Locally advanced gastroesophageal adenocarcinomas commonly relapse early with peritoneal disease, suggesting that a subset of patients harbor occult peritoneal micrometastases at diagnosis. These patients may benefit from peritoneal-directed therapy in the perioperative setting. To facilitate patient selection and evaluation of such therapies, we derived, validated, and compared prediction models for peritoneal recurrence after fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT)-based multimodality treatment using pre- and post-treatment clinicopathologic predictors.

A total of 2,240 patients from the international Survival and Patterns of Care in the Era-FLOT registry were analyzed. Using Fine-Gray competing-risk regression, patients who developed peritoneal recurrence were compared with those with nonperitoneal recurrence, those who died without recurrence, and those who remained disease-free at follow-up. Pre- and post-treatment variables, obtained at staging and post-FLOT/surgery, respectively, were used to construct pre- and post-treatment predictive models of peritoneal recurrence, with internal validation using bootstrap optimism correction.

Peritoneal recurrence was the most frequent (41% of all recurrences) and earliest site of disease relapse (median 9.8 v 11.4 months, P = .024) and was associated with poorer postrecurrence (median 4.4 v 9.8 months, P < .001) and overall (median 17.0 v 24.3 months, P < .001) survival compared with nonperitoneal recurrence. Six pretreatment and eight post-treatment variables independently predicted peritoneal recurrence and were incorporated into pre- and post-treatment models, respectively. At 12, 24, and 36 months postsurgery, both models demonstrated good discriminatory performance in predicting peritoneal relapse with comparable accuracy and risk calibration profiles. Decision curve analysis found that both models were superior to treat-none and treat-all approaches, highlighting their potential clinical utility.

Peritoneal recurrence remains a common and important problem. We derived pre- and post-treatment prediction models for peritoneal recurrence, also available as web-based calculators. These tools can clinically prognosticate and may advance peritoneal-directed therapies for high-risk patients.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, with high recurrence rates after surgical resection posing a significant challenge. While deep learning (DL) approaches show promise in predicting HCC recurrence, their clinical translation is limited by poor interpretability and unclear mechanisms. Our study aimed to develop an interpretable DL framework that predicts recurrence while elucidating underlying biology through integration of radiologic imaging and multiomics profiling.

We developed a DL framework to predict early postoperative HCC recurrence using preoperative multiphase computed tomography imaging and generate an imaging-based early recurrence risk score (ERRS) for risk stratification. To decipher the biological basis of ERRS, we integrated DL features with proteomic data to identify key metabolic alterations, which were validated by metabolomics, immunohistochemistry, and enzymatic assays. Patient-derived organoids (PDOs) were used to assess the therapeutic potential of targeting these alterations.

The Multi-model_NC&ART&PV DL model showed improved performance compared with conventional single-phase models in predicting early postoperative recurrence, with high-ERRS patients exhibiting worse survival and more aggressive features. Mechanistically, radioproteomic analyses linked model predictions to dysregulated pyruvate metabolism, characterized by reduced pyruvate dehydrogenase complex expression/activity and elevated lactate dehydrogenase (LDH) activity. PDOs from patients with HCC were sensitive to LDH inhibitor stiripentol, with high-ERRS tumors showing greater therapeutic vulnerability than low-ERRS tumors.

This study bridges artificial intelligence-driven imaging and mechanism-guided therapy by developing a biologically interpretable DL model for HCC recurrence prediction. Radioproteomic integration identified dysregulated pyruvate metabolism as a hallmark of high-risk HCC, enabling the repurposing of stiripentol as a potential therapy. This framework suggests a potential strategy linking noninvasive risk stratification with pathway-guided treatment although further validation and prospective studies are needed to establish its clinical utility.

The nervous system is now recognized as an enabling hallmark of cancer biology. Neural inputs drive tumor growth in both central nervous system tumors and extracranial tumors through different mechanisms, including synaptic signaling, adrenergic regulation, perineural invasion, neuropeptides, immune remodeling, and bioelectric mechanisms. These insights have facilitated repurposing of neuroactive agents that are now in clinical trials as adjuncts to standard cancer therapy. The central translational challenge now is how to match the right neural circuit to the right patient and to pair appropriate neuromodulators with immunotherapy in combinations designed to restore, rather than merely supplement, antitumor immunity.

Liquid biopsy is a promising, noninvasive approach for cancer detection, but current methods often trade off accuracy, operability, and cost. To address these limitations, we introduce an artificial perception system (APS) for liquid biopsy that combines a structurally defined DNA-carbon nanotube sensor array with machine learning (ML) models. The array produces multichannel fluorescence fingerprints from serum, which are decoded by ML models to classify disease state. In a total of 253 serum samples spanning liver, lung, and ovarian cancers and noncancer controls, the APS achieved mean sensitivity of 89% and specificity of 96%. Notably, early-stage lung cancer was detected with 92% sensitivity and 95% specificity at an estimated cost of ∼$4 USD per test. Insights from SHAP analysis and Mantel test revealed the detection mechanisms of APS, supporting biological plausibility and clinical translation. These results highlight a path toward accurate, scalable, and affordable multicancer detection and early cancer screening.

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective treatment options, and paclitaxel resistance remains a major clinical challenge. This study investigated the role of VASN in mediating paclitaxel resistance in TNBC by integrating transcriptomic and single-cell RNA sequencing data from public databases and clinical samples. Using paclitaxel-resistant TNBC cell lines (MDA-MB-231R and CAL-51R) and xenograft models, we revealed that VASN was significantly upregulated in resistant TNBC cells and tissues, correlating with poor prognosis. Mechanistically, CEBPB directly bound to the VASN promoter to activate its transcription, and VASN interacted with IGF2BP3 via its LRR domain, recruiting USP10 to deubiquitinate and stabilize IGF2BP3 by suppressing K48-linked polyubiquitination. Stabilized IGF2BP3 enhanced ABCB1 expression through m⁶A-dependent mRNA stabilization, activating the PI3K/AKT pathway and driving paclitaxel resistance. Genetic or pharmacological inhibition of VASN resensitized resistant cells to paclitaxel, and computational drug screening identified Trametinib as a candidate to downregulate VASN. Trametinib synergized with paclitaxel to effectively suppress tumor growth without obvious toxicity in resistant models. In summary, we uncovered a new CEBPB-VASN/IGF2BP3/USP10-ABCB1 axis responsible for paclitaxel resistance in TNBC. Targeting VASN with Trametinib in combination with paclitaxel represents a promising therapeutic strategy to overcome chemoresistance, offering a rationale for precision medicine in resistant TNBC.

Oral squamous cell carcinoma (OSCC) is associated with aggressive clinical behavior and poor outcomes. In this study, we investigated the anticancer efficacy and underlying mechanisms of Stellettin B, an isomalabaricane triterpene isolated from the marine sponge Jaspis stellifera, in OSCC cells. Our results demonstrate that Stellettin B significantly inhibited the proliferation of HSC-3 and OC-2 cells while sparing normal oral keratinocytes. Mechanistically, Stellettin B triggers a predominantly caspase-independent apoptotic program, evidenced by the pronounced mitochondrial-to-nuclear translocation of apoptosis-inducing factor (AIF) and endonuclease G (EndoG) following DNA damage, whereas classical caspase activation functions as a dispensable, secondary event. Furthermore, Stellettin B suppressed migration and invasion by reversing epithelial-mesenchymal transition (EMT), characterized by E-cadherin upregulation and downregulation of Vimentin, Snail, Slug, and β-catenin. Transcriptomic profiling further revealed significant suppression of mTORC1 signaling and EDIL3 expression. In conclusion, these findings demonstrate that Stellettin B exerts multimodal antitumor activity in OSCC and highlight its therapeutic potential as a marine-derived anticancer agent.

Programmed death-ligand 1 (PD-L1) has long been characterized as a membrane-bound immune checkpoint ligand that suppresses antitumor immunity through engagement with PD-1 on T cells. This canonical understanding has underpinned the development of therapeutic antibodies that have revolutionized cancer treatment. However, PD-1/PD-L1 immunotherapy still has limitations such as poor response rates and post-treatment resistance. Notably, emerging evidence reveals that the roles of PD-L1 extend beyond its membrane-bound form, with substantial pools residing in the cytoplasm, nucleus, organelles, and extracellular vesicles. These intracellular PD-L1 populations perform distinct, often immune-independent functions including transcriptional regulation, mRNA stability control, DNA damage response modulation, and metabolic reprogramming. This review examines the subcellular localization of PD-L1, the mechanisms governing its trafficking and compartmentalization, its compartment-specific biological functions, and the corresponding clinical significance. Understanding the full spectrum of PD-L1 biology is essential for developing more effective immunotherapeutic approaches and promoting individualized treatment strategies.

Lipid metabolic reprogramming plays a crucial role in modulating tumor responses to radiotherapy by influencing radiation-induced oxidative damage, membrane repair, ferroptosis, energy stress, and immune regulation. Within the context of ionizing radiation, lipid pathways of particular significance include iron-dependent lipid peroxidation and ferroptosis, cholesterol and phospholipid remodeling that impacts membrane integrity and lipid rafts, lipid droplet-mediated buffering of metabolic stress, fatty acid oxidation-dependent energy supply, and sphingolipid-regulated apoptosis. This review delineates pre-existing tumor lipid programs from IR-induced adaptive responses, highlighting that their contributions to radiosensitivity or radioresistance are contingent upon tumor lineage, genetic background, microenvironmental conditions, and treatment context. The coupling of cancer cells with their microenvironment through lipid interactions, encompassing intercellular lipid transfer, nutrient competition, paracrine lipid mediators, and exosome-mediated signaling, is identified as a central component of radioresistance. In conclusion, therapeutic opportunities are evaluated based on their translational maturity, encompassing a spectrum from mechanistic concepts and preclinical radiosensitization strategies to approaches with emerging clinical significance. This synthesis, focused on radiotherapy, seeks to elucidate how lipid vulnerabilities can be strategically and judiciously exploited to enhance radiation outcomes.

Licoricidin (LCD), a natural isoflavonoid compound extracted from Glycyrrhiza species, has been extensively demonstrated to possess diverse biological activities, including anti-inflammatory and potent anti-cancer effects. However, the precise mechanism underlying LCD action against hepatocellular carcinoma (HCC) remains unclear, particularly regarding its regulation of cell death. In this study, we comprehensively explored the effects of LCD on HCC cells in vitro and investigated its role and mechanism of action in the induction of PANoptosis. Our results reveal that LCD exhibited potent anti-HCC activities by decreasing cell viability and significantly inhibiting clonogenic survival in HCC cell lines. Our results demonstrate that LCD triggered a substantial accumulation of reactive oxygen species and induced depolarization of the mitochondrial membrane, leading to profound mitochondrial dysfunction. We further confirmed that LCD activated a comprehensive PANoptosis program by synchronously upregulating the expression of apoptotic proteins (Bax, c-CASP3, and c-PARP1), pyroptotic proteins (c-CASP 1 and c-GSDMD), and the phosphorylation of necroptotic executioners (p-MLKL and p-RIPK1). Treatment with the ROS inhibitor (NAC), apoptosis inhibitor (ZVAD), or necroptosis inhibitor (Nec-1) significantly reduced the expression of PANoptosis-related proteins in LCD-treated cells. Furthermore, molecular docking simulations and cellular thermal shift assay (CETSA) assay confirmed the direct and stable binding of LCD to PANoptosis-related proteins. In summary, we show for the first time that LCD exerts favorable anti-HCC activities via the induction of PANoptosis through a ROS-dependent mechanism and potntial direct modulation of core executive proteins. This multi-target action suggests that LCD could be a novel candidate for the management of hepatocellular carcinoma.

Triple-negative breast cancer (TNBC) primarily relies on traditional adjuvant chemotherapy and radiotherapy, which have significant side effects and are prone to drug resistance. Poly ADP-ribose polymerase inhibitor (PARPi) has been approved for TNBC patients with BRCA mutation, but some BRCA wild-type patients with homologous recombination deficiencies are also sensitive to PARPi. Therefore, it is important to identify potential molecules that influence PARPi sensitivity in BRCA wild-type TNBC and to explore their specific mechanisms. Through CRISPR-cas9 loss-of-function screening, the lncRNA MTUS2-AS1 was identified to be significantly correlated with PARPi sensitivity in BRCA wild-type TNBC cells. In vitro and in vivo experiments were performed to investigate its function and underlying mechanism. We found that MTUS2-AS1 knockdown suppressed DNA damage repair and enhanced the anticancer effects of PARPi in BRCA-wild TNBC cells. Mechanistically, MTUS2-AS1 upregulates DDX5 protein expression by maintaining its stability, thereby promoting R-loop resolution, and suppressing DNA damage. Knocking down MTUS2-AS1 accelerated DDX5 protein degradation, reduced DDX5 protein expression, inhibitd R-loop resolution, promoted DNA damage, and ultimately enhanced the PARPi sensitivity in TNBC cells. Our study provided new insights into exploring the key molecules and mechanisms influencing the sensitivity of PARPi treatment and had great significance for screening benefit population and expanding the indications of PARPi treatment.