Jian Ma

The tumor immune microenvironment plays a decisive role in tumor initiation, progression and therapeutic response. Spatial transcriptomics (ST) enables comprehensive analysis of the whole transcriptome or specific gene sets while preserving the original spatial location information within tissues, offering a revolutionary approach to unraveling the complexity of the tumor immune microenvironment in the spatial dimension. The present review aims to systematically elaborate on the role and application of ST in deciphering the tumor immune microenvironment. Focusing on tumor microenvironment niches at different stages of tumor progression, from precancerous lesions and locally advanced tumors to distant metastasis, recent advances in ST for mapping the spatial distribution and functional states of key cell subpopulations are summarized. The present review further highlights its potential for clinical translation in identifying spatially defined biomarkers and elucidating the mechanisms underlying therapeutic responses and analyze the key technical challenges that constrain the application of ST in clinical practice. In recent years, the rapid development of machine learning algorithms has provided new opportunities to overcome the technical limitations of ST. The deep integration of machine learning with ST is laying a solid theoretical foundation and technical support for precision medicine and early intervention.

Epstein-Barr virus (EBV) is a widely prevalent γ-herpesvirus that primarily infects human B cells and epithelial cells. It is closely associated with the development of various lymphomas and epithelial cancers, posing a significant threat to human life and health. The infection process of EBV relies on interactions between the virus and specific receptors on the surface of host cells, including CD21, NRP1, EphA2, and, more recently, discovered receptors such as R9AP and DSC2. Currently, no specific drugs targeting EBV have been developed, making further research on EBV receptors particularly crucial. This review summarizes the classification, structural characteristics, and molecular mechanisms of the EBV receptors identified to date and compares the differential pathways through which these receptors function in B cells and epithelial cells. Furthermore, this review discusses the potential applications of targeting EBV receptors in antiviral therapy, vaccine development, and cancer immunotherapy, while addressing the limitations of current research and future directions. The aim is to broaden the scope of future research in the field of EBV receptors and provide new perspectives for the prevention and treatment of EBV-associated diseases.

Lactoferrin (LF), an innate immunity molecule, showed a strikingly high expression level in the human prostate compared to other tissues and organs, indicating a significant role in prostate physiology. Despite the tumor‐suppressive role of lactoferrin established in other malignancies, we reveal its paradoxical oncogenic function in prostate cancer through an androgen receptor (AR)‐LF‐ferroptosis axis. Utilizing Lf ^−/− TRAMP genetic mouse models, proteomics, TCGA‐PARD data, and single‐cell RNA‐seq, we demonstrate that AR directly binds the LF promoter, driving LF expression, which in turn upregulates ferritin (FTH1/FTL) expression and suppresses p53‐ALOX12‐mediated ferroptosis in prostate cancer. Crucially, Lf deficiency delayed tumor progression and intensified ferroptotic stress in the TRAMP mice, while iron supplementation accelerated carcinogenesis—effects rescued by Lf knockout. Mechanistically, lactoferrin shields prostate cancer cells from iron‐induced ferroptosis by maintaining iron‐redox homeostasis. Preclinical targeting of this axis suggested a potential therapeutic strategy, as suppressed tumor growth in prostate cancer xenograft was observed following LF knockdown coupled with ferroptosis induction (via IKE) and androgen receptor inhibition (via enzalutamide). This work defines lactoferrin as: (i) an AR‐regulated ferroptosis suppressor, (ii) a regulator of prostate cancer's “iron addiction,” and (iii) a candidate target for therapeutic exploitation of iron‐metabolic vulnerability.

Epstein‐Barr virus (EBV) nuclear antigen 1 (EBNA1) is necessary to maintain stability of EBV episomes, EBV replication, and causes host genomic instability and promotes tumor cells survival. Recent studies have shown that viruses utilize liquid–liquid phase separation (LLPS) within host cells to form sub‐cellular compartments known as “virus factories”. Prion‐like domains (PrLDs), which resemble structural domains of low complexity, are shown to drive LLPS in vivo. In the current study, a PrLD is identified in EBNA1 and aggregation of EBNA1 proteins is observed in EBV‐positive tumors. EBNA1 condensate interacting molecules are examined and are found that EBNA1 interacts with the splicing factor SRSF1 to regulate alternative splicing of SRRM1 and promote tumor progression. Deleting the EBNA1 PrLD results in defects in protein aggregation, LLPS, alternative splicing regulation, and nasopharyngeal carcinoma cells proliferation. Targeting the PrLD of EBNA1 inhibits the formation of protein aggregation, promotes alternative splicing of SRRM1, and inhibits the progression of nasopharyngeal carcinoma. Here, we report for the first time that EBNA1, a protein from the human oncogenic virus EBV, is a prion‐like protein, combining algorithm prediction and experimental validation. That implies a possible molecular pathogenic mechanism of EBNA1 in neurodegenerative diseases.

Epstein‐Barr virus (EBV) infection is closely associated with the development of various tumors such as lymphomas and epithelial cancers. EBV has a discrete life cycle with latency and lytic phases. In recent years, significant progress has been made in the understanding of the mechanism underlying the transition of EBV from latency to lytic replication. Multiple new lytic activation factors have been emerged and promoted our understanding of this field. In addition, we have comprehensively presented the existing therapeutic strategies and their relationship to the mechanism underlying the transition of EBV from latency to lytic replication in this review, such as lytic induction therapy and drugs to prevent EBV from entering the lytic phase fully utilize the EBV reactivation mechanisms. This year marks the 60th anniversary of the discovery of EBV, and building a bridge between the mechanism of EBV reactivation and the treatment may help us to design new approaches for treating EBV‐associated diseases.

EB病毒（EBV）主要感染人B细胞和上皮细胞。作为一种疱疹病毒，它主要有两种感染类型：潜伏感染和裂解感染。EBV感染绝大部分是潜伏感染，根据EBV基因表达谱的差异，可以分为潜伏感染0型、I型、II型、III型。建立终身潜伏感染是EBV的一大特征，在潜伏感染阶段EBV在宿主细胞内维持稳定的病毒拷贝数。裂解感染指病毒在宿主细胞内自主复制、包装、成熟、裂解宿主细胞、释放病毒粒子、再感染其他细胞。本文综述了EBV潜伏、裂解感染的基因表达谱特征，代表性分子的功能，潜伏-裂解感染转换调控的分子机制，及激活裂解性感染策略与临床价值。