Metastatic uveal melanomas are highly resistant to all existing treatments. To identify actionable vulnerabilities, we conducted a CRISPR-Cas9 knockout screen using a library composed of chromatin regulators. We revealed that the lysine methyltransferase, SETDB1, plays a critical role in metastatic uveal melanoma cell proliferation and survival. Functionally, SETDB1 deficiency induces a DNA damage response, senescence-like state and growth arrest. Knockdown of SETDB1 is associated with a decreased expression of genes related to replication and cell cycle. Moreover, deficiency in CDC6, an essential regulator of DNA replication, phenocopies SETDB1 inhibition. Using a pre-clinical model, we further demonstrated that anti-SETDB1 therapy impairs tumor growth in vivo. Therefore, we not only provide evidence that SETDB1 plays a critical role in metastatic uveal melanoma cell growth, but we also identify SETDB1 as a novel relevant therapeutic target for the treatment of metastatic uveal melanoma.

Chordoma is a rare, slow-growing malignant tumor originating from embryonic notochord remnants and is often found in the sacrum or skull base. It is categorized into conventional, poorly differentiated, and dedifferentiated types, with the conventional type being the most common. Owing to its location near critical structures, chordoma has a high rate of local recurrence, making new therapeutic targets essential. The proteasome system, which is responsible for degrading intracellular proteins, plays a vital role in maintaining cellular function. REGγ, a proteasome activator, mediates ubiquitin-, and ATP-independent protein degradation and is overexpressed in various cancers. However, its role in chordoma remains unexplored. Ras GTPases, including RIT1, are involved in cancer progression, and understanding their involvement in chordoma could provide therapeutic insights. This study identified REGγ as a potential therapeutic target for chordoma. REGγ was found to be upregulated in chordoma, and high REGγ expression was correlated with poor clinical outcomes. It promotes cell proliferation and migration, and inhibits apoptosis, while influencing osteoclast differentiation. Mechanistically, REGγ regulates chordoma progression through the ubiquitin- and ATP-independent degradation of RIT1, which modulates the RIT1-MAPK pathway. Inhibition of RIT1 in REGγ-knockdown cells and patient-derived organoids alleviated these effects, suggesting that targeting REGγ may be a promising strategy for chordoma treatment.

Accumulation of genetic mutations in malignant myeloid precursor cells leads to an extremely poor prognosis for patients with acute myeloid leukemia (AML). Immunogenic neoantigens recognized by T cell receptor (TCR) can elicit effective immune responses against malignant cells with corresponding somatic mutations. To broaden the range of targeted treatments for AML, in this study, we explored the feasibility of immunotherapy targeting neoantigens arising from recurrent mutations, which are exclusively present on leukemic cells. We used data-driven methods to select seven neoantigens from four frequently mutated genes (NPM1, FLT3, TP53, and DNMT3A) associated with HLA-A^*02:01-positive AML patients. Functional assays demonstrated that neoantigens derived from NPM1/W288fs, FLT3/D835H, and FLT3/D835Y were shown to induce specific T cell responses in AML patients. We further identified the specific TCR sequences from healthy donors capable of recognizing these neoantigens. In-depth studies of their specific T cells revealed the presence of dominant αβTCRs that could specifically recognize NPM1/W288fs and FLT3/D835H in an HLA-A^*02:01-restricted manner. T cells engineered with each αβTCR selectively recognized and killed HLA-A^*02:01-positive AML targets endogenously expressing corresponding mutations. Overall, our findings support the clinical translation of adoptive neoantigen-specific TCR-engineered T cells as a novel therapeutic strategy for treating AML.

Therapeutic resistance and recurrence in human epidermal growth factor receptor 2-positive breast cancer (HER2 + BC) remain critical challenges that portend poor patient outcomes. Dysregulated autophagy and lipid metabolism contribute to tumor progression, yet the crosstalk between these pathways is poorly understood. This study investigates the role of transmembrane 9 superfamily member 1 (TM9SF1) in lipophagy and lipid metabolic reprogramming in HER2 + BC under metabolic stress. Clinically, TM9SF1 was significantly upregulated in HER2 + BC tissues and correlated with poor prognosis. Functionally, its expression correlated with markers of enhanced autophagy and lysosomal lipid catabolism, and it promoted tumor cell proliferation in vitro and in vivo. Conversely, TM9SF1 knockdown suppressed lipophagy under both basal and starvation conditions, inhibiting lipid droplet (LD) hydrolysis and the conversion of triglycerides to free fatty acids. This suppression was phenotypically characterized by LD accumulation, reduced autophagosomes and lipophagosomes, and altered enzymatic and lipidomic profiles. Mechanistically, TM9SF1 sustained lipophagy by promoting the phosphorylation of AMP-activated protein kinase at Thr172 and UNC-51-like kinase 1 at Ser555. Consequently, TM9SF1 was pivotal for lipid metabolic reprogramming, maintaining energy homeostasis and enhancing adaptation to nutrient deprivation through lipophagy. Overall, our findings identify TM9SF1 as a key HER2 + BC-associated regulator that drives lipophagy via the AMP-activated protein kinase-UNC-51-like kinase 1 pathway, facilitating LD turnover and free fatty acids utilization to sustain energy homeostasis in HER2 + BC. This work establishes a critical link between malignant phenotypes and metabolic resilience. Targeting this regulatory network represents a promising strategy to dismantle the metabolic scaffolds underlying HER2 + BC aggressiveness and therapeutic resistance.

The retroperitoneum, a complex abdominal compartment encompassing the anterior and posterior pararenal spaces, perirenal spaces, and great vessel space, is involved by both organ-based and non-organ-based pathologies. Imaging characteristics are invaluable in localizing pathologies to the either the retroperitoneum or one of its organs. A wide array of primary and metastatic neoplasms, including those of mesodermal, neurogenic, germ cell, sex cord-stromal, and lymphoid origin, may arise in this region. Frequently encountered non-neoplastic entities include fluid collections and retroperitoneal fibrosis. Integrating key clinical and imaging features is essential for the nuanced differentiation of this heterogeneous spectrum of pathologies.

Renal masses are increasingly detected incidentally on abdominal imaging. Upon discovery, dedicated renal imaging, typically multiphasic computed tomography or MR imaging, is performed for characterization. Noninvasive risk-stratification systems, such as the Bosniak classification for cystic masses and the clear cell likelihood score for solid masses, continue to improve characterization. Despite these improvements in imaging, management dilemmas persist. These challenges arise from the limitations in specificity of imaging and the often indolent behavior of small renal masses. This review outlines the techniques of renal mass biopsy and discusses key clinical scenarios where biopsy findings inform management.

Breast cancer remains a significant global health threat to women, with neoadjuvant therapy (NAT) playing a critical role in treatment. Early prediction of NAT efficacy is essential for personalizing therapy and improving patient outcomes. The Miller-Payne (MP) grading system is a widely accepted standard for evaluating treatment response, categorizing patients as non-major histologic responders (MP1∼MP3) or major histologic responders (MP4∼MP5). This study developed a multi-modal fusion model integrating clinicopathological features and pre-treatment serum surface-enhanced Raman spectroscopy (SERS) data to predict NAT response in breast cancer patients. Leveraging Principal Component Analysis (PCA) for spectral dimensionality reduction and a Transformer architecture for feature extraction, the model achieved an accuracy of 92.6 % on the training cohort, significantly outperforming single-modal models using only SERS or clinicopathological features. Double-blind validation on an independent cohort confirmed the model's generalizability with an accuracy of 90 % and an area under the receiver operating characteristic curve (AUC) of 93 %. SERS analysis revealed significant spectral differences related to uric acid, tryptophan, phospholipids, and collagen, which have potential as biomarkers for NAT efficacy prediction. This study innovatively combined serum SERS data with clinicopathological features to predict NAT response in breast cancer patients. The multi-modal fusion model, enhanced by PCA and a Transformer architecture, captured biomolecular and clinical information, improving prediction accuracy and robustness. This non-invasive, cost-effective tool enables clinicians to avoid ineffective NAT, optimize treatment strategies, and improve patient outcomes.

Despite progress in immunotherapy for several solid tumors, pancreatic ductal adenocarcinoma (PDAC) remains largely unresponsive, primarily due to its profoundly immunosuppressive tumor microenvironment (TME) characterized by limited CD8⁺ T cell infiltration. Novel strategies are needed to overcome this immune resistance and enhance the efficacy of checkpoint blockade.

We established a patient-derived organoid (PDO)-autologous T cell co-culture platform using endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) specimens from patients with PDAC unresponsive to anti-programmed cell death protein-1 (PD-1) therapy. This high-throughput system was used to screen a focused library of epigenetic compounds. The effects of candidate drugs were validated in orthotopic PDAC models, integrating functional assays, sequencing analyses, and patient data.

Through screening, we identified the histone demethylase inhibitor JIB04, which synergized with anti-PD-1 therapy to enhance T cell cytotoxicity in PDO-T cell co-cultures. Mechanistically, JIB04 suppressed nuclear-factor-E2-related factor 2 (Nrf2) and reduced chromatin accessibility at distal regulatory regions of its downstream target solute carrier family 40 member 1 (Slc40a1), impairing iron efflux and promoting ferroptosis in tumor cells. This ferroptotic stress facilitated CD8⁺ T cell infiltration and activation, thereby converting the PDAC TME from "cold" to "hot." Patients with PDAC with lower Nrf2 and Slc40a1 expression exhibited higher CD8⁺ T cell infiltration and improved responses to anti-PD-1 therapy.

Our findings establish a PDO-T cell platform for precision immunotherapy screening and identify JIB04 as a promising epigenetic agent that induces ferroptosis and sensitizes PDAC to immune checkpoint blockade. This ferroptosis-based reprogramming provides a potential strategy to overcome resistance and improve clinical outcomes in PDAC.

Breast malignant phyllodes tumors (MPTs) are rare, aggressive neoplasms with high locoregional recurrence rates despite wide-margin resection. Though NCCN recommends postoperative radiation therapy (PORT), its efficacy remains controversial. This study aims to evaluate PORT's survival benefits in non-metastatic MPT and refine individualized radiation therapy strategies in clinical practice.

We retrospectively analyzed 108 non-metastatic MPT patients treated with R0 resection. Comparative analyses employed Kaplan-Meier methods, multivariable Cox models, and recursive partitioning analysis (RPA) to identify high-benefit PORT subgroups for local recurrence-free survival (LRFS).

PORT was identified as an independent prognostic factor for LRFS (P < 0.01), while showing no protective effect on distant metastasis-free survival or overall survival. The final RPA model established three prognostic groups: low-risk (tumor size ≤5.0 cm with N0, and underwent mastectomy), intermediate-risk (tumor size >5.0 cm with N0, and underwent mastectomy), and high-risk (underwent mastectomy but with N+, or underwent BCS with any tumor size). Significant LRFS benefits were observed in intermediate-risk (P = 0.01) and high-risk groups (P < 0.05) compared to non-PORT counterparts, whereas low-risk patients showed no significant improvement (P = 0.29).

PORT significantly improved LRFS for MPT patients, particularly benefiting intermediate- and high-risk subgroups. This proposed risk stratification provided evidence to guide individualized PORT decision making.

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by stem cell-derived clonal myeloproliferation, bone marrow fibrosis, extramedullary hematopoiesis and aberrant inflammation. About 90 % of MF patients carry mutations in JAK2, CALR, or MPL, with JAK2 mutations promoting cytokine independence, STAT proteins activation and enhances reactive oxygen species (ROS) production. Inflammation and oxidative stress are key contributors to thrombotic risk, a major cause of morbidity and mortality in MF. Fibrinogen, a key factor in coagulation and inflammation, may play a central role due to its susceptibility to oxidative modifications. In particular, in MPN patients, impaired fibrinolysis associated with endothelial cell dysfunction, increased ROS and proinflammatory cytokines production have been reported. This study investigates the role of oxidation-induced structural and functional changes in fibrinogen in MF patients compared to healthy controls, also analyzing the effects of ruxolitinib, a first-in-class JAK inhibitor. Plasma samples from 15 untreated MF patients, 39 ruxolitinib-treated MF patients, and 40 matched healthy controls were analyzed for redox status and fibrinogen properties. MF patients showed elevated plasma lipid peroxidation and nitrate/nitrite levels, reduced antioxidant capacity, and lower free thiol content. These changes were associated with significant fibrinogen oxidation, leading to structural alterations and impaired function, including reduced fibrin polymerization and decreased plasmin-mediated fibrinolysis. Strong correlations were observed between oxidative stress markers and fibrinogen dysfunction. Treatment with ruxolitinib improved redox balance and restored fibrinogen structure and function. These findings provide the first evidence of a prothrombotic profile in MF patients, driven by structural and functional fibrinogen modifications.