Spatial transcriptomics allows for the investigation of complex cellular ecosystems directly in their native tissues and enables the dissection of immune niches as spatially organized and functionally diverse microenvironments across homeostatic, inflammatory, and malignant settings. In this review, we examine how spatial transcriptomics tools have been applied to interrogate the cellular and molecular architecture of immune niches, including the emerging studies of B and T cell clonal niches. We focus on immune niches in intestinal and tumor tissues due to their importance to both health and pathology, discuss pressing immunological questions these technologies may help to address, and highlight future developments in the field.

Hepatocellular carcinoma (HCC) remains a major global health burden with limited therapeutic options and poor prognosis. PDRG1 is upregulated in several malignancies, yet its clinical relevance and mechanistic role in HCC are not fully understood. Here, we investigated the contribution of PDRG1 to HCC progression and delineated the underlying molecular mechanism. Using public datasets, patient specimens, in vitro functional assays, and subcutaneous xenograft models, we evaluated PDRG1 expression, biological functions, and downstream pathways. Transcriptome profiling, pathway enrichment analysis, rescue experiments, co-immunoprecipitation, and ChIP-qPCR were performed to define the PDRG1-EZH2-p21 axis. PDRG1 was significantly upregulated in HCC tumor tissues compared with adjacent non-tumor liver tissues and was associated with worse patient survival. Functionally, PDRG1 enhanced HCC cell proliferation, migration, invasion, colony formation, and tumor growth in vivo. RNA-seq and enrichment analyses identified cellular senescence as a prominent downstream program regulated by PDRG1. Mechanistically, PDRG1 directly interacted with EZH2, increased H3K27me3 enrichment at the p21 promoter, and suppressed p21 transcription. Restoration of p21 expression attenuated the oncogenic effects of PDRG1, whereas EZH2 overexpression rescued the impaired malignant phenotypes caused by PDRG1 knockdown. Domain-mapping further indicated that the N-terminal residues 36-70 of PDRG1 contribute to its interaction with EZH2. Collectively, our findings identify PDRG1 as a clinically relevant oncogene in HCC and reveal an epigenetic mechanism by which PDRG1 cooperates with EZH2 to repress p21 and bypass senescence. The PDRG1-EZH2-p21 axis may represent a potential biomarker and therapeutic target for HCC.

Triple-negative breast cancer (TNBC), a distinct breast cancer subtype, poses significant challenges to conventional therapeutic approaches, and effective targeted therapies are limited. CRISPR/Cas9 library screening has demonstrated unprecedented efficiency and revolutionary potential in the identification of therapeutic targets. In this study, we performed In vivo CRISPR/Cas9 library screening and identified the E2 ubiquitin-conjugating enzyme UBE2L3 as a critical regulatory factor in the progression of TNBC. Loss of UBE2L3 restricted tumor cell growth by modulating autophagy in TNBC cells. Mechanistically, UBE2L3 downregulation led to increased tuberous sclerosis complex 2 (TSC2) expression, suppressing mTOR activity and altering autophagic processes in tumor cells. This regulation was mediated through the interaction between UBE2L3 and the E3 ubiquitin ligase SMURF2, which together control TSC2 protein ubiquitination and degradation. Autophagy and the tumor microenvironment are closely associated, and we observed that UBE2L3 knockdown in TNBC tumors significantly increased CD8+ T lymphocyte infiltration and enhanced tumor sensitivity to anti-PD-1 therapy. Collectively, our findings provide a theoretical foundation for considering UBE2L3 as a potential therapeutic target in TNBC.

Colorectal cancer (CRC) is among the most common cancers worldwide. Cellular senescence, characterized by an irreversible state of growth arrest, has been recognized as a promising therapeutic strategy for combating cancer. Here, the oncogenic role of Chromobox homolog 8 (CBX8) in CRC and its regulatory mechanisms in cell senescence and transcriptional regulation were systematically investigated. We demonstrated that CBX8 deficiency suppresses colorectal tumorigenesis and promotes tumor cell senescence in both in vivo and in vitro models. Mechanistically, CBX8 inhibits autophagy-dependent senescence in CRC by modulating the mTOR signaling pathway through transcriptional repression of DDIT4, a known negative regulator of mTOR. CBX8 achieves this by recruiting TRIM28 to bind the promoter region of DDIT4, thereby maintaining the H3K27me3 modification status and repressing expression of DDIT4. Furthermore, our findings highlight the therapeutic potential of CBX8 inhibitors in combination with senescence-targeting agents, which significantly enhances antitumor effects in CRC xenograft models. These results provide novel insights into the molecular mechanisms underlying CRC progression and underscore the potential of CBX8 as a therapeutic target for developing targeted therapies and senolytic-based anticancer strategies. This study advances our understanding of CRC pathogenesis and offers promising directions for precision medicine in CRC treatment.

Renal cell carcinoma (RCC) is a metabolic disorder and VHL gene inactivation is recognized as a crucial event in RCC progression. Investigating the specific metabolite that differ in VHL-mutant RCC and understanding how VHL regulates the metabolite may offer new insights into the underlying mechanisms of RCC. First, we employed untargeted metabolomics and ELISA to identify and confirm the differential metabolite in the plasma and tumor tissues of VHL-mutant RCC patients. Then, we demonstrated the importance of the differential metabolite in RCC progression through cell phenotype and animal experiments. Finally, we utilized western blotting, immunoprecipitation, ubiquitination modification proteomics, TMT proteomics, and RNA sequencing to elucidate the regulatory mechanisms of VHL on the metabolite. By analyzing the metabolomics data from plasma and tumor tissues alongside subsequent expression validation, we identified L-Asparagine (L-Asn) as the differential metabolite in VHL-mutant RCC, with its levels significantly decreased in these tumors. L-Asn was found to promote the growth and metastasis of RCC cell lines and mouse orthotopic renal tumors. Mechanistically, VHL interacted with L-Asparagine synthase (ASNS) and facilitated its ubiquitination, leading to decreased ASNS expression, and ASNS overexpression activated PI3K-AKT and MAPK signaling pathways by binding to Junction plakoglobin (JUP) and inhibiting its expression. Conversely, use of an ASNS inhibitor significantly restrained the growth and metastasis of RCC cells in vitro and in vivo. In summary, our findings highlighted the critical role of L-Asn in RCC and identified ASNS as a novel substrate for VHL-mediated ubiquitination, presenting a potential new target for RCC treatment.

The development of novel therapeutic strategies for advanced and metastatic hepatocellular carcinoma (HCC) remains an urgent clinical need. Despite suboptimal efficacy, the breakthrough of tyrosine kinase inhibitors in HCC treatment therapy underscores the advantage of targeted therapy. Therefore, innovative targeted therapies are urgently needed to enhance treatment efficacy, decrease recurrence rates, and improve patient survival outcomes. The forkhead box M1 (FOXM1) transcription factor serves as a master regulator of oncogenic signaling networks that drive cancer progression. Our study identified budding uninhibited by benzimidazoles 1 (BUB1) as a crucial downstream effector of FOXM1, with demonstrated direct protein-protein interaction. Moreover, FOXM1 directly bound to the GTAAACC motif at the -293 bp region of the BUB1 promoter and activated its transcription, thereby driving HCC cell proliferation. Mechanism studies have shown that the FOXM1/BUB1 axis regulated multiple oncogenic processes in HCC, including cell proliferation, DNA repair, G2/M cell cycle transition, stemness, invasion, and migration. Knockdown of BUB1 significantly sensitized HCC cells and xenograft tumors to the FOXM1 inhibitor FDI-6. Furthermore, combined pharmacological inhibition of FOXM1 (FDI-6, RCM-1, thiostrepton) and BUB1 (BAY-1816032) synergistically inhibited the proliferation of HCC cells and xenograft tumors. These findings establish FOXM1-mediated BUB1 upregulation as a key driver of HCC malignancy. Targeting the FOXM1/BUB1 axis represents a promising therapeutic strategy for the treatment of advanced and metastatic HCC, offering new opportunities for HCC therapy.

High mobility group AT-hook 1 (HMGA1) is a chromatin regulator overexpressed in various cancers, often predicting poor outcomes. However, its role in head and neck squamous cell carcinoma (HNSCC) remains unclear. A hallmark of HNSCC is the rapid growth of its vasculature. Here, we identify an epigenetic mechanism whereby HMGA1 promotes tumor progression and angiogenesis via upregulation of fibroblast growth factor-binding protein 1 (FGFBP1). HMGA1 silencing suppressed oncogenic properties in vitro and reduced tumor initiating cells in HNSCC xenograft mice. RNA sequencing revealed that HMGA1 regulated transcriptional networks involved in tumor progression and angiogenesis, including the FGFBP1 gene. HMGA1 directly binds to the FGFBP1 promoter to induce its expression. This upregulation increased secretion of FGFBP1's target, FGF2. Interestingly, disrupting FGFBP1 via gene silencing or the FGFR1 inhibitor PD166866 recapitulated phenotypes observed with HMGA1 silencing. Blocking HMGA1, FGFBP1, or FGFR1 also reduced stromal formation and increased tumor necrosis. In human HNSCC, the combined analysis of HMGA1 and FGFBP1 provides a more detailed evaluation of patient prognosis. Our findings highlight a novel paradigm where HMGA1 and FGFBP1 drive tumor progression and angiogenesis, presenting them as potential therapeutic targets for HNSCC.

Immune checkpoint pathways are central to tumor immune evasion, and genetic variants of programmed death-1 (PD-1) may influence cancer susceptibility. This study evaluates the association between the PD-1.5 (rs2227981) polymorphism and the risk of bladder cancer (BC) in the Turkish population.

Urological malignancies, primarily including renal cell carcinoma, bladder cancer and prostate cancer, underscore the critical importance of early screening, diagnosis and treatment in inhibiting disease progression and improving patient prognosis. Advancements in molecular biology have established urinary biomarkers as promising noninvasive tools with considerable potential for early tumour detection and screening high-risk populations, potentially overcoming limitations associated with traditional invasive procedures and imaging. This review systematically summarises urinary biomarkers related to renal cell carcinoma, bladder cancer and prostate cancer. It focuses on protein biomarkers (e.g., cytokeratin and nuclear matrix protein 22), epigenetic and transcriptional biomarkers (e.g., microRNAs and long noncoding RNAs), genetic biomarkers (e.g., telomerase reverse transcriptase and fibroblast growth factor receptor 3) and emerging biomarkers (metabolomic markers, circulating tumour DNA and mass spectrometry-based high-throughput proteomics). This review provides an in-depth exploration of the molecular mechanisms, diagnostic performance (sensitivity and specificity), current clinical applications and limitations of various biomarkers, placing a particular emphasis on comparing the differential expression of the same biomarker across different cancer types. By building on this foundation, this review further outlines future development pathways, including multibiomarker combination strategies, AI-assisted analysis and standardised testing protocols, to offer comprehensive references for the early, noninvasive and precise diagnosis of urological tumours.

Urological cancers, such as prostate, bladder and renal cell carcinoma, contribute substantially to the global cancer burden. Their management remains challenging due to extensive molecular and clinical heterogeneity. Conventional single-omics approaches (e.g., genomics and transcriptomics) have led to important discoveries but provided only partial views of tumour biology, which limit the robustness of biomarkers and therapeutic precision. Multi-omics integration offers a systems-level perspective that captures the complex regulatory networks underlying tumour initiation, progression and treatment resistance.

Family genetic testing facilitates early cancer diagnosis and prevention for relatives of individuals carrying Breast Cancer Susceptibility Genes 1 and 2 (BRCA1/2) pathogenic variants. This study evaluates perceptions of family genetic testing among Korean cancer patients and the general public, providing foundational data to guide strategies for implementation.

Glioma is a highly invasive and drug-resistant malignant primary tumor. Increasing research is focusing on the function of neutrophil extracellular traps (NETs) in glioma progress. We aimed to explore the mechanism of NETs-related genes (NETs-RGs) in glioma to find potential biomarkers for glioma.

Temozolomide (TMZ) resistance in glioblastoma (GBM) remains a critical barrier to treatment success, driven by O6-methylguanine-DNA methyltransferase (MGMT) overexpression, glioma stem cell (GSC) persistence, and redox adaptation.

Tumor necrosis factor receptor-associated factor interacting protein (TRAIP) has emerged as a critical regulator of multiple oncogenic processes across various malignancies. However, its specific functional role and underlying mechanisms in breast cancer pathogenesis remain to be fully elucidated. Integrated bioinformatics analysis of TCGA and GTEx datasets was performed to assess TRAIP expression patterns. Complementary experimental validation was conducted using immunohistochemistry, qRT-PCR, and western blot in clinical specimens. Functional characterization of TRAIP in breast cancer cells was achieved through CCK-8 proliferation assays, colony formation analysis, transwell migration/invasion tests, wound healing experiments, and flow cytometric apoptosis detection. Mechanistic investigations employed co-immunoprecipitation and ubiquitination assays to delineate the TRAIP-PLSCR4 interaction, supplemented by rescue experiments to confirm functional interdependence. Consistent overexpression of TRAIP was observed in breast cancer tissues compared to normal controls. Genetic knockdown of TRAIP significantly attenuated malignant phenotypes, including: (1) reduction in cellular proliferation, (2) decrease in colony-forming capacity, (3) reduction in migratory/invasive potential, and (4) increase in apoptosis rates (Annexin V staining). Mechanistically, TRAIP functioned as an E3 ubiquitin ligase mediating proteasomal degradation of PLSCR4 through K48-linked polyubiquitination (co-IP validation). Notably, PLSCR4 silencing effectively rescued the tumor-suppressive effects of TRAIP knockdown. This study identifies a novel TRAIP/PLSCR4 regulatory axis in breast cancer pathogenesis, wherein TRAIP exerts its oncogenic function via ubiquitination-dependent degradation of tumor-suppressive PLSCR4. These findings position TRAIP as a promising therapeutic target for precision breast cancer interventions.

Helicobacter pylori (H. pylori) has been identified as a pathogenic factor in gastric cancer (GC). Building on our previous findings that VacA upregulates TRAF1, which in turn transcriptionally activates OASL, we explored the role of this TRAF1-OASL-PANoptosis axis in GC using clinical samples, cell lines, and mouse models. Functional assays (CCK-8, colony formation, migration, invasion, TUNEL) demonstrated that TRAF1 promotes GC cell proliferation, migration, and invasion via OASL, while suppressing apoptosis. RNA-seq revealed that upregulation of TRAF1 and OASL, combined with H. pylori infection in gastric epithelial cells, enriched pathways associated with PANoptosis. Rescue experiments showed that TRAF1 knockdown increased PANoptosis, and this increase was attenuated by the pan-caspase inhibitor Z-VAD-FMK, whereas subsequent OASL overexpression reversed the suppression of PANoptosis caused by TRAF1 knockdown, whereas LPS further induced PANoptosis. Both in vitro and in vivo models confirmed that H. pylori infection triggers PANoptosis. Co-Immunoprecipitation assays uncovered a protein interaction between OASL and the ZBP1-PANoptosome. Critically, under H. pylori infection conditions, OASL overexpression rescued the PANoptosis suppressed by TRAF1 knockdown in gastric epithelial cells. This study demonstrates that H. pylori infection induces PANoptosis, and defines a pathway wherein TRAF1 promotes PANoptosis by regulating OASL-mediated activation of the ZBP1-PANoptosome. Our findings reveal a novel, context-dependent duality of the TRAF1/OASL axis: it promotes PANoptosis, contributing to mucosal damage during the precancerous inflammatory stage, yet in established GC, this axis appears to suppress PANoptosis, facilitating tumor progression. These insights provide a theoretical foundation for targeting this pathway in treating H. pylori-associated gastritis-cancer progression.

Cancer-associated fibroblasts (CAFs) are central to the pancreatic ductal adenocarcinoma (PDAC) microenvironment, promoting tumor progression and therapeutic resistance. However, the expression landscape of CAF membrane proteins in PDAC remains poorly defined. We integrated scRNA-seq (n = 33; 87,949 cells), spatial transcriptomics (n = 2; 7,011 spots), and bulk RNA-seq (n = 7; 642 samples) to systematically identify PDAC-specific CAF membrane genes. A LASSO-based Cox model was developed to construct a prognostic signature, PaFMS, and evaluated through multi-cohort validation. Functional enrichment, immune infiltration, drug sensitivity, and immunotherapy response analyses were further conducted. Validation was performed using multiple database-driven analyses. We identified a PDAC-enriched myoCAF-c1 cluster closely associated with epithelial-mesenchymal transition (EMT) and angiogenesis. From this cluster, 33 candidate CAF membrane genes were defined, whose protein-protein interactions were predominantly linked to extracellular matrix organization and collagen remodeling, and spatially colocalized with myoCAF-c1 and EMT regions. An 11-gene prognostic signature, PaFMS that robustly stratified patients across six independent cohorts, achieving high predictive accuracy for overall survival. High-risk patients exhibited proliferative signaling activation, immune suppression, and reduced T/B-cell infiltration. PaFMS was associated with responses to 33 anticancer agents and predicted enhanced benefit from anti-PD-L1 immunotherapy in the low-risk group. Multi-cohort validation confirmed the expression specificity of PaFMS genes, including PLAU, TMEM158, and TRIM59. Together, these findings reveal that myoCAF-c1 promotes angiogenesis and tumor progression, and establish PaFMS as a robust CAF membrane-based prognostic model in PDAC with potential utility for precision prognosis and therapeutic decision-making. KEY MESSAGES: Integrated single-cell, spatial, and bulk RNA-seq analyses identified PDAC-specific CAF membrane genes. Discovered a PDAC-enriched myoCAF-c1 subtype linked to EMT and angiogenesis. Developed an 11-gene CAF membrane-based prognostic model (PaFMS) validated across six cohorts. PaFMS predicts patient survival, drug sensitivity, and immunotherapy response in PDAC.

The tumor suppressor gene TP53 is the most frequently mutated gene in human cancers and has been a popular area of research in the field of oncology. The p53 protein, encoded by the TP53 gene, not only binds to many targeted genes but also regulates apoptosis, autophagy, cell cycle arrest, metabolism, senescence and the tumor immune microenvironment to suppress tumorigenesis. In recent years, an increasing number of new functions of p53 have been discovered, and p53-mediated tumor suppressor functions have been greatly expanded. Mutations in TP53 not only abolish its ability to suppress tumorigenesis but also confer carcinogenic properties to p53-mutant cells. Because of the prevalence of p53 dysfunction in various disease types, p53 has long been considered an attractive target for new anticancer drugs. However, drugs targeting p53 are still under investigation in early clinical trials and have not been approved for clinical use. This finding is consistent with the speculation that p53 is widely regarded as "undruggable." Surprisingly, several novel therapeutic approaches targeting p53, including MDM2/4 antagonists, compounds that target specific p53 mutants or restore the wild-type function of the mutated p53 protein, p53-based genetic therapies and p53-based tumor immunotherapy, have been developed in recent years. Here, we present a review of the structure, inactivation, and roles of p53 in diseases. In addition, this review discusses the efforts to target diseases associated with p53 dysfunction and the challenges encountered in the clinical development of these approaches.

Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies, exhibits a 5-year survival rate below 10% and extremely poor clinical prognosis. Over 90% of PDAC patients harbor KRAS gene driver mutations, which promote tumor proliferation, invasion, and immunosuppression of the tumor microenvironment through constitutive activation of downstream RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways. Although the therapeutic potential of targeting KRAS has been recognized for decades, its smooth protein structure and lack of traditional drug-binding pockets led to its long-standing classification as an "undruggable" target, resulting in limited efficacy of early targeted agents. Recent breakthroughs with next-generation KRAS inhibitors have transformed the therapeutic landscape for pancreatic cancer. This review synthesizes evidence from basic research and clinical translation to provide a theoretical foundation and practical guidance for the precision treatment of KRAS-mutant pancreatic cancer.

Patient-derived cells (PDCs) and patient-derived organoids (PDOs) are complementary preclinical models widely used in translational cancer research. However, their molecular and functional differences have not been systematically characterized. This study established and analyzed paired PDC and PDO models derived from the same gastric cancer ascites to delineate platform-dependent molecular and functional profiles.

Although gastric cancer (GC) exhibits significant genomic heterogeneity, the clinical implications of its immune microenvironment remain poorly understood.