We have previously defined the constitutive photomorphogenic protein 1 (COP1) gene as a therapeutic target in hepatocellular carcinoma (HCC). A recent study demonstrated that COP1 induces non-alcoholic fatty liver disease (NAFLD), a precursor to HCC, in normal hepatocytes and that reducing COP1 expression significantly improves high-fat diet-induced hepatic steatosis. Thus, in this study, we investigated if the function of COP1 was associated with HCC metabolism and evolution. Silencing of COP1 expression by a target siRNA significantly suppressed long-term colony formation in Huh7, HepG2, Huh1, and PLC/PRF/5 HCC cell lines. RNA sequencing of COP1-silenced Huh7 and HepG2 cells revealed the same directional regulation of 24 (14 up- and 10 down-regulated) genes. Notable molecular alterations were upregulation of AKR1D1 and downregulation of TMEM65, which involves negative regulation of lipid metabolism and promotion of metastasis, respectively. Correlation analysis using GEPIA2 supported inverse relationship between COP1 and AKR1D1 expression and positive relationship between COP1 and TMEM65 expression in HCC clinical samples. Targeting of COP1 reduced fat accumulation and metastatic potential in both HCC parental cells and CD133+ liver cancer stem cells. Overexpression of COP1 reversed the phenotypic changes. Collectively, our findings indicate that the COP1 is functionally correlated with HCC lipid metabolism and stemness.

Immunotherapy resistance represents a major unmet clinical need for patients with metastatic non-small cell lung cancer (NSCLC). Preclinical studies have identified PCSK9 as an immunosuppressive regulator of antigen presentation, providing a compelling rationale for therapeutic PCSK9 inhibition as a strategy to overcome resistance to immune checkpoint blockade. Building on this evidence, we present the scientific rationale and study design of TOP2201, an ongoing single-arm phase II trial evaluating the addition of the PCSK9 inhibitor alirocumab to anti-PD-1 therapy in patients with metastatic NSCLC who have experienced disease progression on prior immune checkpoint inhibitor-based regimens. The primary endpoint is objective response rate, with secondary endpoints assessing additional efficacy outcomes and safety. Findings from TOP2201 are expected to generate preliminary clinical and safety data on this combination strategy in the immunorefractory NSCLC setting.Clinical Trial Registration: www.clinicaltrials.gov identifier is NCT05553834.

Interleukin-18 (IL-18) is a pro-inflammatory cytokine, and higher IL-18 expression in pancreatic tumors is associated with poor prognosis. Although 5-fluorouracil (5-FU) has been reported to induce the release of bioactive (mature/cleaved) IL-18 from the pancreatic cancer cell line Capan-2, the underlying mechanism remains unclear. Here, we investigated IL-18 activation in pancreatic cancer cells after 5-FU treatment under low-nutrient conditions that mimic key features of the tumor microenvironment, using a monoclonal antibody we generated that specifically recognizes cleaved, active IL-18. We detected the release of active IL-18 from both Capan-2 and MIA PaCa-2 cells after 5-FU treatment. Analysis of separated attached and detached cell fractions showed that IL-18 cleavage occurred predominantly in detached cells. We also clarified that caspase-8-but not caspase-1/4-was activated in detached cells and was required for IL-18 and GSDMD cleavage that is a hallmark of pyroptosis. Surprisingly, detached cells from only nutrient starvation showed the same phenomenon, and 5-FU contributed to increased pyroptotic cells. On the other hand, the release of active IL-18 was not observed with gemcitabine. These findings suggest that a low-nutrient tumor microenvironment and 5-FU therapy can promote caspase-8-dependent pyroptotic cell death with IL-18 activation, potentially contributing to chronic inflammation in pancreatic tumors.

We present a case of diffuse hemispheric glioma (DHG), H3 G34-mutant, NEC. Postoperative histological examination and DNA sequencing detected some features consistent with DHG, H3 G34-mutant; however, no canonical H3 alterations or ATRX variants were detected. The diagnosis could only be established based on the DNA methylation profiling result. In light of these distinctive molecular findings, we propose some insights into the current WHO diagnostic criteria for DHG H3-G34 and emphasise the value of comprehensive molecular diagnosis.

During the diagnosis and treatment of non-small cell lung cancer (NSCLC), detecting the risk of its recurrence in an early phase is still challenging. Recent studies have investigated the radiomics-based machine learning (ML) models for detecting the risk of recurrence in NSCLC. However, there is still insufficient systematic evidence to prove its efficiency.

Kinesin family member 23 (KIF23) is recognised as an important tumour promoter involved in the pathogenesis of various cancers. However, its role and underlying molecular mechanisms in regulating cervical cancer (CC) growth and primary chemoresistance remain to be fully elucidated.

Accurate prediction of pathological complete response (pCR) following neoadjuvant therapy (NAT) is critical for optimizing treatment in breast cancer. This study develops and validates an interpretable, cost-effective machine learning (ML) model integrating computed tomography (CT)-based body composition parameters with routine inflammatory and nutritional biomarkers to predict pCR.

Transthoracic echocardiography and global longitudinal strain are pivotal in evaluating myocardial structure and function in cardio-oncology patients, but there are limited reports of using global longitudinal strain to identify intracardiac masses. This case presents a patient with metastatic renal cell carcinoma and cardiac metastasis that was identified using global longitudinal strain on transthoracic echocardiography and subsequently confirmed by cardiac magnetic resonance imaging.

T cell-based immunotherapies have improved outcomes in lung adenocarcinoma (LUAD), yet many patients develop primary or acquired resistance. Tumor-intrinsic mechanisms that suppress CD8+ T cell function remain incompletely understood.

Pulmonary fibrosis (PF) significantly increases the risk of lung cancer (LC), but the mechanisms underlying this transition remain unclear. This overview positions macrophage heterogeneity as a central node within the PF-LC continuum. First, we describe important subpopulations of profibrotic and pro-tumor macrophages, including SPP1+, MERTK+, TREM2+, and MARCO+ cells, using high-resolution spatial and single-cell omics technologies. Next, we analyze the fundamental mechanisms that determine their function: the fibrotic microenvironment (e.g., extracellular matrix stiffness, hypoxia) induces profound metabolic reprogramming (e.g., Warburg effect, lipid peroxidation) and stabilizes epigenetic memory (e.g., DNA methylation, histone modifications), locking them into a pathogenic state. This reprogramming occurs through two main pathways: (1) metabolic reprogramming, characterized by aerobic glycolytic conversion and dysregulated lipid metabolism, which stimulates both pathogenic functions and suppression of T cell activity; (2) Epigenetic modifications, including stabilized alterations in DNA methylation, histone modifications, and superactivator patterns, which maintain cells in a tumor-promoting phenotype. As central nodes of communication, these macrophages interact pathologically with fibroblasts and epithelial cells through secreted factors and extracellular vesicles, forming self-reinforcing feedback loops that promote disease progression. We are studying the crucial role of new technologies, particularly multi-omic spatial models and high-precision organoids, in fostering mechanistic discoveries. These discoveries pave the way for new macrophage-focused therapeutic strategies, including the precise stratification of patients using biomarkers from liquid biopsies (such as soluble SPP1 and MARCO) and the development of targeted drug delivery systems for the selective modulation of macrophage function, thus establishing a new paradigm for therapeutic interventions in pulmonary fibrosis with concomitant lung cancer.

The efficacy of immune checkpoint inhibitors (ICI) combined with chemotherapy as a neoadjuvant/adjuvant therapy for locally advanced penile squamous-cell carcinoma (PSCC) remains unclear.

The molecular link between Hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC) progression remains elusive. Here, we identify glutathione peroxidase 2 (GPX2) as a pivotal mediator of this process. Single-cell analysis of HBV-positive HCC reveals a distinct GPX2+ CSC population characterized by high MYC and CD44 expression. We demonstrate that GPX2 preserves stemness intrinsically by mitigating ROS-mediated c-MYC nuclear-cytoplasmic distribution, while extrinsically fostering immune evasion via the CCL26-CCR3 signaling axis. specifically, GPX2-derived CCL26 recruits and educates B cells towards an immunosuppressive LGALS1+ state, which predicts adverse patient outcomes. In vivo, GPX2 overexpression accelerates tumorigenesis, whereas targeting CCR3 with ALK4290 sensitizes tumors to anti-PD-1 checkpoint blockade. These findings delineate a dual mechanism whereby GPX2 couples oxidative stress regulation to immune modulation, positioning the GPX2-B cell axis as a promising therapeutic target for HBV-driven liver cancer.

At initial diagnosis, approximately 30% of renal cell carcinoma (RCC) patients have de novo metastasis. This study aims to develop and validate a diagnostic nomogram for predicting cancer metastasis in patients with initially diagnosed RCC.

Gliomas are the most common primary malignant tumors of the adult central nervous system, characterized by rapid growth, high recurrence rates, and limited response to standard treatments, with median survival under 15 months. The SIX transcription factor family has been implicated in tumor development, but the role and regulatory mechanism of SIX5 in glioblastoma (GBM) remain unclear. This study systematically investigates the biological function of SIX5 and its regulatory network in GBM. Differential expression and weighted gene co-expression network analyses of GSE4290 and GSE50161 datasets, combined with machine learning algorithms including LASSO, identified SIX5 as a core candidate gene. Functional enrichment analyses and evaluation using TCGA and UALCAN databases revealed that SIX5 is highly expressed in GBM and associated with poor prognosis. Single-cell RNA sequencing and spatial transcriptomics showed enrichment of SIX5 in the tumor core and in astrocyte-like and stem cell-like subsets at the invasion front. In vitro, U87 and U251 cells with lentivirus-mediated SIX5 knockdown or overexpression were assessed for proliferation, migration, invasion, apoptosis, and colony formation. SIX5 knockdown significantly inhibited proliferation, migration, invasion, epithelial-mesenchymal transition, and tumorigenicity, while promoting apoptosis. Mechanistically, KDM5C positively regulates SIX5, which directly binds the UBE2C promoter to activate its transcription, enhancing AKT/mTOR signaling and promoting aerobic glycolysis via upregulation of GLUT1, HK2, PGK1, and LDHA. Rescue experiments showed that UBE2C overexpression partially restored malignant phenotypes under SIX5 downregulation. In vivo xenograft studies confirmed that the KDM5C-SIX5-UBE2C axis drives GBM growth. In conclusion, SIX5 functions as a critical oncogenic driver in GBM, regulated by KDM5C and promoting tumor progression through UBE2C-mediated activation of AKT/mTOR signaling and glycolytic reprogramming. The KDM5C-SIX5-UBE2C regulatory axis represents a potential prognostic biomarker and therapeutic target in glioblastoma.

The tumor microenvironment (TME) exerts significant metabolic limitations that influence the activity of invading immune cells. Among them, macrophages and natural killer (NK) cells are essential for coordinating anti-tumor immunity; however, the metabolic conditions of solid tumors have a significant impact on their functional states. Emerging evidence indicates that metabolic competition and nutrition availability regulate the dynamic interactions between these two innate immune populations, eventually influencing immune activation, suppression, and tumor growth. In this review, we discuss how key metabolic factors, including glucose depletion, lipid metabolism, hypoxia, and lactate accumulation, reshape NK cell activity and macrophage polarization in the TME. We emphasize how cytokine signaling and spatial organization within tumors influence NK-macrophage interactions, resulting in either synergistic anti-tumor responses or immunosuppressive networks. Finally, we explore novel therapeutic approaches designed to target metabolic pathways to restore NK cell function and reprogram macrophages toward pro-inflammatory phenotypes. Understanding the metabolic regulation of NK-macrophage interactions could provide new opportunities to improve immunotherapy efficacy in solid tumors.

Endotoxin tolerance (ET) is an immunological state in which repeated exposure to endotoxins such as lipopolysaccharide (LPS) leads to reprogramming of the immune system and a diminished inflammatory response. In this study, we used a murine model to explore the role of ET in breast cancer progression, hypothesizing that ET may foster a tumor-permissive immune environment. We compared endotoxin tolerant breast cancer-bearing mice (ETBC group) with non-endotoxin tolerant breast cancer-bearing controls (BC group). ETBC mice exhibit significantly faster tumor progression and earlier disease onset. Hematological analysis revealed reduced leukocyte counts in the ETBC group, indicating compromised immune cell recruitment. Additionally, ETBC mice showed decreased spleen weight relative to that in the BC group, further supporting systemic immune suppression. Gene expression profiling in both spleen and tumor tissues revealed marked immunological alterations in ETBC mice. In the spleen, there was notable downregulation of key pro-inflammatory cytokines, including interleukin (IL) 6 and interferon (IFN) γ. Conversely, genes associated with immune modulation and tumor progression such as IL-1β, inducible nitric oxide synthase (NOS2), cyclooxygenase (COX) 2, vascular endothelial growth factor (VEGF), and colony stimulating factor 1 (CSF-1) were upregulated. Notably, IL-1β, NOS2, COX-2, IL-10, and VEGF were consistently upregulated in tumor tissues of ETBC mice. We conclude that ET not only impairs immune surveillance but also reshapes the tumor microenvironment in favor of cancer growth. This highlights the potential role of ET in oncology and suggests that its modulation could represent a novel avenue for therapeutic intervention.

Adoptive cell therapy with Vγ9Vδ2 T cells represents a promising approach for melanoma treatment. However, its efficacy is often limited by poor persistence, inadequate tumor infiltration, and functional suppression within the tumor microenvironment. Peptide-based hydrogel as a vehicle has exhibited great potential for delivery of biologics and enhancement of their function, but their ability to directly modulate the metabolic and cytotoxic fitness of Vγ9Vδ2 T cells remains largely unexplored.

Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy, typically presenting at an advanced stage with distant metastases. We report a unique case of a 49-year-old female with metastatic ACC in the liver who exhibited an abscopal effect following pulse electric field (PEF) ablation. The patient initially presented with hypertension, male-patterned hair loss, voice hoarseness, and weight gain and was subsequently diagnosed with a large left adrenal mass along with liver and pulmonary metastases. Following surgical interventions-including left salpingo-oophorectomy, hepatic wedge resection, and left adrenalectomy-and initial systemic treatment with doxorubicin, etoposide, and cisplatin-mitotane (EDP-M), disease progression prompted initiating therapy with pembrolizumab and mitotane. The patient then received Y90 treatment in the right lobe; however, imaging demonstrated viable metastatic disease in the left lobe, which prompted PEF treatment. The patient received PEF almost 7 months post-pembrolizumab and mitotane initiation. Remarkably, two months post-PEF treatment, PET/CT imaging demonstrated complete resolution of three of the four untreated lesions, suggesting an abscopal response. This case adds to the limited literature on PEF ablation, highlighting its potential not only as a local control strategy but also as an adjunct to systemic immunotherapy in liver tumors. Further prospective studies incorporating immune profiling are warranted to elucidate the underlying mechanisms and long-term benefits of this approach.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract, with its pathogenesis primarily linked to activating mutations in the KIT or platelet derived growth factor receptor alpha (PDGFRA) genes. Surgical resection remains the standard curative treatment for localized GIST; however, ~50% of patients eventually develop recurrence or metastasis. Since the introduction of imatinib in the early 21st century, the management of metastatic GIST has shifted from solely surgical intervention to a systemic, chronic disease management model centered on tyrosine kinase inhibitors (TKIs). However, during the course of treatment, most patients develop drug resistance. Despite the transformative impact of TKIs, some critical clinical challenges remain unresolved. Intratumoral heterogeneity, in particular, poses a significant obstacle, as tumors often comprise diverse populations of cells with varying genetic and molecular profiles. This diversity means that while some subclones may initially respond well to TKI therapy, others harboring inherent or acquired resistance mutations can continue to proliferate, ultimately leading to treatment failure. Additionally, the limited durability of TKIs responses, even in tumors initially sensitive to treatment, remains a pressing concern. Moreover, the lack of curative systemic options for advanced GIST, along with adverse drug reactions, underscores the unmet needs within this patient population. These challenges underscore the necessity of this review, which discusses current standard drug treatment strategies for advanced GIST, including sequential TKIs therapy and investigations into mechanisms of drug resistance. Finally, the review explores precise and actionable future directions for GIST drug development and clinical management, including mutation-stratified therapeutic sequencing, rational TKI-based combination regimens, and circulating tumor DNA (ctDNA)-guided real-time treatment monitoring and resistance surveillance.

Previous research has demonstrated the effectiveness of lenvatinib and programmed death-1 (PD-1) blockades in the treatment of sarcoma. However, there is limited information regarding the efficacy and safety of combining lenvatinib with PD-1 blockades as a re-challenge therapy in patients with metastatic soft tissue sarcoma (STS) following prior treatment failure with tyrosine kinase inhibitors (TKIs).