Hepatitis B virus (HBV) is clinically associated with poor prognosis in diffuse large B-cell lymphoma (DLBCL), while cellular communication in the tumour microenvironment (TME) is recognized as a critical driver of tumour progression. Nevertheless, whether HBV infection mediates DLBCL cell-immune cell crosstalk remains undefined, with the precise mechanisms and associated key molecules remaining elusive.

SsGSEA, Cox regression (univariate/multivariate), WGCNA, and Kaplan-Meier analyses identified prognostic immune subsets and miRNAs in HBV⁺ DLBCL. Dual luciferase assay, qRT-PCR, western blot, ChIP, Co-IP, flow cytometry, enzyme-linked immunosorbent assay, immunohistochemistry, and murine models were employed together to evaluate CD4⁺ T cell dysfunction in vitro and in vivo. ScRNA-seq analyses encompassed clustering, pseudotemporal trajectory, and ligand-receptor networks to decode TME dynamics.

TME profiling identified diminished CD4⁺ T cell infiltration as an independent predictor of poor survival in HBV⁺ DLBCL. Mechanistically, HBx-mediated down-regulation of miR-19a-3p activated the BAMBI/Wnt signalling pathway, thereby enhancing TGF-β1 secretion and suppressing the anti-tumour activity of CD4⁺ T cells. Single-cell analysis revealed that BAMBI^high DLBCL cells engage CD4⁺ T cells via TGFB1-TGFBR2 pair, with TGFBR2 enriched in exhausted subsets of CD4⁺ T cells and shaping their dysfunctional fate. Therapeutic restoration of miR-19a-3p or blockade of TGF-β reinforced the CD4⁺ T cell anti-tumour activity and restrained the progression of HBx-overexpressing DLBCL in vivo.

HBx promoted TGF-β1 hypersecretion via miR-19a-3p repression-mediated Wnt/β-catenin activation, directly driving CD4⁺ T cell depletion and functional exhaustion in DLBCL. Our work provided important insights into the immune determinants of poor prognosis in HBV⁺ DLBCL, highlighting the pivotal role of CD4⁺ T cell dysfunction in driving disease progression and adverse clinical outcomes.

Reduced CD4⁺ T cell enrichment in the TME predicted poor survival in HBV⁺ DLBCL. Down-regulation of miR-19a-3p by HBx activated the BAMBI-mediated Wnt signalling, amplifying TGF-β1 secretion to suppress anti-tumour activity of CD4⁺ T cells. The TGF-B1/TGFBR2 pair mediated the HBV⁺ DLBCL-CD4⁺ T cell communication. Targeting TGF-β or miR-19a-3p improved CD4⁺ T cell immunity to suppress HBV⁺ DLBCL progression.

Tumor suppressor Phosphatase and Tensin Homolog Deleted on Chromosome TEN (PTEN) shows a differential sub-cellular distribution, with its nuclear presence being particularly critical for its multifaceted tumor-suppressive functions. Nuclear PTEN mediates its arsenal of tumor suppressive actions viz., genomic stability maintenance, cell cycle regulation, DNA damage response, and transcriptional modulation, in both phosphatase-dependent and non-phosphatase-dependent manners. Diverse mechanisms exist to facilitate its nuclear import, including passive diffusion, active transport, and post-translational modifications such as monoubiquitination, phosphorylation, and SUMOylation as well as their crosstalk. Similarly, a number of mechanisms dictate the nuclear export of PTEN. Nucleo-cytoplasmic shuttling of PTEN is closely guarded by several protein factors. This review comprehensively explores the proteins involved in the transport and regulation of nuclear PTEN. Furthermore, it highlights the clinical significance of nuclear PTEN levels, which are closely associated with tumor grade, disease prognosis, and patient survival across multiple cancer types. By elucidating these mechanisms, this review underscores the importance of nuclear PTEN in cancer biology and its potential as a therapeutic target.

Magnetic resonance imaging (MRI) is a defining feature of magnetic resonance image-guided radiotherapy (MRigRT), providing superior soft-tissue contrast compared to conventional cone beam CT (CBCT). However, conventional MRI protocols typically require prolonged acquisition times. High-speed scanning techniques implemented to improve clinical workflow efficiency often produce low-quality images, characterized by reduced resolution and blurring, which compromise the accuracy of downstream tasks. Although deep learning-based enhancement methods have shown promise, most fail to adequately correct residual errors between predicted and actual images, introducing uncertainties in clinical decisions.

This study aims to propose and evaluate a deep learning-based approach to enhance the image quality of accelerated MRI acquisitions, with the dual objectives of ensuring registration accuracy for precise tumor targeting, and shortening in-room time to minimize patient discomfort on the treatment couch.

We acquired 72 paired 3D T2-weighted MRI scans from 62 glioma patients using a 1.5T Unity MR-Linac, with each pair comprising a standard protocol scan and an accelerated protocol scan. We proposed Residual Refinement Enhancement Network (RRENet), a novel end-to-end deep learning framework that combines generative adversarial network (GAN) and diffusion model (DM) for accelerated MRI enhancement. The framework operates in a two-stage process: first, a GAN-based predictor generates the low-frequency content; subsequently, a DM-based module refines the output by estimating residual errors. To further improve performance, an additional High-frequency Separation Training Module (HSTM) was incorporated to preserve fine anatomical details. Image quality was assessed using peak signal-to-noise ratio (PSNR), structural similarity index measure (SSIM), and root mean square error (RMSE). Clinical applicability was evaluated through rigid registration analysis with commercial software.

RRENet demonstrated superior performance compared to competing methods, achieving a 70% reduction in imaging time (vs. standard protocol) while maintaining high quality (SSIM = 92.27 ± $\pm$ 2.03%, PSNR = 32.84 ± $\pm$ 1.54dB, RMSE = 0.025). Enhanced images retained fine anatomical structures alignment ( ≤ $\le$ 2.2 mm translation, ≤ $\le$ 0.2 ∘ $^\circ$ rotation) to planning CT, ensuring the accuracy of patient setup correction.

The proposed method can generate high-quality images from high-speed scanning sequences, reducing acquisition time while ensuring precise tumor targeting through reliable image registration.

The immunomodulatory potential of radiotherapy provides a strong rationale for its combination with immunotherapies and other immunostimulatory agents. However, current combinations yield suboptimal clinical benefits. As the mechanisms behind radiotherapy-induced immunomodulation are gradually unraveled, various key factors have been identified as critical modulators of this process, opening new possibilities for adapting radiotherapy to immunotherapy. Here, we discuss seven factors: dose‒fractionation regimens of radiotherapy (RT), sequence and timing of RT and immunotherapy, radiation field, type of ionizing radiation, normal tissue effects, choice of the lesion to irradiate and identification of biomarkers. Preclinical and clinical studies on the combination of immunotherapy and radiotherapy are discussed, novel immunotherapeutic approaches are highlighted and improvements in study design are suggested.

Immune checkpoint blockade (ICB) has revolutionized tumour therapy by relieving immunosuppression and restoring effector T cell cytotoxicity. However, its clinical utility is constrained by low response rates and acquired resistance. Tumour-associated neutrophils (TANs), key players in tumour immunoregulation, have emerged as critical mediators of ICB responsiveness and resistance, highlighting the therapeutic potential of combining TAN-targeted strategies with immune checkpoint inhibitors (ICIs). This review systematically synthesizes current knowledge of neutrophils in ICB resistance from several dimensions: (1) clinical indicators of neutrophils, such as the neutrophil-to-lymphocyte ratio (NLR) and tissue TANs abundance, as predictors of ICI response and patients prognosis; (2) multifaceted TAN-involved resistance mechanisms, including direct T cell inhibition, antigen presentation impairment, function modulation of other immune cells, promotion of tumour angiogenesis, and elevation of tumour mutation burden (TMB); (3) combination therapeutic strategies targeting TAN generation/ exhaustion, recruitment, phenotypic polarization, activation, proangiogenic functions, and neutrophil extracellular traps (NETs), along with progress in related clinical trials. Combinatorial approaches integrating TAN-targeted therapies with ICIs hold substantial promise for overcoming resistance by reshaping the immune microenvironment. Elucidating neutrophil-mediated resistance mechanisms and optimizing combination strategies will pave the way for precision tumour immunotherapy. KEY POINTS: TANs drive ICI resistance via antitumour immune remodelling, angiogenesis promotion, and elevation of tumour mutation burden Neutrophil biomarkers (e.g., NLR, TAN abundance) show strong predictive value for ICI response and prognosis. Targeting TAN recruitment, polarization, function and NETosis represents a promising strategy to overcome ICI resistance. Numerous clinical trials are evaluating combination therapies targeting neutrophils to enhance immunotherapy efficacy.

Lactate, traditionally considered just a byproduct of metabolism, is now understood to be a vital regulator in energy metabolism, immune function, and epigenetic changes. Besides serving as an alternative energy source through the "lactate shuttle," it acts as a signaling molecule influencing both normal and abnormal processes in various organs. New research has emphasized its role in lactylation of histones and non-histones, a novel post-translational modification linking metabolic activity with gene expression and immune response. Lactate contributes to immunosuppression, angiogenesis, and the spread of tumors within the tumor microenvironment. Its accumulation is also linked to cardiovascular, metabolic, and neurodegenerative conditions. This shift in metabolism underscores lactate's growing importance in both health and disease, presenting novel therapeutic opportunities, especially in the treatment of cancer and metabolic disorders. This review synthesizes emerging insights into lactate's multifaceted roles and discusses promising therapeutic strategies targeting lactate metabolism, transport, and downstream signaling pathways, with an emphasis on candidates advancing toward clinical translation.

Hepatocellular carcinoma (HCC) is the most common primary liver carcinoma with high lethality. Both of hepatitis B virus (HBV) and Clonorchis sinensis (C. sinensis) are critical infectious contributors to HCC development. However, the inter-tumor heterogeneity and tumor microenvironment (TME) of HCC patients with different infectious background remain largely unknown.

We compiled a cohort of 269 primary HCC patients to assess the clinical impact of C. sinensis and HBV infections on patient prognosis. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomic (ST-seq) analyses were performed on tumor and adjacent normal samples from C. sinensis-associated HCC (CP), and double-infection HCC (DP) patients. Additionally, we integrated publicly available scRNA-seq and ST-seq datasets from HBV-associated (HP) patients. Immunofluorescence, immunohistochemistry and in vitro experiments were conducted to validate inter-tumor heterogeneity among the three HCC subtypes.

C. sinensis infection is significantly associated with poorer prognosis in HCC patients. Multi-omics analyses revealed distinct inter-tumor heterogeneity in epithelial, immune, and stromal compartments across different HCC subtypes. Tumor cells in the DP group exhibited more malignant marker expression, higher copy number variation scores, increased activation of p53 pathway, and worse survival outcomes. Compared with other HCC subtypes, the TME in DP samples was enriched with SPP1⁺ macrophages, exhausted CD8⁺ T cells and COL1A1⁺ fibroblasts. In contrast, the CP and HP groups showed higher proportions of M2-like macrophages and ENPP2⁺ liver vascular endothelial cells, respectively.

These findings decipher the cellular signatures and their interactions within the TME, shedding light on the inter-tumoral heterogeneity driven by different infections, and the development of targeted therapies for infectious HCC.

In medical practice, intraocular space-occupying lesions are a major category of diseases that are prone to clinical misdiagnosis and mistreatment. In the process of diagnosing these lesions caused by different etiologies, special attention should be paid to the establishment of diagnostic and therapeutic thinking patterns and clinical diagnosis, and vigilance should be exercised against the negative trend of using auxiliary examination results instead of clinical diagnosis. Ophthalmologists should enhance their understanding of intraocular space-occupying lesions, make accurate diagnoses, choose appropriate treatments, and perform enucleation surgery with caution.

Undifferentiated pleomorphic sarcoma (UPS) is a rare and aggressive soft tissue tumor of unknown histogenesis. UPS most often arises in the extremities or trunk, where wide surgical excision is feasible. Rarely, UPS involves the intracranial space, where critical structures may inhibit complete resection. Given its rarity and historical misclassification as malignant fibrous histiocytoma (MFH), knowledge of intracranial UPS is limited, and there are no clear treatment guidelines. We systematically reviewed all available cases of intracranial UPS to consolidate existing literature and assess prognosis and management considerations. A systematic review was conducted according to PRISMA guidelines. PubMed and Embase were searched for reports of intracranial UPS or storiform-pleomorphic MFH. Eligible studies included at least one histologically confirmed case treated with surgery, chemotherapy, or radiotherapy and reported outcomes. Data on demographics, tumor location, treatment, follow-up, and survival were extracted. Event-free survival (EFS) and overall survival (OS) were analyzed by treatment modality, age, sex, and tumor location using Kaplan-Meier and log-rank tests. From 801 records, 40 studies with 48 patients were included. The median age was 45 years, and 50% were female. 15% had prior radiotherapy. Most tumors were extra-axial (45%) and nearly all patients underwent surgery, with 82.1% achieving gross total resection. Median EFS and OS were 18 and 24 months, respectively. No survival differences were seen by treatment modality, age, or sex. Overall survival was longer for extra-axial tumors compared to intra-axial or skull base tumors (p = 0.016). Intracranial UPS is a rare and aggressive tumor, with worse prognosis compared to those that are extracranial. Among factors that we evaluated, extra-axial location was the strongest positive prognostic factor. Surgical resection with adjuvant chemoradiation showed the longest median survival. Ongoing case reports are required to refine management guidelines and improve patient outcomes.

Patient-reported outcomes (PROs) are increasingly recognized as essential endpoints in neuro-oncology, yet their prognostic value for survival across brain tumor trials remains incompletely defined. We conducted a systematic review and meta-analysis to quantify the association between key PRO domains and overall survival (OS) and progression-free survival (PFS)in patients with glioma.

Following PRISMA 2020 guidelines, we included randomized controlled trials that reported baseline PROs using the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 or European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Brain Neoplasm-20 questionnaires, with corresponding survival outcomes. Hazard ratios (HRs) per 10-point increase in each PRO domain were extracted. Random-effects models generated pooled HRs. Heterogeneity, risk of bias (ROB 2), and certainty of evidence (GRADE) were assessed.

Eight trials comprising 6,846 patients were included. Higher baseline cognitive functioning was significantly associated with improved OS (HR = 0.94, 95% CI [0.91–0.97]), as was physical functioning (HR = 0.97, 95% CI [0.94-1.00]). Pooled functional domains showed a protective association (HR = 0.96, 95% CI [0.93-1.00]), while BN-20 domains showed no association with overall survival. Pooled analysis of studies reporting EORTC QLQ-C30 scales was associated with improved PFS (HR = 0.99, 95% CI [0.99–0.99]). Subgroup analysis of physical functioning showed an association with improved PFS (HR = 0.99, 95% CI [0.97-1.0]), and the pooled analysis of all functional scales showed the same direction (HR = 0.99, 95% CI [0.99–0.99]).

Functional and cognitive PRO domains appear to have potential to be robust prognostic markers of survival in glioma trials, and these findings support the complementary role of PROs alongside clinical, radiographic, and molecular measures. Our findings support integrating PROs into response assessment selection in future neuro-oncology trials.

The online version contains supplementary material available at 10.1007/s11060-025-05419-w.