ABSTRACT Background Docetaxel (DTX) is one of the commonly used chemotherapeutic agents for breast cancer. Cuproptosis, a newly defined form of cell death, significantly influences tumor progression. This study aims to identify cuproptosis-related long non-coding RNAs (lncRNAs) involved in regulating the sensitivity of breast cancer to DTX. Materials Cuproptosis-related prognostic lncRNAs in breast cancer were identified through integrated co-expression, differential expression, and prognostic analyses based on the TCGA-BRCA cohort. The role of the identified lncRNA AC008406.3 in regulating cuproptosis in breast cancer cells was experimentally verified. The impact of DTX on the induction of cuproptosis was investigated, and rescue experiments were conducted to validate the involvement of AC008406.3 in modulating breast cancer sensitivity to DTX. Results AC008406.3 was identified as a potential cuproptosis-related prognostic lncRNA in breast cancer, exhibiting high expression in breast cancer samples, which was associated with unfavorable prognostic outcomes. Knockdown of AC008406.3 specifically induced cuproptosis in breast cancer cells, as evidenced by increased intracellular copper levels and downregulation of lipoylated proteins and Fe–S cluster proteins, thereby suppressing cell proliferation, invasion, and migration; conversely, AC008406.3 overexpression elicited opposite phenotypic changes. Notably, DTX induced the occurrence of cuproptosis in breast cancer, whereas AC008406.3 suppressed this process, thereby diminishing DTX efficacy. However, AC008406.3 knockdown synergistically enhanced the anti-tumor efficacy of DTX in inhibiting breast cancer growth. Conclusion AC008406.3 reduces the sensitivity of breast cancer to DTX by suppressing cuproptosis. Targeting AC008406.3 may represent a potential strategy to sensitize breast cancer cells to DTX.

ABSTRACT Background Cancer during pregnancy is a fragile scenario where the maternal body undergoes significant molecular changes, including at proteomic and metabolomic levels, with damage to placenta and fetal development. Proteomic and metabolomic interaction analyses can clarify the complex dynamics in cancer associated with pregnancy. Leucine is involved in protein synthesis and metabolic regulation and may attenuate tumor-induced damage. Objective We investigated placental proteomic and metabolomic profiles in the complex relationships among pregnancy, cancer, and leucine supplementation. Materials Exploratory, non-targeted proteomic (mass spectrometry) and metabolomic (NMR spectrometry) analyses were performed on the placenta tissue of four pregnant groups: control (PC), Walker-256 tumor-bearing (PW), leucine (PL), and tumor-bearing fed a leucine-rich diet (PWL). Statistical comparisons were performed on technical replicate data within each group. Results Tumor affected maternal weight, but leucine attenuated the decrease in placental weight and fetal resorption. Leucine supplementation restored the placental proteins involved in the nuclear structure, cytoskeleton, and immune response. Tumor evolution impaired pathways related to protein folding and chromosome localization, whereas leucine modulated interferon-gamma and hydrogen peroxide responses. PW placentas exhibited decreased adenosine, glucose, glutamate, and succinate, with enhanced lactate, creatine, and histamine levels, whereas leucine supplementation restored adenosine and pyridoxine and reduced lactate levels. The affected alanine/aspartate/glutamate and purine metabolism, beta-alanine metabolism, and the citrate cycle were minimized in leucine treatment (PWL), which mainly modulates purine and alanine/aspartate/glutamate pathways and pyruvate metabolism. Conclusion A leucine-rich diet partially restored placental protein and metabolite levels, leading affected pathways to shift towards amino acid biosynthesis and pyruvate metabolism and minimizing effects on fetal development.

Natural killer (NK) cells are a unique subset of cytotoxic lymphocytes within the innate immune system. They play a pivotal role in antiviral and antitumor immunity. NK cell-based adoptive immunotherapy has advanced rapidly in recent years. Innovative approaches, such as autologous/haploidentical NK cell infusion, chimeric antigen receptor NK cells, and NK cell engagers, have emerged, demonstrating promising potential in the treatment of various diseases. Currently, enhancement strategies for NK cell therapy primarily focus on two key aspects: improving expansion efficiency and persistence, with a positive effect on the therapy's potency and cytotoxic efficacy. The present review systematically introduces the functional mechanisms of NK cells and their specialized functional subsets. This review discusses the progress and optimization methods of NK cell therapy and provides an outlook on future research directions.

Introduction The selection of an optimal maintenance agent in diffuse large B-cell lymphoma (DLBCL) continues to pose a significant clinical challenge. This study aims to evaluate the prognostic impact of maintenance therapy (MT) in DLBCL. Methods We conducted a retrospective analysis of data from DLBCL patients undergoing first-line MT at four hospitals in Beijing between January 2019 and August 2024. The REMoDL-B trial database was selected as the control group. Results The MT group comprised 106 cases and a median follow-up duration of 25.4 months. The rates of progression and death were 11.32% (12/106) and 1.89% (2/106), respectively. The 2-y progression-free survival (PFS) and overall survival (OS) rates were 90% and 98%, respectively. The MT group demonstrated significantly superior PFS and OS compared to the control group (p = 0.024, p = 0.008). Furthermore, multivariate analysis indicated that MT (p = 0.021, OR = 0.037, 95% CI, 0.002–0.605) was an independent prognostic factor associated with improved PFS. For patients receiving Bruton tyrosine kinase inhibitors (BTKi), the 2-y PFS and OS rates were 87.6% and 97.2%, respectively, both significantly better than those of the control group (p = 0.048, p = 0.024). Despite 43.6% of patients being at high risk for central nervous system (CNS), no CNS recurrences were observed. The PFS of the MCD subtype is better than that of the A53 subtype. Conclusions While limited by the retrospective study, our analysis raises the hypothesis that MT may correlate with improved DLBCL outcomes. A similar trend suggesting potential benefit from BTKi maintenance was noted, meriting further investigation in controlled settings.

ABSTRACT Background Esophageal squamous cell carcinoma (ESCC) remains a deadly disease, with no effective therapeutics available for advanced stages. The application of the “synthetic lethality” principle to cancers with abnormal epigenetic changes provides more opportunities for developing novel therapeutic strategies. It is necessary to identify more molecules that are involved in the DNA damage repair response or cell fate determination to reach this end. Malignant brain tumor (MBT) domain proteins are important for development and cell fate. L3MBTL4 is a new member of this family, but its function remains to be clarified. Methods Lentiviral infection was used to re-express L3MBTL4. Immunoprecipitation, immunofluorescence, comet, homologous recombination (HR), and non-homologous end joining (NHEJ) reporter assays were performed to explore the mechanism involved. Results The expression of L3MBTL4 was regulated by methylation of the promoter region. L3MBTL4 inhibited cell proliferation and colony formation, and induced G1/S arrest and apoptosis in ESCC cells. L3MBTL4 promoted ATM signaling and inhibited NHEJ signaling by interacting with KU70. Epigenetic silencing of L3MBTL4 sensitized ESCC cells to NU7441, a DNA-PKcs inhibitor, both in vitro and in vivo. Conclusion L3MBTL4 is a potential tumor suppressor and methylation of L3MBTL4 is a sensitive marker of DNA-PKcs inhibitors.

ABSTRACT Background Laryngeal squamous cell carcinoma (LSCC) is a common head and neck malignancy with poor prognosis. The role of MYBL2, an oncogenic transcription factor, in the glycolytic reprogramming of LSCC remains unclear. Methods We integrated RNA-sequencing with public databases (TCGA, GEO) and tissue microarrays to assess MYBL2 expression and its clinical significance. Transcriptional regulation was verified by ChIP-qPCR and luciferase reporter assays. Signaling pathways and metabolic profiles were examined using Western blotting and Seahorse analysis (ECAR/OCR). Biological functions were evaluated by in vitro functional assays and in vivo xenograft models in female BALB/c nude mice. Results MYBL2 was significantly overexpressed in LSCC tissues and correlated with poor prognosis. Mechanistically, MYBL2 directly activates GTSE1 transcription. This regulation stimulates PI3K/AKT signaling to upregulate key glycolytic proteins (PKM2, HK2, GLUT1, LDHA), thereby driving metabolic reprogramming characterized by elevated glycolysis (ECAR) and suppressed mitochondrial respiration (OCR). Functionally, MYBL2 overexpression enhanced the proliferation, migration, and invasion of LSCC cells in vitro and promoted tumor growth in vivo. Importantly, these oncogenic effects were effectively reversed by GTSE1 knockdown or PI3K inhibition with LY294002, validating the pathway's functional significance. Conclusion The MYBL2-GTSE1 axis promotes LSCC progression through PI3K/AKT-mediated metabolic reprogramming, representing a promising therapeutic target.

Background Perineural invasion (PNI) represents a uniquely distinctive pathway for tumor metastasis, but its underlying molecular mechanisms and therapy remain unclear. Methods Bioinformatics analysis and transcriptomic sequencing were first employed to investigate the involvement of the BDNF/TrkB axis in the ESCC PNI, which was validated with ESCC cells co-cultured with a dorsal root ganglia system (ESCC/DRG model), a mouse PNI model, and ESCC tissues, mainly using microscopic imaging, IVIS Spectrum in vivo imaging, Western blot (WB), and immunohistochemistry (IHC). Additionally, transcriptomic sequencing and WB were conducted to analyze the downstream molecular mechanisms of the BDNF/TrkB axis. Similar experiments were applied to investigate the role of Deguelin in ESCC PNI. Deguelin's interaction with BDNF was assessed using computational docking, pull-down assays, cellular thermal shift assays, surface plasmon resonance (SPR) and WB. Its inhibitory effects on the ESCC PNI were further evaluated through rescue experiments, where BDNF overexpression was used to counteract Deguelin's activity. Results The BDNF/TrkB axis is closely associated with the PNI in ESCC. This pathway plays a pivotal role in driving PNI progression via Akt signaling. Deguelin was identified as an effective inhibitor of PNI in ESCC. Mechanistically, BDNF was revealed to be a key binding target of Deguelin, which disrupts PNI development by modulating the BDNF/TrkB/Akt axis. Notably, overexpression of BDNF can counteract Deguelin's inhibitory effects on ESCC growth and PNI progression. Conclusion The BDNF/TrkB axis promotes the progression of ESCC PNI, and Deguelin inhibits ESCC PNI by targeting this axis, enhancing the understanding of PNI's molecular mechanisms and offering new therapeutic options.

ABSTRACT Recent research has highlighted the critical role of copper metabolism and a novel form of copper-dependent cell death, termed cuproptosis, in the progression and treatment of these cancers. Copper, an essential trace element, plays a crucial role in various cellular processes, including mitochondrial function, antioxidant defense, and angiogenesis. However, the dysregulation of copper homeostasis in cancer cells can exacerbate genomic instability, promote angiogenesis, and reshape the immune microenvironment, thereby driving tumor progression. This review systematically explores the mechanisms of copper homeostasis and cuproptosis in digestive system cancers. We also explore innovative strategies for overcoming drug resistance and reshaping immune responses through copper chelators, copper ionophores, and nanomedicines that induce cuproptosis. By integrating basic research with clinical evidence, this review aims to provide a scientific perspective on understanding the biological significance of cuproptosis and developing new anticancer strategies, while also stimulating in-depth thinking on the intersection of metabolic intervention and cell death.

Background PARP inhibitors (PARPis) are new targeted agents that exploit homologous recombination DNA repair deficiencies (HRDs), which are present in 50% of high-grade serous carcinoma (HGSC) cases. Currently, olaparib is approved as maintenance therapy for BRCA1/2-mutated HGSC, and niraparib is approved for platinum-sensitive recurrent disease. However, research is currently expanding their potential as front-line agents or in combination with carboplatin, a standard HGSC chemotherapeutic. Methods Immortalized ovarian cancer (iOvCa) cell lines, developed from HGSC patient ascites, were treated with carboplatin, olaparib and niraparib to determine their sensitivity. Immunofluorescence analysis of RAD51 was conducted for HRD testing of all the cell lines. The cell lines were cultured as three-dimensional organoids and spheroids to mimic tumor growth and metastasis, respectively, and then treated to assess the effects of different drug combinations. Results The half-maximal inhibitory concentrations of olaparib and niraparib varied across our iOvCa cell lines, with iOvCa195 BRCA1-mutant line exhibiting the expected high sensitivity to both PARPis. Direct combination of carboplatin with olaparib or niraparib enhanced cell killing, yet achieved cell viability levels to those of carboplatin alone. In sequential experiments, carboplatin followed by either PARPi or vice versa showed no significant difference in cell viability to carboplatin alone, except in iOvCa195 organoids when treated with a PARPi first. Conclusions Overall, first-line carboplatin treatment remains ideal, yet there may be select utility for PARPi prior to chemotherapy. Using patient-derived tumor models such as spheroids and organoids may provide insights for on-going and future clinical trials to enhance therapeutic outcomes for HGSC patients.