Renal cell carcinoma (RCC) is a highly vascularized and immunogenic malignancy with a complex tumor microenvironment (TME) that shapes disease progression and therapeutic resistance. Despite advances in immune checkpoint inhibitors (ICIs) and targeted therapies, clinical responses remain heterogeneous, underscoring the need for a deeper understanding of RCC immunobiology. This review comprehensively examines the immunosuppressive TME of RCC, emphasizing the roles of cytotoxic and immunosuppressive immune cells, carcinoma-associated fibroblasts (CAFs), abnormal vasculature, and extracellular matrix (ECM) remodeling in fostering immune evasion. This review summarized emerging biomarkers—including PD-L1 expression, tumor mutational burden (TMB), gene mutations, and immune-based subtypes—that may predict ICI response. Furthermore, we evaluate current immunotherapeutic strategies, such as ICIs, combination therapies, and novel approaches targeting immunosuppressive cells and metabolic pathways. While combination therapies have improved outcomes, challenges like toxicity and resistance persist, necessitating biomarker-driven patient stratification and optimized treatment sequencing. Future directions should focus on deciphering TME heterogeneity and developing precision immunotherapy strategies to enhance clinical efficacy in RCC.

Background: Salvianolic acid C (SAC) is a natural compound derived from Salvia miltiorrhiza that can protect against renal diseases. The aims of this work were to explore the effect of SAC on kidney tubulointerstitial fibrosis and study the associated mechanism. Methods: Models for unilateral ureteral obstruction (UUO) and aristolochic acid I (AAI) were established in mice to study renal tubulointerstitial fibrosis. Rat kidney fibroblasts (NRK-49F) and human kidney epithelial cells (HK2) were used as cellular models to evaluate the effects of SAC on kidney fibrosis. Results: Treatment with SAC for two weeks reduced the level of renal tubulointerstitial fibrosis in UUO- and AAI-induced fibrotic kidneys, as demonstrated by Masson’s staining and Western blot. SAC inhibited extracellular matrix protein expression in NRK-49F cells and TGF-β-stimulated HK2 cells in dose-dependent fashion. Moreover, SAC inhibited the expression of epithelial-mesenchymal transition (EMT) factors in animal and cellular models of kidney fibrosis, as well as the EMT-related transcription factor snail. Furthermore, SAC inhibited the fibrosis-related signaling pathway Smad3 in the fibrotic kidneys of two mouse models and in renal cells. Conclusions: We conclude that SAC inhibits EMT and ameliorates tubulointerstitial fibrosis through involvement of the signaling pathway for transforming growth factor-β (TGF-β)/Smad.

Renal fibrosis, a hallmark of chronic kidney disease, is closely associated with dysregulated gluconeogenesis. Tanshinone I (Tan I), a bioactive compound derived from the traditional Chinese medicine Danshen, exhibits antifibrotic and anti-inflammatory properties. However, its effects on gluconeogenesis and the mechanisms through which it alleviates renal fibrosis remain unclear. This study aimed to investigate whether Tan I promotes gluconeogenesis and mitigates renal fibrosis. Both in vivo and in vitro experiments were conducted. A unilateral ureteral obstruction (UUO) mouse model was used. Masson's trichrome, HE, and immunofluorescence staining, along with Western blotting, were employed. Lactate concentrations and a pyruvate tolerance test were conducted to assess glucose metabolism. In vitro, HK2 cells and primary renal tubular cells were treated with transforming growth factor-β (TGFβ) to induce fibrosis, and the effects of Tan I on glucose and lactate levels were examined. In the UUO model, Tan I reduced fibrosis, decreased lactate accumulation, and modulated fibrosis markers while upregulating gluconeogenesis markers. Tanshinone I restored impaired renal gluconeogenesis, as evidenced by increased pyruvate levels. In vitro, Tan I inhibited fibrosis, reduced lactate levels, and increased glucose levels in cell supernatants. It also restored gluconeogenesis protein expression and decreased fibrotic protein levels. Peroxisome proliferator-activated receptor-γ coactivator (PGC1α) expression was downregulated in UUO and TGFβ-stimulated models, and Tan I reversed this downregulation. Inhibition of PGC1α in TGFβ-stimulated cells counteracted the antifibrotic and gluconeogenesis-promoting effects of Tan I. Tanshinone I ameliorated renal fibrosis by enhancing gluconeogenesis through upregulation of PGC1α.

Introduction: The presence of abdominal aortic calcification (AAC) is strongly linked to the development of atherosclerosis and the incidence of morbidity and mortality related to cardiovascular diseases (CVD). Urinary albumin creatinine ratio (UACR) was found related with the increased risk of CVD. The aim of this study is to explore the relationship between the UACR and severe AAC (SAAC).Methods and Results: This study included a total of 2,379 individuals aged over 40 years, and their information was obtained from the National Health and Nutrition Examination Survey conducted (NHANES) in 2013–2014. The measurement of AAC was conducted through dual-energy x-ray absorptiometry and assessed using the Kauppila scoring system. SAAC was characterized by a Kauppila score of 6 or higher. Multivariate regression models were used to analyze the relationship between UACR level and SAAC, with covariate adjustment. In the completely adapted model, the top third subgroup exhibits increased likelihood of SAAC (odds ratio 1.50; 95%CI: 0.98, 2.29; p = 0.030) in contrast to the bottom third subgroup. The subgroup analyses revealed a more pronounced correlation among the older participants (p-value for interaction = 0.013).Discussion: In the United States, SAAC was more likely to occur in adults who had a higher probability of UACR. The use of UACR has the potential to be a valuable method for forecasting the likelihood of SAAC.