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Abstract Objective Immunotherapy, specifically immune checkpoint inhibitors (ICIs), has revolutionized cancer treatment. However, it can also cause immune‐related adverse events (irAEs). This study aimed to develop a clinically practical animal model of irAEs using BALB/c mice. Methods Subcutaneous tumors of mouse breast cancer 4T1 cells were generated in inbred BALB/c mice. The mice were treated with programmed death‐1 (PD‐1) and cytotoxic t‐lymphocyte antigen 4 (CTLA‐4) inhibitors once every 3 days for five consecutive administration cycles. Changes in tumor volume and body weight were recorded. Lung computed tomography (CT) scans were conducted. The liver, lungs, heart, and colon tissues of the mice were stained with hematoxylin–eosin (H&E) staining to observe inflammatory infiltration and were scored. Serum samples were collected, and enzyme‐linked immunosorbent assay (ELISA) was used to detect the levels of ferritin, glutamic‐pyruvic transaminase (ALT), tumor necrosis factor‐α (TNF‐α), interferon‐gamma (IFN‐γ), and interleukin‐6 (IL‐6). Mouse liver and lung cell suspensions were prepared, and changes in macrophages, T cells, myeloid‐derived suppressor cells (MDSCs), and regulatory (Treg) cells were detected by flow cytometry. Results Mice treated with PD‐1 and CTLA‐4 inhibitors showed significant reductions in tumor volume and body weight. The tissue inflammatory scores in the experimental group were significantly higher than those in the control group. Lung CT scans of mice in the experimental group showed obvious inflammatory spots. Serum levels of ferritin, IL‐6, TNF‐α, IFN‐γ, and ALT were significantly elevated in the experimental group. Flow cytometry analysis revealed a substantial increase in CD3+T cells, Treg cells, and macrophages in the liver and lung tissues of mice in the experimental group compared with the control group, and the change trend of MDSCs was opposite. Conclusions The irAE‐related animal model was successfully established in BALB/c mice using a combination of PD‐1 and CTLA‐4 inhibitors through multiple administrations with clinical translational value and practical. This model offers valuable insights into irAE mechanisms for further investigation.

This article explores the impact mechanism of different types of environmental regulations on corporate green technology innovation (GTI). The research focuses on analyzing three types of environmental regulations: command based environmental regulation (ER1), market-oriented environmental regulation (ER2), and voluntary environmental regulation (ER3), and how they affect corporate GTI. This study selected enterprise GTI as the dependent variable and measured it by the number of applications for green invention patents and green utility model patents. The independent variables are the three types of environmental regulations mentioned above. According to data from Chinese A-share listed companies. Using benchmark regression models to analyze the impact of different environmental regulations on GTI, and constructing a moderating effect model to study the role of corporate R&D investment and government support in the process of environmental regulations affecting GTI. The results indicate that (1) ER1, ER2, and ER3 can all promote enterprise GTI, and the three environmental regulatory methods have a better synergistic effect. (2) R&D investment has a positive correlation with the relationship between ER2 and GTI, and a negative correlation with ER 3 and ER 1. (3) There are differences in the GTI performance of enterprises in different regions, ownership nature, factor density, and industry types under the influence of environmental regulations. (4) The impact of environmental regulatory policies on corporate GTI is mainly short-term. This study provides a new perspective on how environmental regulations affect corporate GTI, especially in the context of developing countries like China. The research findings emphasize the role of different types of environmental regulations in incentivizing corporate GTI, while also pointing out factors that governments need to consider when formulating environmental policies, such as regional differences and corporate characteristics, which are of great significance for promoting green development of enterprises and achieving broader sustainable development goals.

Summary: B lymphocytes undergo metabolic reprogramming upon activation to meet the bioenergetic demands for proliferation and differentiation. Yet, little is known if and how the fate of naive B cells is metabolically regulated. Here, we specifically delete von Hippel-Lindau protein (VHL) in B cells using CD19-Cre and demonstrate that metabolic balance is essential for naive B cell survival. Loss of VHL disturbs glycolytic and oxidative metabolic balance and causes severe reduction in mature B cells. Mechanistically, the metabolic imbalance in VHL-deficient B cells, arising from over-stabilization of hypoxia-inducible factor-1α (HIF-1α), triggers reductive glutamine metabolism leading to increased Fas palmitoylation and caspase-8-mediated apoptosis. Blockade of reductive glutamine metabolic flux by lactate supplementation and ATP citrate lyase inhibition restores the metabolic balance and rectifies the impaired survival of VHL-deficient B cells. Hence, we unravel that the VHL/HIF-1α pathway is required to maintain the metabolic balance of naive B cells and ensure their survival. : Biological Sciences; Immunology; Cell Biology Subject Areas: Biological Sciences, Immunology, Cell Biology