Lung cancer, LUAD, and LUSC are both among the leading causes of cancer-related deaths. T cell exhaustion within the tumor microenvironment compromises the immune response and limits the benefits of immune checkpoint therapy. Adrenergic signaling primarily through ADRB1 induces T cell exhaustion and immune suppression. ADRB1 + T cells have not yet been studied regarding their role in lung cancer progression or prognosis. scRNA-seq analysis for tumor and adjacent nontumor tissues from patients with LUAD and LUSC. Dimensionality reduction and clustering with Scanpy, followed by ssGSEA for adrenergic signaling activity. CNV was processed with inferCNV, and cell-to-cell communication was inferred via CellChat. Integration with TCGA bulk RNA-seq data enables prognostic modeling of ADRB1+ T cells. Kaplan-Meier survival analysis and univariate Cox regression were used to study the signature of ADRB1 + T cells for prognostic value. scRNA-seq data confirm the presence of exhausted markers in ADRB1 + T cells. The higher proportion in LUAD tumors as compared to LUSC was linked to more pronounced immune suppression and decreased T cell diversity. CellChat predicted extensive contacts between ADRB1 + T cells and macrophages, mainly through CCL and IFN-II signaling pathways. Inferred CNV evidenced evidence of malignant cells interacting with ADRB1 + T cells. In prognostic modeling based on ADRB1 + T cell signatures, high-risk populations were characterized by very poor overall survival, and ADRB1 was an independent prognostic factor in LUAD and LUSC. This paper describes ADRB1 for the first time as a novel immune checkpoint involved in T cell exhaustion in lung cancer. Indeed, ADRB1 + T cells are promising biomarker candidates; they may even become therapeutic targets in lung cancer. Indeed, proposing a pathway by which ADRB1 may be targeted, anti-tumor immunity may be boosted and better patient prognosis secured. Thus, functional studies and clinical trials will have to be done to test and discuss this proposed concept under a new heading in therapeutic strategy.
Fenofibrate, an active pharmaceutical ingredient (API) of the fibrate class approved by the U.S. Food and Drug Administration (FDA) for the treatment of hypercholesterolemia and hyperlipidemia, has emerged as a promising candidate for repurposing in cancer. Indeed, beyond its lipid-lowering effects, fenofibrate has demonstrated antitumor properties, including antiproliferative and cytotoxic effects in normoxia (21% O2) in preclinical models of GBM. In addition, fenofibrate may inhibit hypoxia-inducible factor-1 alpha (HIF-1α) and reduce the expression of hypoxia-inducible genes, potentially overcoming hypoxia-induced chemoresistance. These findings, combined with its established clinical safety profile, support further investigation of fenofibrate as a potential therapeutic strategy in GBM. On this basis, physico-chemical characterization of fenofibrate was assessed to determine its ability to cross the blood-brain barrier. We determined in vitro on GBM cell lines U251-MG, U87-MG and GL261, the efficacy of fenofibrate in decreasing GBM cell viability and proliferation under normoxia (21% O2) and hypoxia (1% and 0.2% O2). We investigated the kinetics of its internalization by HPLC. In addition, the safety of fenofibrate was evaluated on non-tumoral brain cells. Dunn's post-hoc test was used after a significant Kruskal-Wallis. Being practically insoluble in water, fenofibrate was dissolved in dimethyl sulfoxide (DMSO) for studies. Primary astrocytes showed no signs of toxicity following treatment with fenofibrate. The effect of fenofibrate on GBM cell lines was studied at various time points and exhibited a cell type-, time- and concentration-dependent cytotoxicity with an LC50 of 25, 43.7 and 49.6 µM for U251-MG, U87-MG and GL261 cells, respectively. Interestingly, fenofibrate uptake was confirmed, 12.9 ± 5.7% and 14.2 ± 6.6% of fenofibrate was found in U251-MG and U87-MG cells, respectively. Intracellular concentrations of fenofibrate increased over time and no precipitation was observed. In hypoxia (1% and 0.2% of O2), the cytotoxic effect of fenofibrate was still present, albeit decreased. Furthermore, fenofibrate induced a cytostatic effect on U251-MG and U87-MG under both normoxia (21% O2) and hypoxia (1% and 0.2% O2), reducing their proliferation. Under the experimental conditions tested, namely in vitro studies, fenofibrate appeared more efficient compared with temozolomide, the standard treatment for GBM. This study demonstrated the cytotoxic and cytostatic effect of fenofibrate on GBM cells. These results indicate that fenofibrate may be a therapeutic alternative for GBM treatment.
Esophageal cancer is a global burden, and multiple international societies exist to address the issue in international collaboration. This study aims to analyze the characteristics of esophageal cancer and robot-assisted minimally invasive esophagectomy (RAMIE) across geographic areas. We performed a retrospective analysis of the Upper GI International Robotic Association (UGIRA) international database from January 2016 to April 2024. Forty centers worldwide that were known to perform RAMIE were involved in establishing this consortium. The patient characteristics, surgical techniques, and short-term outcomes of RAMIE were compared by each regional area (Europe, Asia, North America, and South America). A total of 3,916 RAMIE cases were registered in the UGIRA database (2,643 in Europe, 1,130 in Asia, 111 in North America, and 32 in South America). The median age was 66 years, and 80.5% of patients were male. Notably, Asia had a high prevalence of squamous cell carcinoma (91.2%) and predominant use of the McKeown approach (94.9%). BMI was lower in Asia, whereas comorbidities were more common in Western countries across all types. The use of neoadjuvant chemotherapy and radiation was lower in Asia (48.2% and 20.8 %, respectively). Postoperative complications also differed by region; pneumonia was most common in Europe and South America, cardiopulmonary complications in North America, and recurrent nerve injury in Asia. In conclusion, regional differences were observed in baseline characteristics, treatment approaches, and complication patterns in patients treated by RAMIE for esophageal cancer. Recognizing these variations is essential for fostering mutual understanding and advancing the field through international collaboration.
Cervical cancer represents one of the most common malignant tumors affecting women worldwide with unsatisfactory therapeutic outcome. CD24 is well acknowledged that could express on cancer cell and block the phagocytosis of macrophages in tumor microenvironment. However, it is unclear whether the cervical cancer derived extracellular vesicles (CC-EVs) block the phagocytosis of macrophages. CD24 expression was detected in cervical cancer tissues. The CC-EVs were isolated to treat the macrophages. Furthermore, the CD24 expression was detected in CC-EVs. Then we isolated CD24-EVs through transient transfection and CD24KO-EVs through CRISPR/Cas9, to treat the macrophages. The phagocytic ability and phenotype of macrophages were detected accordingly. Cervical cancer derived EVs could decrease the phagocytosis of macrophages. The CC-EVs expressed high level of CD24, which play the key role in blocking the phagocytosis of macrophages. The cervical cancer derived EVs express higher level of CD24, which inhibits the phagocytosis of macrophages.
Compared with cancers of other organs, precursor lesions of renal cell neoplasms are rarely discussed. However, there are specific scenarios where cysts or microscopic solid lesions are thought to precede tumor formation. In 2024, the International Society of Urological Pathology (ISUP) held a consensus meeting on precursor lesions of urologic neoplasms in Florence, Italy. This report details the findings of Working Group 3-Precursor Lesions of the Kidney. Papillary adenoma is likely the best-established precursor lesion in the kidney, thought to be an incipient form of papillary renal cell carcinoma (RCC) with shared morphology, immunohistochemistry, and genetics. Likewise, in patients with VHL disease, the kidney often contains multiple small nodules of clear cells and/or cysts lined by one or more layers of clear cells, likely representing early tumor or precursor lesions. Interestingly, a precursor counterpart for clear cell RCC in the sporadic setting is not well established. In other scenarios, cysts are considered potential precursors of neoplasia, such as those in acquired cystic kidney disease (ACKD) and possibly in some hereditary renal tumor syndromes. The consensus panel proposes the following terms "cyst with epithelial proliferation" for tufted/hyperplastic/cribriform cyst lining in ACKD without solid tumor, and "papillary hyperplasia" for tufting of cyst lining in autosomal dominant polycystic kidney. Terms such as "tumorlet," "microtumor," or "incipient tumor" are acceptable for incidental unencapsulated microscopic lesions in hereditary syndrome patients. There is insufficient evidence for the diagnosis of "tubular dysplasia" as a precursor to RCC at the present time.
Lung cancer resection is curative but associated with postoperative morbidity and mortality. This study evaluated whether elevated blood eosinophil count (BEC) was associated with postoperative outcomes in early-stage lung cancer. This was a retrospective cohort study of consecutive adult patients undergoing lung resection for stage I and II non-small cell lung cancer in a large tertiary referral center from September 2017 to June 2021. Data were drawn from the institution's Data Warehouse. The primary outcome was 90-day healthcare utilization defined as emergency department visit or hospital readmission. Secondary outcomes were postoperative complications, index hospitalization length of stay, and 1-year survival. Preoperative 90-day BEC was categorized by a threshold of 200 cells/µL. Covariates were age, sex, smoking status, Charlson Comorbidity Index, chronic obstructive pulmonary disease (COPD), asthma, tumor size, nodal status, surgical approach, and blood results (white blood cells, hemoglobin, and creatinine). The main analyses were validated by a second international cohort. Log-Poisson with robust variance estimation and Cox proportional hazards regression models were fit for primary and secondary outcomes. Analyses were replicated for BEC thresholds of 150 and 300 cells/µL. Among 715 patients undergoing lung resection (median age = 69 years, 42% male, 29% with COPD), 146 patients (20%) had high preoperative BEC ≥ 200 cells/µL. BEC ≥ 200 cells/µL was associated with a higher rate of 90-day healthcare utilization:19% vs. 14% for BEC < 200 cells/µL. This association remained after adjustment (Risk Ratio [RR], 1.52; 95% Confidence Interval [CI], 1.02-2.25) and the validation cohort (RR, 2.23; 95% CI, 1.06-4.69). BEC as a continuous measure was also associated with the primary outcome in both cohorts: RR, 2.15 (95% CI, 1.49-3.12) and RR, 1.42 (95% CI, 1.10-1.94), respectively. BEC ≥ 200 cells/µL was associated with higher probability of death 1 year post-surgery (adjusted Hazard Ratio, 2.41; 95% CI, 1.08-5.35). There was no difference in the risk of postoperative pulmonary complications between high and low BEC (RR, 0.86; 95% CI, 0.58-1.27). Elevated preoperative BEC was associated with higher risk of postoperative healthcare utilization and lower 1-year survival after lung cancer resection among patients with or without respiratory disease.
Computed Tomography (CT) scans allow opportunistic evaluation of body composition. We investigated whether body composition and change through time are associated with lung cancer incidence and all-cause/lung cancer-specific mortality in a lung cancer screening cohort. A machine learning segmentation method was used in this retrospective cohort study to measure skeletal muscle area and density, and subcutaneous adipose tissue area (SAT) on repeated chest CTs from the Dutch-Belgian lung cancer screening trial. Hazard ratios by sex adjusted for age, smoking status, and smoking pack-years (aHR) were calculated for each outcome. During median follow-up of 12.2 (interquartile range, 1.2) years, 4.1% of 6187 subjects (85.5% male, mean age ± SD, 58.6 ± 5.5 years, smoking pack-years 41.2 ± 18.3) developed lung cancer, 12.2% died, and 2.1% died due to lung cancer. For males, SAT loss was associated with lung cancer incidence (aHR 1.19, 95% CI 1.02-1.39) and lung cancer-specific mortality (aHR 1.26, 95% CI 1.03-1.55), and less baseline muscle and muscle loss with all-cause mortality (aHR 1.20, 95% CI 1.10-1.31 and 1.17, 1.07-1.27). For females, less baseline SAT and SAT loss was associated with all-cause mortality (aHR 1.44, 95% CI 1.06-1.97 and 1.48, 1.13-1.94) and lung cancer-specific mortality (aHR 2.85, 95% CI 1.50-5.39 and aHR 1.96, 1.11-3.44). Models improved by including body composition trends for all-cause mortality (males: p < 0.001; females: p = 0.012) and for lung cancer-specific mortality (males: p = 0.102; females: p = 0.005). Body composition trends based on automated analysis of chest CT are associated with worse outcomes in participants screened for lung cancer. Dutch Cancer Society, Health Holland, Siemens Healthineers.
Chicoric acid (CA), a bioactive natural compound found in Chicory and Echinacea purpurea, exhibits antiinflammatory, antioxidant, and apoptosis-inducing properties. However, its therapeutic potential and underlying mechanisms in non-small cell lung cancer (NSCLC) remain unclear. We utilized bioinformatics analysis to identify potential hub genes targeted by CA. The clinical relevance of glycogen phosphorylase liver form (PYGL) was assessed via immunohistochemistry in NSCLC tissues. Functional assays, including Cell Counting Kit-8, flow cytometry, and xenograft models, were employed to evaluate the impact of PYGL on tumor growth. Glycogen metabolism and glycolytic flux were monitored using PAS staining and Seahorse assays. Direct binding between CA and PYGL was confirmed through virtual screening, molecular docking, cellular thermal shift assay, and surface plasmon resonance. Binding specificity was further validated using site-directed mutagenesis. Here, we demonstrate that CA restores glucose metabolic homeostasis and inhibits the proliferation of NSCLC cells. We identified PYGL as a key driver of NSCLC, where its upregulation enhances glycogenolysis to fuel glycolytic flux and promote tumor growth. Mechanistically, CA allosterically inhibits PYGL by binding to specific residues (Glu162, Arg247, Glu273) and inducing conformational changes, thereby suppressing glycogenolysis and reducing glycolysis. Furthermore, CA disrupts the interaction between PYGL and lactate dehydrogenase A (LDHA), accelerating the proteasomal degradation of LDHA and further reshaping glucose metabolic homeostasis. Our findings highlight PYGL as a metabolic vulnerability in NSCLC and establish CA as a promising lead compound that targets the PYGL-LDHA axis to reprogram glucose metabolism and inhibit tumor growth.
The therapeutic efficacy of cancer vaccines is critically contingent upon CD8+ T cell-mediated antitumor immunity, but the effectiveness is hindered due to insufficient T cell activation. Inspired by the close interplay between cellular physiological states and immunoregulatory functions, we propose ASCENT, a nanovaccine platform integrating nanovesicles derived from activated platelets and senescent tumor cells to naturally co-present antigens and co-stimulatory molecules, thereby enabling dual-pathway T cell activation. Specifically, senescent tumor cells promote antigen presentation via upregulated major histocompatibility complex-I (MHC-I) molecules, whereas activated platelets increase the surface expression of CD40L and OX40L, thereby enhancing immune activation. Thus, without genetic or chemical engineering, ASCENT can effectively stimulate CD8+ T cells through both antigen self-presentation and dendritic cell-mediated antigen presentation, ultimately eliciting robust immune responses. This non-engineered, physiologically modulated nanovaccine exhibits broad-spectrum antitumor activity while simultaneously inducing durable systemic immune memory to effectively suppress tumor recurrence and metastasis. Overall, the ASCENT nanovaccine provides new perspectives on rational vaccine design, emphasizing the importance of engaging both direct and indirect T cell activation in reinforcing cancer immunotherapy.
Paraptosis represents a mode of cell death, which is separate from classical apoptosis. Classical apoptotic pathways are caspase-dependent, accompanied by cell shrinkage, chromatin condensation, and apoptotic body formation. In contrast, paraptosis is characterized by cytoplasmic vacuolization without typical apoptotic nuclear alterations, and its signaling operates independently of the caspase enzyme system. Unlike apoptosis, paraptosis primarily depends on the mitogen-activated protein kinase (MAPK) signaling pathway for its mediation, highlighting its unique regulatory framework separate from classical apoptotic pathways. Since it does not overlap with apoptotic resistance mechanisms, inducing paraptosis holds great potential to overcome resistance to conventional chemotherapy and radiotherapy. Therefore, inducing paraptosis in cancer cells has crucial potential value for current cancer treatment. This article thoroughly explores the regulatory mechanisms of paraptosis and synthesizes its dual functions in the progression of cancer cells. Additionally, we discuss in detail cancer treatment strategies based on targeting paraptosis and analyze the feasibility and potential advantages of combining paraptosis with other cell death forms and various therapeutic methods to enhance cancer treatment efficacy.
Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous malignancy with poor prognosis and limited predictive biomarkers for therapy response. Characterizing malignant cell heterogeneity may improve prognostic and therapeutic stratification. We integrated single-cell RNA sequencing (scRNA-seq) data from 58 HNSCC patients (181,003 cells) to define malignant cell subpopulations, their differentiation states, developmental trajectories, cell-cell interactions, and spatial localization. Coexpression gene modules and meta-programs were identified using hdWGCNA and NMF. These programs were projected onto bulk RNA-seq datasets to classify HNSCC subtypes and examine associations with clinical outcomes, tumor microenvironment (TME), genomic instability, and predicted response to immune checkpoint inhibitors (ICIs). Twelve malignant clusters were identified with distinct clinical and molecular features. MC-5 exhibited a stem-like phenotype associated with poor prognosis, while MC-7 and MC-11 showed high TME communication and immune engagement. Coexpression analysis revealed 16 modules and eight meta-programs encompassing proliferation, differentiation, stress response, and immune activity. Translation to bulk RNA-seq defined three HNSCC subtypes (MS-1, MS-2, MS-3) with divergent survival, immune infiltration, stromal composition, and genomic features. MS-2, an immune-enriched subtype, demonstrated superior survival, high HPV positivity, and predicted ICI responsiveness. A 25-gene malignant cell score (MCScore) robustly predicted both prognosis and immunotherapy response. This study provides a comprehensive map of malignant cell heterogeneity in HNSCC, identifies key functional expression programs, and defines molecular subtypes with clinical and therapeutic relevance. Malignant cell-specific signatures, such as MCScore, offer promising tools for patient stratification and precision immunotherapy.
Artesunate (ART) is one of the semi-synthetic derivatives of artemisinin. It is currently mainly used in the clinic for the rescue of cerebral malaria and various critical malaria. Recent studies have shown that it has a wide range of anti-tumor effects. However, its treatment for hepatocellular carcinoma (HCC) and its specific mechanism remain unclear. This study aims to investigate ART therapeutic effects on HCC and elucidate its molecular mechanisms. This study explored the inhibitory effect of ART on HCC through in vivo and in vitro experiments. Cellular experiments evaluated the effects of ART on HCC cell lines (HepG2, H22, Hepa1-6) using CCK-8, Annexin/PI staining, wound healing, and Immunofluorescence. In vivo, ART was tested in HepG2 xenografts and H-ras12V transgenic mice, with tumor growth monitored by Doppler ultrasound. Multi-omics (transcriptomics, network pharmacology, single-cell sequencing) identified MMP9 as a key target. Mechanisms were explored via molecular docking/dynamics, thermal shift assays, and Western blot analysis. Flow cytometry and immunofluorescence confirm CD8 + T cell infiltration. ART inhibited the proliferation of HCC cell lines and promoted its apoptosis. In vivo experiments showed that it had a certain inhibitory effect on the development of immune-deficient mice transplanted tumors. Continuous monitoring of tumor growth by Doppler ultrasound found that its effect was more obvious in the immune-competent spontaneous H-ras12V mouse model of liver cancer, especially for the development of small tumors. Mechanistically, ART can inhibit tumor growth by inhibiting the classic PI3K-AKT signaling pathway, which is consistent with the results in other tumor studies. At the same time, ART can directly target MMP9 and promote its degradation, thereby inhibiting tumor's angiogenesis. To explain why its effect was more pronounced in immune-competent mice, we found ART can significantly increase the tumor infiltration of CD8 + T cells and its effect is also achieved by degrading MMP9. Our findings reveal that ART inhibits HCC tumorigenesis and progression by targeting MMP9 to suppress angiogenesis and enhance CD8+ T cell infiltration. This study provides a mechanistic basis for the potential clinical application of ART in HCC therapy and identifies MMP9 as a promising therapeutic target.
Programmed cell death 1 ligand 1/programmed cell death protein 1 inhibitors, with or without chemotherapy, are standard first-line treatment for patients with advanced non-small cell lung cancer (NSCLC); however, survival benefit is limited, and many patients experience disease progression. To evaluate the efficacy and safety of tiragolumab plus atezolizumab plus chemotherapy vs placebo plus pembrolizumab plus chemotherapy in patients with advanced nonsquamous NSCLC. SKYSCRAPER-06 was a phase 3 randomized clinical trial that recruited patients with previously untreated, locally advanced unresectable or metastatic NSCLC at 129 sites in 21 countries between December 15, 2020, and September 14, 2023 (data cutoff, April 19, 2024). Patients were randomized 1:1 to receive either tiragolumab, 600 mg, plus atezolizumab, 1200 mg, plus chemotherapy (pemetrexed, 500 mg/m2, and carboplatin [area under the curve 5], or cisplatin, 75 mg/m2) or placebo plus pembrolizumab, 200 mg, plus chemotherapy via intravenous infusion on day 1 of each 21-day cycle until disease progression, loss of clinical benefit, unacceptable toxic effect, or withdrawal of consent. Primary end points were investigator-assessed progression-free survival and overall survival. The safety and tolerability of the study drugs were also evaluated. Of 542 patients in the full analysis set (mean [SD] age, 63.6 [9.3] years; 353 [65.1%] male), 269 were randomized to tiragolumab plus atezolizumab plus chemotherapy and 273 to placebo plus pembrolizumab plus chemotherapy. Overall, baseline demographics were similar between treatment groups. At data cutoff (median follow-up, 11.8 months), median investigator-assessed progression-free survival was 8.3 months (95% CI, 7.1-9.6 months) with tiragolumab plus atezolizumab plus chemotherapy vs 9.9 months (95% CI, 8.7-11.9 months) with placebo plus pembrolizumab plus chemotherapy (hazard ratio, 1.27; 95% CI, 1.02-1.57; P = .99); median overall survival was 18.9 months (95% CI, 15.2-23.8 months) vs 23.1 months (95% CI, 20.7-33.0 months) in each treatment group, respectively (hazard ratio, 1.33; 95% CI, 1.02-1.73; P = .98). Grade 3 to 4 adverse events occurred in 164 of 267 patients (61.4%) in the tiragolumab plus atezolizumab plus chemotherapy group and 165 of 272 patients (60.7%) in the placebo plus pembrolizumab plus chemotherapy group, with grade 5 AEs occurring in 27 of 267 patients (10.1%) and 16 of 272 patients (5.9%) in each group, respectively. In the phase 3 SKYSCRAPER-06 randomized clinical trial, the primary end points were not met and the study has been terminated. ClinicalTrials.gov Identifier: NCT04619797.
Bromodomain and extraterminal motif (BET) inhibitors, such as JQ1, are promising cancer therapeutics that target epigenetic regulators, particularly BRD4. However, resistance to BET inhibitors (BETi) limits their clinical utility, necessitating a better understanding of adaptive mechanisms. We identified BRD2 upregulation as a conserved response to BET inhibition across multiple cancer types and hypothesized that BRD2 compensates for BRD4 loss, sustaining essential transcriptional programs upon treatment. Consistent with this, BRD2 knockdown sensitized cancer cells to BETi in vitro, and combining BRD2 depletion and JQ1 treatment significantly impaired tumor growth in vivo. At the chromatin level, BRD2 and BRD4 ChIP-seq analysis of pancreatic cancer cells showed consistent BRD4 loss from chromatin after JQ1 treatment, while BRD2 displacement differed by sensitivity. Resistant cells maintained higher BRD2 occupancy than sensitive cells, suggesting a link between BRD2 retention and drug response. Mechanistically, NFYA mediates BRD2 upregulation as NFYA depletion attenuated BRD2 upregulation upon BETi treatment. Collectively, our findings establish BRD2 as a critical mediator of pan-cancer adaptive resistance to BETi and identify NFYA as a novel transcriptional regulator of this process. Co-targeting BRD2 or its regulatory network offers a rational strategy to enhance the durability and efficacy of BET-based therapies.
Ferroptosis is an iron-dependent form of regulated cell death characterized by excessive lipid peroxidation. Molecules like GPX4, ACSL4, and SLC7A11 form the core regulatory network. GPX4 inhibits lipid peroxide accumulation, ACSL4 promotes ferroptosis through lipid metabolism remodeling, and SLC7A11 confers resistance to ferroptosis by maintaining redox homeostasis. Ferroptosis has a dual role in cancer: inducing it eliminates cancer cells, while its evasion enhances drug resistance and metastasis. Targeting ferroptosis represents an emerging investigational direction for anticancer therapeutic development, with single-target agents, combination regimens, and nanocarrier-based delivery systems exhibiting preliminary tumor-suppressive signals across diverse preclinical model systems. Despite extensive research, existing reviews lack systematic integration of ferroptosis-tumor microenvironment (TME) crosstalk, comparative analysis of cancer type-specific ferroptosis sensitivity, and critical evaluation of recent clinical progress. This review addresses these gaps by synthesizing molecular mechanisms, cancer-specific roles, TME interactions, and therapeutic applications, along with a critical assessment of clinical translation barriers, providing a framework for ferroptosis-targeted cancer therapy.
Current risk stratification for non-clear cell renal cell carcinoma (nccRCC) is largely derived from clear cell RCC (ccRCC) data. We evaluated recurrence patterns following surgery for nccRCC and compared the prognostic performances of various international guidelines. We retrospectively analyzed patients with surgically managed nonmetastatic nccRCC (2003-2015). Patients were stratified by American Urological Association (AUA), European Association of Urology (EAU), and National Comprehensive Cancer Network (NCCN) risk groups. Model performance was assessed via C-index, integrated Brier score (IBS), and calibration plots. Optimal surveillance duration was defined as the time required to capture 95% of recurrences and the time until the 10-yr conditional recurrence risk fell below 5%, accounting for non-RCC deaths as a competing risk. Papillary RCC (pRCC) was the most common subtype (420/712, 59%). Median follow-up was 11.6 yr (IQR: 133-148 mo). Recurrences occurred in 116 patients, most frequently in the abdomen (44/116, 38%). The 5-yr recurrence-free survival (RFS) was 86% (95% confidence interval [CI]: 83-89). Chromophobe RCC (chRCC) had the lowest stage-adjusted subdistribution hazard of recurrence (sHR) (sHR: 0.21, 95% CI: 0.12-0.40). AUA risk-stratification schema provided higher discrimination and lower prediction error (C-index 0.69, IBS 0.104) compared with that of EAU (C-index 0.67, IBS 0.118) and NCCN (C-index 0.66, IBS 0.115). Late recurrences (>5 yr) were common, comprising 27% of all observed recurrences. As a single-center, retrospective study, these findings may not be broadly generalizable. Surveillance duration metrics should be interpreted with caution. Outcomes in this predominantly pRCC and chRCC cohort challenge the current nccRCC surveillance guidelines: abdominal recurrences were the most common, supporting continued cross-sectional imaging. Late recurrences (>5 yr) argue against stopping surveillance at 5 yr and highlight the need for improved risk-adapted surveillance schedules. Current national guidelines for postsurgery follow-up for kidney cancer are based on its most common type. However, their appropriateness for less common forms remains unknown. This study shows that the less common form, non-clear cell renal cell carcinoma, primarily comes back after surgery in the abdomen and can often come back more than 5 yr postoperatively. Therefore, doctors should monitor these patients for a longer duration and focus on abdominal imaging to enable earlier detection. Advancing practice.
Ferroptosis, an iron-dependent form of programmed cell death driven by lipid peroxidation, represents a new potential therapeutic target in cancer. However, emerging evidence indicates that hepatocellular carcinoma (HCC) frequently exhibits resistance to ferroptosis induction, while the underlying molecular mechanism is poorly understood. Here, we found that aldo-keto reductase family 1 member C3 (AKR1C3), a protein highly expressed in ferroptosis-resistant HCC cells, negatively regulates ferroptosis in an enzyme-independent manner. Mechanistically, AKR1C3 promotes ubiquitin-proteasomal degradation of the transferrin receptor (TFRC), which is indispensable for cellular iron uptake. AKR1C3 knockdown restores TFRC expression, increases the level of labile iron pool, and sensitizes HCC cells to ferroptosis. Furthermore, AKR1C3 acts as a scaffolding protein to promote the degradation of TFRC and reduce iron uptake by promoting nuclear export of Beta-transducin repeats-containing proteins (β-TrCP) and its binding to TFRC. Notably, AKR1C3 is upregulated in NRF2-driven sorafenib-resistant HCC, and its inhibition reversed ferroptosis and sorafenib resistance. Our work uncovers AKR1C3 suppresses ferroptosis in HCC by promoting β-TrCP-mediated TFRC degradation, positioning AKR1C3 as a promising therapeutic target to enhance ferroptosis-based anticancer strategies.
Protein evidence derived from mass spectrometry (MS) across cancer cohorts and model systems is extensive but remains fragmented across individual studies and repositories, limiting rapid retrieval and evidence-based benchmarking of cancer-context protein detection. Here we present the Mass Spectrometric Detected Cancer Proteins (MSCP) resource, an integrated database assembled from 27 large-scale cancer proteomics sources spanning human tumor cohorts, cancer cell lines, and patient-derived xenograft (PDX) models. Protein identifications were harmonized to UniProtKB-Swiss-Prot (release 2025_01) and integrated under FDR-controlled identification outputs to generate a unified catalog of 15,964 MS-supported human proteins. Benchmarking against neXtProt PE1 identified 525 proteins newly supported by MS evidence in the integrated cancer context, including proteins previously associated with chromosome-level evidence inconsistencies. Functional interpretation of the newly identified set using GO and Reactome enrichment highlighted immune- and barrier-associated processes and chromatin- and genome-regulatory pathways, including DNA methylation and histone deacetylation. Orthogonal verification using synthetic unique peptides confirmed representative newly identified proteins by concordant precursor m/z and fragment-ion patterns. MSCP provides a provenance-aware, UniProtKB-aligned resource for cancer proteomics that supports both cohort- and model-specific querying and coverage-oriented evidence aggregation, enabling standardized comparisons to reference proteomes and facilitating downstream assay planning and translational studies.
Extragonadal germ cell tumors are rare and have a poorer prognosis compared to testicular germ cell tumors. Although the therapeutic options are similar to those for advanced testicular germ cell tumors, there is uncertainty regarding the efficacy of first-line treatment and effective therapeutic options for second-line treatment or beyond due to the limited cases treated. We retrospectively studied 25 cases of extragonadal germ cell tumorstreated between April 1999 and March 2020. Prognosis was poor in cases that progressed to tertiary treatment, had nonseminomatous tumors, or were categorized as having a poor prognosis according to the International Germ Cell Classification. The findings of this case series indicate that achieving complete remission by up to second-line treatment through multidisciplinary treatment, including surgical resection, is important to avoid cancer mortality.
Single-fraction stereotactic ablative radiotherapy (SABR) is a curative treatment option for patients with early lung cancer. We undertook a feasibility study to assess whether simulation, planning and treatment could be undertaken within a single day and whether this expedited pathway was acceptable to patients. A multidisciplinary team of radiation oncologists, radiation therapists and medical physicists developed a workflow to permit all aspects of planning and treatment to be conducted within a single working day. All aspects of the pathway were timed. Prescription dose was 30 Gray. Patients completed an Experience Survey within two weeks of treatment. The study would be deemed successful if it met both dual primary endpoints of feasibility (7/10 patients treated within 8 working hours) and patient satisfaction (7/10 expressing overall satisfaction). Ten patients were treated. These included 6 women and 4 men. Median age was 76.5 and 9 patients had been deemed to be medically inoperable. Median time from commencement of CT simulation to end of treatment was 6 h 50 min (IQR 6 h 42 m - 7 h 4 m); 9/10 patients were treated within the target 8-hour window. All 10 patients expressed overall satisfaction with the service. All 10 felt it was more convenient than our usual treatment pathway would have been. Same-day single-fraction SABR is feasible and acceptable to patients. This pathway should be considered for those who live a significant distance from treatment centres or who have other difficulties in attending for multiple visits.