Natural killer (NK) cell-derived exosomes have demonstrated anti-cancer activity against various cancers, but the role in regulating ferroptosis in lung cancer remains unclear. This study investigates whether exosomes derived from NK-92 cells (NK92-exo) can trigger ferroptosis in A549 cells and elucidates the underlying mechanisms, providing a novel strategy for lung cancer treatment.

NK92-exo were isolated via ultracentrifugation and density-gradient ultracentrifugation and characterized. The changes related to ferroptosis were determined using specific detection kits and transmission electron microscopy (TEM). Predict miR-663a and SLC11A2 associated with ferroptosis in A549 cells through bioinformatics analysis and validated. Lentivirus infection was used to overexpress SLC11A2 in A549 cells, and the expression levels of GPX4, NRF2, and PTGS2 were analyzed.

NK92-exo were successfully isolated and characterized. Co-culturing NK92-exo with A549 cells significantly increased ferroptosis-related changes, such as elevated MDA, ROS, and Fe²⁺ levels, decreased GSH level and mitochondrial membrane potential, and observed shrunken mitochondria and mitochondrial rupture. The expression level of miR-663a was significantly downregulated by NK92-exo treatment, resulting in evident upregulation of its potential target SLC11A2 in A549 cells. Additionally, SLC11A2 overexpression significantly enhanced ferroptosis in A549 cells, an effect that was further enhanced by NK92-exo treatment.

NK92-exo decreased intracellular miR-663a abundance and increased SLC11A2 expression, thereby promoting ferroptosis in A549 cells. These findings suggest that NK92-exo may serve as a novel therapeutic bioproduct for lung cancer treatment.

Ovarian cancer is predominantly diagnosed in the late stages of the disease. Ascites can be collected before the start of neoadjuvant treatment or during the treatment course and may serve as a potential biological surrogate for tumor tissue (TT), representing metastases located in the peritoneal cavity. The minimally invasive nature of ascites collection makes it an alternative to tumor biopsies. The aim was to investigate ascites samples alongside corresponding fresh frozen TT to clarify the potential of ascites in reflecting the genetic composition of TT. Secondly, we wanted to investigate if ascites can be used as biological material for molecular analyses, predicting possible molecular targets associated with FDA-approved drugs.

We used next-generation sequencing, natural language processing, and network analysis to assess the recall of genetic variants between corresponding TT and ascites samples in a cohort of 32 patients with ovarian cancer.

Patients median age was 68.5 years. Seventy two percent were diagnosed at late stage disease. Overall, the analysis showed that 156 (76%) of the identified variants overlapped between ascites and TT. Ascites had 28 (14%) unique identified variants, while TT had 21 (10%). We identified 25 (76%) pathogenic or likely pathogenic variants in TT that were also present in the corresponding ascites sample. Three variants (9%) were unique for the ascites samples, while five (15%) were unique for the TT samples.

We identified all pathogenic and likely pathogenic actionable variants within a clinical perspective in ascites. Clinicians may consider using ascites, particularly for patients with fluid accumulation who are not candidates for surgery at the time of diagnosis.

Response assessment in colorectal cancer (CRC) still relies largely on anatomic imaging, which does not capture dynamic immune or stromal adaptation. Techniques like cytometry by time-of-flight (CyTOF) and imaging mass cytometry (IMC) enable high-dimensional single-cell proteomic and spatial profiling, thereby enhancing our understanding of therapeutic responses in CRC. This narrative review summarizes current evidence from human, preclinical, and organoid studies describing how CyTOF and IMC have been applied to characterize therapeutic response in CRC.

Relevant publications applying suspension CyTOF or IMC to CRC tissue, blood, or model systems were identified through PubMed and major oncology journals. Studies linking single-cell features to treatment response or pharmacodynamics were prioritized and organized by biological theme and clinical applicability.

Spatial analyses have identified macrophage-T-cell niches enriched for CD68⁺CD74⁺ and C1QC⁺ resident-tissue macrophages that predict benefit from PD-1 blockade more accurately than bulk T-cell density. Conversely, cancer-associated fibroblast (CAF)-dense matrices and granulocytic proximity associate with resistance. Systemic CyTOF studies have demonstrated peri-operative lymphopenia, persistent HLA-DR^low monocytes, and chemotherapy-induced depletion of mature CD56^dimCD16⁺ natural killer (NK) cells on a STAT5-biased background. Organoid and phospho-signaling studies show that cellular differentiation states determine oncogenic ERK activation and therapy tolerance. Collectively, these datasets outline pharmacodynamic and predictive biomarkers relevant to immunotherapy and chemotherapy.

CyTOF and IMC provide actionable biomarkers - including C1QC⁺ macrophage-T-cell proximity, HLA-DR^low monocytes, and NK-cell maturation profiles - that refine response assessment beyond imaging criteria. Harmonization of antibody panels, prospective validation, and integration into clinical workflows are required to apply these findings in clinical practice.

Bortezomib, a proteasome inhibitor, exhibits limited efficacy against colorectal cancer (CRC); therefore, strategies to enhance bortezomib sensitivity in CRC are required. Previous studies have reported that 6-O-carboxypropyl-α-tocotrienol (T3E) enhances bortezomib sensitivity in several cancer cells. In this study, we investigated the anticancer effect of combined treatment with T3E and bortezomib in CRC cells.

Cells were treated with T3E and bortezomib in combination, and cell viability, apoptosis, proteasome activity, and endoplasmic reticulum stress induction were evaluated. In addition, we assessed the effects of T3E on the activation of nuclear factor erythroid 2-related factor 1 (NRF1) and nuclear factor erythroid 2-related factor 3 (NRF3), which are involved in bortezomib resistance.

The combined treatment with T3E and bortezomib induced more potent cytotoxicity against CRC cells than either treatment alone. Furthermore, T3E enhanced bortezomib-induced proteasome inhibition and endoplasmic reticulum stress. Notably, the combined treatment with T3E and bortezomib did not induce cytotoxicity in non-cancerous cells. We also observed that T3E did not suppress NRF1 and NRF3, which are resistance factors to bortezomib. Rather, T3E sustained the activation of NRF1 induced by bortezomib.

T3E enhanced the anticancer effects of bortezomib without suppressing NRF1 and NRF3. T3E may be a promising compound for expanding the therapeutic use of bortezomib in CRC.

Tumor cells generate energy through glycolysis and produce lactate as a byproduct. The lactate can be used as a substrate for lysine lactylation (Kla), a post-translational modification that may contribute to cell survival and growth in certain tumors. The colorectal cancer cell line SW480 was identified to have lactylated proteins, however, the role and mechanism of lactylation in colorectal cancer (CRC) are still not well known.

The lactylation modification in HCT116 cells was analyzed by mass spectrometry, followed by bioinformatics analysis. Treatment of 2-DG, oxamate, or siLDH was performed to study the regulatory roles of lactylation in proliferation measured by CCK-8 assays and colony formation assays. Lactylation levels were assessed via Western blotting, immunofluorescence staining, and co-immunoprecipitation followed by Western blotting.

CRC patients had higher levels of Kla in tumor tissues than those in adjacent tissues. Patients with higher levels of Kla had a shorter survival time. We found that Kla was higher in CRC cell line HCT116 and identified 1,295 sites from 699 lactylated proteins in HCT116 cells. These lactylated proteins in CRC cells are enriched in processes such as histone modification and cell proliferation. The inhibition of protein lactylation can suppress the proliferation of CRC cells.

Our characterization of Kla demonstrated the importance of protein lactylation in CRC, thereby providing an important foundation for future elucidation of the pathogenesis of CRC and for the development of treatments to improve the survival time of CRC patients.

Borderline ovarian tumours (BOTs) frequently affect women of reproductive age. Fertility-sparing surgery (FSS) is commonly offered, but recurrence risk varies by surgical approach and histological subtype, while malignant transformation remains incompletely defined. This systematic review and meta-analysis aimed to quantify recurrence and malignant transformation risks following different surgical strategies for BOTs.

A prospectively registered protocol (PROSPERO: CRD420251172155) was followed. Studies of adult women with histologically confirmed BOTs undergoing FSS - unilateral or bilateral cystectomy, unilateral salpingo-oophorectomy (USO), or USO with contralateral cystectomy - or radical surgical staging (pelvic clearance) were included. Random-effects meta-analyses generated pooled risk estimates with 95% confidence intervals (CIs); heterogeneity was assessed using I². Methodological quality was evaluated using MINORS.

Forty-one studies including 5,364 women were analyzed, with follow-up ranging from 7 months to 15 years. Recurrence following FSS was highest after cystectomy-based procedures: 0.31 (95%CI=0.15-0.47; I²=97.24%) after unilateral cystectomy and 0.41 (0.26-0.57; I²=80.59%) after bilateral cystectomy. Lower recurrence was observed after USO (0.13; 0.10-0.16; I²=81.55%) and USO with contralateral cystectomy (0.31; 0.17-0.45; I²=91.40%). Radical surgery was associated with the lowest recurrence risk (0.03; 0.02-0.04; I²=26.42%). In serous BOTs, recurrence after cystectomy was 0.29 (0.23-0.56) and after USO 0.15 (0.09-0.24). In mucinous BOTs, corresponding estimates were 0.26 (0.14-0.38) and 0.08 (0.02-0.13). Overall malignant transformation occurred in 1% of women (0.01; 0.01-0.02) but increased substantially following recurrence (0.22).

Cystectomy-based FSS is associated with significantly higher recurrence than oophorectomy-based approaches or radical surgery. Although malignant transformation is rare overall, its marked increase following recurrence highlights the need for histology-informed counselling and long-term, risk-adapted surveillance.

Oral squamous cell carcinoma (OSCC), a main histological subtype of oral cavity cancer, remains one of the most prevailing tumors worldwide with the increasing incidence and mortality. Since a high rate of early local recurrence is one of the major risk factors for poor outcome of OSCC, its prognostic biomarkers are urgently needed. Peroxiredoxin 4 (PRDX4), a member of PRDXs, which are involved in the antioxidant defense, is a unique secreted subtype of PRDXs. A certain number of previous studies have disclosed that the overexpression of the PRDX4 protein has a clear relationship with tumor initiation and progression in many cancers. Furthermore, recent studies have revealed that PRDX4 promotes tumor development through the Wnt/β-catenin signaling pathway.

To assess the status of the PRDX4/β-catenin expression and its association with clinical outcomes, including early local recurrence in OSCC, we immunohistochemically examined PRDX4 expression levels and cytoplasmic β-catenin protein accumulation levels in a total of 72 postoperative OSCC samples.

The immunohistochemically high expression of PRDX4 was significantly correlated with poorer early phase 2-year recurrence-free survival (RFS), associated closely with higher PRDX4 expression levels especially the OSCC nests of invasive fronts or perineural invasion. In addition, a multivariate Cox regression analysis revealed that PRDX4 was an independent prognostic factor for 2-year RFS. Moreover, high β-catenin accumulation is significantly associated with distant metastasis. A comparison of the combination of a high expression of PRDX4 and high β-catenin protein accumulation groups with the other groups only showed a significant predominance among men.

The increased expression of PRDX4 may be a useful independent prognostic biomarker for recurrence of OSCC, especially in the early postoperative phase.

Neuroblastoma remains a major cause of pediatric cancer mortality and although intensive multimodal treatment strategies have improved survival, they have also led to an increased risk of long-term treatment-related toxicities among survivors. This study aimed to evaluate the potential involvement of (Musashi) Msi1 in neuroblastoma oncogenesis and etoposide treatment response.

The expression of Msi1, an RNA-binding protein and stem cell marker, was examined in MYCN amplified and non-amplified cells, which were then quantified by densitometry. Immunoblotting was used to assess total protein levels in all cell lines. In addition, the impact of Msi1 silencing on etoposide sensitivity was also assessed.

The study found that increased Msi1 expression is associated with MYCN-amplification and, in a publicly available clinical database, Msi1 upregulation correlates with decreased overall survival and is seen in older patients and those with more advanced disease. Furthermore, in vitro silencing of Msi1 was associated with decreased cell proliferation and colony formation, as well as increased sensitivity to etoposide treatment. These changes correlated with altered expression of several cell cycle, proliferation, and DNA damage repair genes that are known Msi1 targets in other malignancies.

These findings indicate that Msi1 could serve as a novel therapeutic target for high-risk, treatment-refractory neuroblastoma.

Ovarian cancer is a heterogeneous disease characterized by diverse molecular, metabolic, and immunological features, which contribute to limited and inconsistent responses to immunotherapy. Recent advances in cancer metabolism have revealed that metabolic reprogramming plays a pivotal role in shaping the tumor immune microenvironment. This review aims to summarize recent progress in understanding how distinct metabolic programs in Type I and Type II ovarian cancer regulate immune escape and determine therapeutic vulnerability, with a particular focus on immunotherapy-related implications. This review is based on selective searches of the scientific literature published mainly within the past decade, using databases such as PubMed and Scopus. Relevant original and review articles addressing ovarian cancer metabolism, tumor immunology, immune checkpoint inhibition, and translational therapeutic strategies were analyzed and integrated. Type I ovarian cancer is characterized by glycolysis-dominant metabolism, frequently associated with ARID1A loss and PI3K/AKT/mTOR pathway activation, leading to nutrient competition and lactate-mediated immune suppression. However, immune infiltration is often preserved, indicating potentially reversible immune dysfunction. In contrast, Type II ovarian cancer exhibits strong dependence on lipid metabolism and adapts to adipocyte-rich metastatic niches, resulting in profound immune exclusion. Growth factor-mediated survival signaling further reinforces resistance to immune-mediated cytotoxicity. These metabolic differences critically influence responses to immune checkpoint inhibitors and provide a biological rationale for subtype-specific combination strategies. Metabolic reprogramming represents a central determinant of immune escape and immunotherapy responsiveness in ovarian cancer. Recognizing the distinct metabolic-immune landscapes of Type I and Type II tumors supports the development of precision immunotherapy strategies that integrate metabolic targeting with immune modulation. Such an approach may help overcome therapeutic resistance and improve clinical outcomes in ovarian cancer.

Nasopharyngeal carcinoma (NPC) in endemic regions remains prone to treatment failure and poor prognosis due to distant metastasis, underscoring the need for novel therapeutic strategies. Metformin exhibits anticancer activity in NPC; however, the mechanism underlying its single-agent inhibition of tumor cell viability remains incompletely defined. This study investigated the molecular basis of metformin-induced viability inhibition in NPC cells.

NPC/HK1 cells were used in this study. Cell viability was quantified using the MTT assay. Apoptosis- and autophagy-associated markers were assessed by immunoblotting. Parthanatos-related events were evaluated by measuring poly(ADP-ribose) (PAR) accumulation, mitochondrial membrane potential (MMP) disruption using JC-1 staining, and the subcellular localization of poly(ADP-ribose) polymerase 1 (PARP1) and apoptosis-inducing factor (AIF) by nuclear/cytoplasmic fractionation. Functional validation was performed using the PARP inhibitors 3-aminobenzamide (3-ABA) and DPQ.

Metformin reduced NPC/HK1 cell viability in a dose- and time-dependent manner (IC₅₀=2.5 mg/ml). Metformin did not significantly induce apoptosis or autophagy, as canonical markers were not increased. In contrast, metformin increased PAR accumulation, disrupted MMP, elevated nuclear PARP1 levels, and promoted AIF translocation, consistent with parthanatos activation. Importantly, 3-ABA and DPQ partially rescued metformin-induced loss of viability in NPC/HK1 cells.

Metformin suppresses NPC/HK1 cell viability predominantly via PARP1-mediated cell death rather than apoptosis or autophagy, highlighting the PARP1/PAR/AIF axis as a mechanistically informed therapeutic target and potential response biomarker in NPC.