Glioblastoma (GBM) constitutes the most lethal primary brain tumor for which immunotherapy has provided limited benefit. The unique brain immune landscape is reflected in a complex tumor immune microenvironment (TIME) in GBM. Here, single-cell sequencing of the GBM TIME revealed that microglia were under severe oxidative stress, which induced nuclear receptor subfamily 4 group A member 2 (NR4A2)–dependent transcriptional activity in microglia. Heterozygous Nr4a2 (Nr4a2+/−) or CX3CR1+ myeloid cell–specific Nr4a2 (Nr4a2fl/flCx3cr1Cre) genetic targeting reshaped microglia plasticity in vivo by reducing alternatively activated microglia and enhancing antigen presentation capacity for CD8+ T cells in GBM. In microglia, NR4A2 activated squalene monooxygenase (SQLE) to dysregulate cholesterol homeostasis. Pharmacologic NR4A2 inhibition attenuated the protumorigenic TIME, and targeting the NR4A2 or SQLE enhanced the therapeutic efficacy of immune-checkpoint blockade in vivo. Collectively, oxidative stress promotes tumor growth through NR4A2–SQLE activity in microglia, informing novel immune therapy paradigms in brain cancer. Significance: Metabolic reprogramming of microglia in GBM informs synergistic vulnerabilities for immune-checkpoint blockade therapy in this immunologically cold brain tumor. This article is highlighted in the In This Issue feature, p. 799

Plasma cells shape the mesenchymal identity of ovarian cancers through exosome-mediated miR-330-3p/JAM2 axis.

Objectives The aim of this analysis was to investigate the worldwide distribution and trends in the burden of female infertility (FI). Design and setting Analysis of cross-sectional data from 1990 to 2019 from the Global Burden of Disease (GBD) Study 2019. Participants Adults aged 20–49 years in various geographical regions, Sociodemographic Index (SDI) levels and populations across 204 countries worldwide. Outcome measures Disability-adjusted life years (DALYs), age-standardised DALY rates and estimated annual percentage changes (EAPCs) for FI over the research period. Results The global burden of FI, as measured by DALYs and age-standardised DALY rates among adults aged 20–49 years, exhibited an upward trend from 1990 to 2019. Regions such as Tropical Latin America (EAPC: 3.76, 95% CI 2.76 to 4.77), South Asia (EAPC: 1.74, 95% CI 1.01 to 2.48) and Andean Latin America (EAPC: 8.54, 95% CI 6.79 to 10.32) had higher DALYs. The age-standardised DALY rates notably increased in low-middle-SDI and low-SDI countries, with EAPCs of 1.42 (95% CI 0.76 to 2.10) and 1.25 (95% CI 0.30 to 2.21), respectively. Despite lower overall DALYs in high-SDI countries, they experienced the highest EAPC in DALYs (1.57, 95% CI 1.30 to 1.83) during the period 1990–2019. China and India consistently had the highest DALYs for FI globally in both 1990 and 2019, while Africa and Latin America bore a significantly greater burden of the disease compared with other regions. Conclusion The GBD Study data on FI among adults aged 20–49 years revealed a rising global trend in FI from 1990 to 2019, with notable variations across different regions.

Background: Neutrophil infiltration and hepatocyte damage are indispensable hallmarks in alcohol-associated hepatitis (AH), yet the underlying crosstalk between neutrophils and hepatocytes and its role in AH pathogenesis remain unclear. Objective: We investigate the regulatory role of leucocyte cell-derived chemotaxin 2 (LECT2) in hepatocyte–neutrophil interaction and its impact on AH progression. Design: We used bulk and single-cell RNA sequencing to identify hepatocyte-secreted factors targeting neutrophils. We analysed serum and liver samples from AH patients and employed genetically modified mice alongside in vitro studies. Results: RNA-sequencing analysis identified several neutrophil chemokines that are elevated in hepatocytes from AH patients, including LECT2 whose role in AH remains largely unknown. AH patients exhibited increased levels of LECT2 in hepatocytes, positively correlating with the severity of AH. Ethanol-fed mice also exhibited elevated liver LECT2, which was abolished by inhibiting endoplasmic reticulum stress. Functional studies revealed that ethanol-induced liver injury was ameliorated in Lect2 -deficient mice but was exacerbated in mice with hepatic overexpression of Lect2 . Furthermore, LECT2 exacerbated ethanol-induced liver injury by promoting reactive oxygen species (ROS) through its interaction with prohibitin 2 (PHB2), a neutrophil membrane protein. By directly binding to PHB2, LECT2 disrupts the stable structure of PHB1/PHB2 heterodimerisation, consequently leading to PHB2 degradation, ROS accumulation, neutrophil activation and neutrophil extracellular trap formation. Moreover, therapeutic intervention of LECT2 via Lect2 shRNA ameliorated ethanol-induced liver injury. Conclusion: Our studies identified a novel vicious cycle between neutrophils and hepatocytes through the LECT2–PHB2 interaction, presenting a promising therapeutic intervention by targeting LECT2 to mitigate AH in patients.