, Zr-CeO enhances the antitumor effect of PD-1 inhibition in murine renal and breast tumor models, accompanied with substantially decreased MDSC recruitment and reprogrammed phenotype of TAMs in the tumor mass. Upon cell isolation, reversed immunosuppressive phenotypes of MDSCs and TAMs are identified. In addition, Zr-CeO alone or combination therapy enhances T lymphocyte infiltration and IFN-γ production within the TME. Collectively, a promising strategy to impair the quantity and function of immunosuppressive myeloid cells and sensitize immunotherapy in both renal and breast cancers is provided.

Reactive Oxygen Species- and Cell-Free DNA-Scavenging Mn3O4 Nanozymes for Acute Kidney Injury Therapy.

Reactive oxygen species (ROS) scavenging therapy toward acute kidney injury (AKI) is promising, but no effective ROS scavenging drug has been developed yet. Moreover, cell-free DNA (cfDNA) is also involved in AKI, but the corresponding therapies have not been well developed. To tackle these challenges, Mn3O4 nanoflowers (Nfs) possessing both ROS and cfDNA scavenging activities were developed for better AKI protection as follows. First, Mn3O4 Nfs could protect HK2 cells through cascade ROS scavenging (dismutating ·O2- into H2O2 by superoxide dismutase-like activity and then decomposing H2O2 by catalase-like activity). Second, Mn3O4 Nfs could efficiently adsorb cfDNA and then decrease the inflammation caused by cfDNA. Combined, remarkable therapeutic efficacy was achieved in both cisplatin-induced and ischemia-reperfusion AKI murine models. Furthermore, Mn3O4 Nfs could be used for the T1-MRI real-time imaging of AKI. This study not only offered a promising treatment for AKI but also showed the translational potential of nanozymes.

68Ga-PSMA-11 PET/CT Parameter Correlates with Pathological VEGFR-2/PDGFR-ß Expression in Renal Cell Carcinoma Patients.

BACKGROUND: Response prediction is necessary for renal cell carcinoma (RCC) tumors. We aim to evaluate parameters derived from 68 Ga-PSMA-11 PET/CT images for prediction of pathological VEGFR-2/PDGFR-ß expression of primary RCC tumors. METHODS: Forty-eight RCC patients were retrospectively enrolled with preoperative 68 Ga-PSMA-11 PET/CT scan and surgical specimen. Radiological parameters including tumor diameter, mean CT value, and maximal standard uptake value (SUVmax) were derived from PET/CT images and pathological VEGFR-2/PDGFR-ß/PSMA expression were identified with immunohistochemistry. Mann-Whitney U test was performed for continuous variables and the chi-square test for categorical variables. ROC was used for determining the effectiveness of preoperative parameters in differentiating VEGFR-2/PDGFR-ß expression. Univariate and multivariate logistic regression analyses were performed for significant parameters to predict VEGFR-2 & PDGFR-ß co-expression. RESULTS: Of the 48 tumors, 25 (52.1%) harbored positive VEGFR-2 expression, 28 (58.3%) harbored positive PDGFR-ß expression, and 24 (50%) were both VEGFR-2 positive and PDGFR-ß positive. SUVmax significantly differed by subgroups of VEGFR-2/PDGFR-ß expression (both P < 0.001). SUVmax demonstrated superior performance for differentiating VEGFR-2 & PDGFR-ß co-expression (positive vs. negative), with area under the curve 0.87 (95% CI 0.78-0.96, P < 0.001), sensitivity 93% and specificity 78%. Moreover, SUVmax was identified as the significant predictor for VEGFR-2 & PDGFR-ß co-expression (odds ratio 4.01, 95% CI 1.99-8.08, P < 0.001). Concordant with radiological findings with 68 Ga-PSMA-11 PET/CT, pathological PSMA staining intensity was significantly higher in both VEGFR-2-positive tumor and PDGFR-ß-positive tumor (P = 0.009 and P < 0.001, respectively). CONCLUSION: 68 Ga-PSMA-11 PET/CT could effectively identify pathological VEGFR-2/PDGFR-ß expression of primary RCC tumors, which may help with selection of mRCC patients suitable for TKIs treatment.

[68Ga]Ga-PSMA-11 PET/CT has potential application in predicting tumor HIF-2α expression and therapeutic response to HIF-2α antagonists in patients with RCC.

OBJECTIVE: To evaluate the efficacy of parameters derived from [68Ga]Ga-PSMA-11 PET/CT images in predicting pathological HIF-2α expression in primary tumors among patients with renal cell carcinoma (RCC). METHODS: Fifty-three RCC patients with preoperative [68Ga]Ga-PSMA-11 PET/CT scans and complete surgical specimens were retrospectively enrolled in this study. Radiographic parameters were obtained from PET/CT images, and immunohistochemistry was used to measure the expression of HIF-2α and PSMA. Continuous variables and categorical variables were analyzed by the Mann-Whitney U test and chi-square test, respectively. ROC analysis was used to test the efficacy of several preoperative parameters in identifying pathological HIF-2α expression. Univariable logistic regression analyses were performed for significant parameters to predict pathological HIF-2α expression in RCC. RESULTS: Of the 53 tumors, 29 (54.7%) had high expression of HIF-2α. The SUVmax was significantly different in the HIF-2α expression subgroups (p < 0.001). SUVmax emerged as the most significant parameter to differentiate HIF-2α expression subgroups (high vs. low), with the AUC of 0.93 (95% CI 0.85-1.00, p < 0.001), sensitivity of 90%, and specificity of 88%. Furthermore, SUVmax was confirmed as the most significant predictor of HIF-2α expression level by univariable logistic regression model analysis (odds ratio 1.39, 95% CI 1.17-1.65, p < 0.001). Consistent with the radiographic results of [68Ga]Ga-PSMA-11 PET/CT, the staining intensity of pathological PSMA was significantly higher in HIF-2α-high-expressing tumors (p = 0.003). CONCLUSIONS: [68Ga]Ga-PSMA-11 PET/CT was superior in identifying pathological HIF-2α expression in primary tumors of RCC patients, demonstrating its potential application in predicting responses to HIF-2α antagonists. KEY POINTS: • [68Ga]Ga-PSMA-11 PET/CT could potentially predict the HIF-2α expression of primary tumors among patients with RCC. • SUVmaxof [68Ga]Ga-PSMA-11 PET/CT was the most significant predictor of HIF-2α expression level. • This probability could help predict the therapeutic response of patients with RCC to HIF-2α antagonists.

Fumarate inhibits PTEN to promote tumorigenesis and therapeutic resistance of type2 papillary renal cell carcinoma.

Fumarate is an oncometabolite. However, the mechanism underlying fumarate-exerted tumorigenesis remains unclear. Here, utilizing human type2 papillary renal cell carcinoma (PRCC2) as a model, we show that fumarate accumulates in cells deficient in fumarate hydratase (FH) and inhibits PTEN to activate PI3K/AKT signaling. Mechanistically, fumarate directly reacts with PTEN at cysteine 211 (C211) to form S-(2-succino)-cysteine. Succinated C211 occludes tethering of PTEN with the cellular membrane, thereby diminishing its inhibitory effect on the PI3K/AKT pathway. Functionally, re-expressing wild-type FH or PTEN C211S phenocopies an AKT inhibitor in suppressing tumor growth and sensitizing PRCC2 to sunitinib. Analysis of clinical specimens indicates that PTEN C211 succination levels are positively correlated with AKT activation in PRCC2. Collectively, these findings elucidate a non-metabolic, oncogenic role of fumarate in PRCC2 via direct post-translational modification of PTEN and further reveal potential stratification strategies for patients with FH loss by combinatorial AKTi and sunitinib therapy.