Previous
Aim:
Intravesical Bacillus Calmette–Guérin (BCG) is the standard therapy for non-muscle invasive bladder cancer (NMIBC); however, many patients experience recurrence or progression. We examined how urinary immune signals and the urinary microbiome change across BCG and are related to outcomes.
Methods:
In this single-center prospective cohort study, adults with NMIBC underwent transurethral resection of bladder tumor (TURBT), followed by BCG induction. Urine was collected before TURBT, before BCG, after BCG induction, and three months later. Urine sediment mRNA (PD-L1, PD-L2, CD33, and CD204) was quantified using TaqMan ΔCt. The urinary microbiome was profiled using 16S rRNA gene sequencing, and diversity, composition, and taxon balance were evaluated using nonparametric tests, PERMANOVA, repeated-measures correlations, and mixed-effects models. We analyzed the relationship between the urinary microbiome and prognosis.
Results:
Twenty-three patients were analyzed; ten recurrences, eight progressions, and three deaths were observed. Relative to baseline, CD33 increased after BCG and after three months; PD-L2 increased immediately after BCG and returned to baseline by three months; PD-L1 and CD204 increased after BCG. Shannon alpha-diversity was unchanged, but total read count was higher at three months, with stable beta-diversity and dispersion. Higher PD-L1 expression was associated with lower Actinobacteria abundance in the bladder cancer microenvironment. A higher post-BCG Firmicutes/Bacteroidetes ratio was associated with worse prognosis, with the clearest signal for progression-free survival (PFS) observed in the univariate Cox models. Higher post-BCG Corynebacterium and Enterobacteriaceae abundance was associated with better PFS.
Conclusions:
BCG was associated with higher urinary PD-L1/PD-L2 and myeloid marker transcripts, while overall community structure remained stable. These exploratory data support that pre-BCG microbial features may be related to early response, and post-BCG profiles may reflect durability and survival. Urine immune-microbiome profiling could be a feasible, noninvasive adjunct for monitoring and risk stratification in NMIBC.
Aim:
Intravesical Bacillus Calmette–Guérin (BCG) is the standard therapy for non-muscle invasive bladder cancer (NMIBC); however, many patients experience recurrence or progression. We examined how urinary immune signals and the urinary microbiome change across BCG and are related to outcomes.
Methods:
In this single-center prospective cohort study, adults with NMIBC underwent transurethral resection of bladder tumor (TURBT), followed by BCG induction. Urine was collected before TURBT, before BCG, after BCG induction, and three months later. Urine sediment mRNA (PD-L1, PD-L2, CD33, and CD204) was quantified using TaqMan ΔCt. The urinary microbiome was profiled using 16S rRNA gene sequencing, and diversity, composition, and taxon balance were evaluated using nonparametric tests, PERMANOVA, repeated-measures correlations, and mixed-effects models. We analyzed the relationship between the urinary microbiome and prognosis.
Results:
Twenty-three patients were analyzed; ten recurrences, eight progressions, and three deaths were observed. Relative to baseline, CD33 increased after BCG and after three months; PD-L2 increased immediately after BCG and returned to baseline by three months; PD-L1 and CD204 increased after BCG. Shannon alpha-diversity was unchanged, but total read count was higher at three months, with stable beta-diversity and dispersion. Higher PD-L1 expression was associated with lower Actinobacteria abundance in the bladder cancer microenvironment. A higher post-BCG Firmicutes/Bacteroidetes ratio was associated with worse prognosis, with the clearest signal for progression-free survival (PFS) observed in the univariate Cox models. Higher post-BCG Corynebacterium and Enterobacteriaceae abundance was associated with better PFS.
Conclusions:
BCG was associated with higher urinary PD-L1/PD-L2 and myeloid marker transcripts, while overall community structure remained stable. These exploratory data support that pre-BCG microbial features may be related to early response, and post-BCG profiles may reflect durability and survival. Urine immune-microbiome profiling could be a feasible, noninvasive adjunct for monitoring and risk stratification in NMIBC.
DOI: https://doi.org/10.37349/etat.2026.1002365
Aim:
Glioblastoma (GBM), a rare, highly aggressive and chemoresistant brain cancer, exhibits profound metabolic plasticity that relies, in part, on aberrant transforming growth factor-β (TGF-β) signaling. Such plasticity was recently associated with TGF-β-regulated apoptosis and autophagy. Here, we questioned whether TGF-β-regulated apoptotic/autophagic phenotypes are recapitulated in a preclinical in vitro 3D spheroid culture model of human U87 GBM-derived cells, and how metabolic alterations affect such phenotypes.
Methods:
3D U87 spheroids were cultured using the hanging drop method. Western blotting was used to assess protein expression, while RT-qPCR was used to assess gene expression levels.
Results:
3D spheroids exhibited decreased AKT phosphorylation, and increased TGF-β, fibronectin, and Smad2 phosphorylation, indicative of both cell death signaling and epithelial-mesenchymal transition molecular signatures. 2-Deoxy-D-glucose (2DG), a glycolytic inhibitor, depleted ATP dose-dependently (30–300 μM) and prevented those increases both at the protein and transcriptional levels. This was also observed in 3D spheroids upon TGF-β transient siRNA-mediated silencing or when TGF-βR1 kinase activity was inhibited by galunisertib. Transcriptomic profiling revealed shared upregulation of apoptosis-related (BCL2, CASP7, FAS, FASLG, GADD45A) and autophagy-related (ATG7, ATG16L1, IRGM, PIK3C3, ULK1) genes in response to TGF-β or upon 3D spheroid formation. 2DG, transient silencing of TGF-β, or galunisertib treatment prevented these increases.
Conclusions:
3D spheroids require ATP and a TGF-β/TGF-βR1 autocrine signaling axis to recapitulate the apoptosis/autophagy phenotypes. Combining glycolysis inhibition with TGF-β signaling inhibition could offer a promising therapeutic strategy for this rare and lethal brain cancer.
Aim:
Glioblastoma (GBM), a rare, highly aggressive and chemoresistant brain cancer, exhibits profound metabolic plasticity that relies, in part, on aberrant transforming growth factor-β (TGF-β) signaling. Such plasticity was recently associated with TGF-β-regulated apoptosis and autophagy. Here, we questioned whether TGF-β-regulated apoptotic/autophagic phenotypes are recapitulated in a preclinical in vitro 3D spheroid culture model of human U87 GBM-derived cells, and how metabolic alterations affect such phenotypes.
Methods:
3D U87 spheroids were cultured using the hanging drop method. Western blotting was used to assess protein expression, while RT-qPCR was used to assess gene expression levels.
Results:
3D spheroids exhibited decreased AKT phosphorylation, and increased TGF-β, fibronectin, and Smad2 phosphorylation, indicative of both cell death signaling and epithelial-mesenchymal transition molecular signatures. 2-Deoxy-D-glucose (2DG), a glycolytic inhibitor, depleted ATP dose-dependently (30–300 μM) and prevented those increases both at the protein and transcriptional levels. This was also observed in 3D spheroids upon TGF-β transient siRNA-mediated silencing or when TGF-βR1 kinase activity was inhibited by galunisertib. Transcriptomic profiling revealed shared upregulation of apoptosis-related (BCL2, CASP7, FAS, FASLG, GADD45A) and autophagy-related (ATG7, ATG16L1, IRGM, PIK3C3, ULK1) genes in response to TGF-β or upon 3D spheroid formation. 2DG, transient silencing of TGF-β, or galunisertib treatment prevented these increases.
Conclusions:
3D spheroids require ATP and a TGF-β/TGF-βR1 autocrine signaling axis to recapitulate the apoptosis/autophagy phenotypes. Combining glycolysis inhibition with TGF-β signaling inhibition could offer a promising therapeutic strategy for this rare and lethal brain cancer.
DOI: https://doi.org/10.37349/etat.2026.1002364
This article belongs to the special issue Novel Precision Medicine Approaches to Brain Tumors (Primary and Metastatic)
Aim:
Chromodomain-helicase-DNA-binding protein 4 (CHD4) is a core NURD remodeling complex ATPase that plays a crucial role as a gene repressor. Its overexpression has been reported in several cancers. In papillary thyroid carcinomas (PTCs), CHD4 is overexpressed and associated with aggressive features of the tumor, such as proliferation, migration, and epithelial-mesenchymal transition (EMT). We previously showed in PTCs that NADPH oxidase NOX4 expression is positively regulated by BRAFV600E mutation, which is the most aggressive alteration in PTCs. In this retrospective study, we wondered whether there is a link between CHD4 and NOX4 protein expression in malignant thyroid tissues.
Methods:
We explored CHD4 protein expression by immunostaining analysis in 86 human thyroid tissues: 44 thyroid tumor tissues [28 classical forms of PTCs (C-PTCs), 13 follicular variants of PTCs (F-PTCs), and three anaplastic thyroid carcinomas (ATCs)] and 42 of their normal adjacent tissues (NATs). The detection of BRAFV600E mutation was performed using Sanger sequencing and digital droplet PCR. Statistical analyses were conducted using GraphPad Prism 8 software. Various tests were used to assess the statistical relevance of different correlations, such as the chi-square test, Fisher’s exact test, and the Pearson correlation coefficient. A p-value of less than 0.05 indicates statistical significance.
Results:
The CHD4 protein expression analysis with already published data from our group (BRAFV600E status and NOX4 expression) reveals a highly significant level of CHD4 protein expression in C-PTCs compared to F-PTCs and ATC. Importantly, 70% of C-PTCs-BRAFV600E overexpress CHD4 at the protein level, confirming the positive correlation between the CHD4 expression and BRAFV600E mutation. Furthermore, a high level of CHD4 is associated with the presence of capsular breach and vascular emboli, affirming the involvement of CHD4 in thyroid tumor aggressiveness. Interestingly, we showed for the first time, to our knowledge, a positive correlation between CHD4 and NOX4 protein expression in malignant thyroid tissues.
Conclusions:
The results of this study suggest that CHD4 could be used as a complementary molecular marker to improve the diagnosis and the management of PTCs-BRAFV600E.
Aim:
Chromodomain-helicase-DNA-binding protein 4 (CHD4) is a core NURD remodeling complex ATPase that plays a crucial role as a gene repressor. Its overexpression has been reported in several cancers. In papillary thyroid carcinomas (PTCs), CHD4 is overexpressed and associated with aggressive features of the tumor, such as proliferation, migration, and epithelial-mesenchymal transition (EMT). We previously showed in PTCs that NADPH oxidase NOX4 expression is positively regulated by BRAFV600E mutation, which is the most aggressive alteration in PTCs. In this retrospective study, we wondered whether there is a link between CHD4 and NOX4 protein expression in malignant thyroid tissues.
Methods:
We explored CHD4 protein expression by immunostaining analysis in 86 human thyroid tissues: 44 thyroid tumor tissues [28 classical forms of PTCs (C-PTCs), 13 follicular variants of PTCs (F-PTCs), and three anaplastic thyroid carcinomas (ATCs)] and 42 of their normal adjacent tissues (NATs). The detection of BRAFV600E mutation was performed using Sanger sequencing and digital droplet PCR. Statistical analyses were conducted using GraphPad Prism 8 software. Various tests were used to assess the statistical relevance of different correlations, such as the chi-square test, Fisher’s exact test, and the Pearson correlation coefficient. A p-value of less than 0.05 indicates statistical significance.
Results:
The CHD4 protein expression analysis with already published data from our group (BRAFV600E status and NOX4 expression) reveals a highly significant level of CHD4 protein expression in C-PTCs compared to F-PTCs and ATC. Importantly, 70% of C-PTCs-BRAFV600E overexpress CHD4 at the protein level, confirming the positive correlation between the CHD4 expression and BRAFV600E mutation. Furthermore, a high level of CHD4 is associated with the presence of capsular breach and vascular emboli, affirming the involvement of CHD4 in thyroid tumor aggressiveness. Interestingly, we showed for the first time, to our knowledge, a positive correlation between CHD4 and NOX4 protein expression in malignant thyroid tissues.
Conclusions:
The results of this study suggest that CHD4 could be used as a complementary molecular marker to improve the diagnosis and the management of PTCs-BRAFV600E.
DOI: https://doi.org/10.37349/etat.2026.1002363
Aim:
Triple-negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options and poor survival outcomes. Prognostic models developed in Western cohorts rarely assess algorithmic fairness. This study aimed to develop and internally validate a clinically interpretable Cox survival model for TNBC using baseline diagnostic variables and to evaluate its fairness according to ISO/IEC TR 24027:2021 guidelines in a Middle East and North Africa (MENA) cohort.
Methods:
A total of 138 TNBC patients were included after merging two institutional datasets and removing variables with > 25% missingness. Baseline features comprised age, tumor size, lymph node involvement, tumor grade, Ki-67, type of surgery, metastasis at diagnosis, chemotherapy, and radiotherapy. A Cox proportional hazards (CoxPH) model with six clinically established predictors was fitted to reduce overfitting. Model performance was assessed through five-fold stratified cross-validation using Harrell’s concordance index (C-index), receiver operating characteristic area under the curve (AUROC), and calibration curves. Fairness was evaluated using demographic parity, equality of opportunity, predictive equality, and equalized odds metrics following ISO/IEC TR 24027:2021.
Results:
During follow-up, 34 patients (24.6%) died. Metastasis at diagnosis, high tumor grade, and radical mastectomy were significantly associated with mortality. The CoxPH model achieved a C-index of 0.80 [SE = 0.04; 95% confidence interval (CI): 0.72–0.87] and an AUROC of 0.81 (95% CI: 0.72–0.90). Calibration plots showed strong agreement between predicted and observed survival probabilities, with a modest overall bias of –8.8%. Fairness assessment revealed small but notable disparities in false-positive rates across age groups and surgical categories, while lymph node status and other variables showed no significant bias.
Conclusions:
This study presents a robust and fairness-aware survival prediction model for TNBC using routinely available clinical features. The model demonstrates strong discrimination, good calibration, and quantifiable fairness across patient subgroups, offering a clinically interpretable and ethically aligned tool to support TNBC risk stratification and decision-making in the MENA region.
Aim:
Triple-negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options and poor survival outcomes. Prognostic models developed in Western cohorts rarely assess algorithmic fairness. This study aimed to develop and internally validate a clinically interpretable Cox survival model for TNBC using baseline diagnostic variables and to evaluate its fairness according to ISO/IEC TR 24027:2021 guidelines in a Middle East and North Africa (MENA) cohort.
Methods:
A total of 138 TNBC patients were included after merging two institutional datasets and removing variables with > 25% missingness. Baseline features comprised age, tumor size, lymph node involvement, tumor grade, Ki-67, type of surgery, metastasis at diagnosis, chemotherapy, and radiotherapy. A Cox proportional hazards (CoxPH) model with six clinically established predictors was fitted to reduce overfitting. Model performance was assessed through five-fold stratified cross-validation using Harrell’s concordance index (C-index), receiver operating characteristic area under the curve (AUROC), and calibration curves. Fairness was evaluated using demographic parity, equality of opportunity, predictive equality, and equalized odds metrics following ISO/IEC TR 24027:2021.
Results:
During follow-up, 34 patients (24.6%) died. Metastasis at diagnosis, high tumor grade, and radical mastectomy were significantly associated with mortality. The CoxPH model achieved a C-index of 0.80 [SE = 0.04; 95% confidence interval (CI): 0.72–0.87] and an AUROC of 0.81 (95% CI: 0.72–0.90). Calibration plots showed strong agreement between predicted and observed survival probabilities, with a modest overall bias of –8.8%. Fairness assessment revealed small but notable disparities in false-positive rates across age groups and surgical categories, while lymph node status and other variables showed no significant bias.
Conclusions:
This study presents a robust and fairness-aware survival prediction model for TNBC using routinely available clinical features. The model demonstrates strong discrimination, good calibration, and quantifiable fairness across patient subgroups, offering a clinically interpretable and ethically aligned tool to support TNBC risk stratification and decision-making in the MENA region.
DOI: https://doi.org/10.37349/etat.2026.1002362
Breast cancer is a leading cause of cancer death in women worldwide. One of the major causes of death from breast cancer is metastatic disease, which results from the malignant cells invading and migrating through blood vessels to distant sites. Several studies have shown that metastasis is facilitated by haemostatic proteins. Breast cancer is characterized by a haemostatic imbalance, which is tilted more to a procoagulant state with resultant thrombotic complications. These elements that are involved in thrombosis also play key roles in different aspects of breast cancer growth, including cancer proliferation and progression, cancer survival, angiogenesis, and metastasis. Some of these elements include platelets, endothelial cells, coagulation factors, and fibrinolytic proteins. There is a close relationship between cancer and many of the haemostatic elements. They are usually increased in metastatic breast cancer and have found use as predictive and prognostic markers. Some have been validated in breast cancer. Due to their seemingly active roles in breast cancer progression, some of the haemostatic proteins are being developed as diagnostic tools in the management of breast cancer. They are equally seen as potential targets for the development of novel therapies in breast cancer or repurposing drugs in current use for the same gain. This review highlights the role haemostatic proteins play in breast cancer progression, and their diagnostic and therapeutic relevance.
Breast cancer is a leading cause of cancer death in women worldwide. One of the major causes of death from breast cancer is metastatic disease, which results from the malignant cells invading and migrating through blood vessels to distant sites. Several studies have shown that metastasis is facilitated by haemostatic proteins. Breast cancer is characterized by a haemostatic imbalance, which is tilted more to a procoagulant state with resultant thrombotic complications. These elements that are involved in thrombosis also play key roles in different aspects of breast cancer growth, including cancer proliferation and progression, cancer survival, angiogenesis, and metastasis. Some of these elements include platelets, endothelial cells, coagulation factors, and fibrinolytic proteins. There is a close relationship between cancer and many of the haemostatic elements. They are usually increased in metastatic breast cancer and have found use as predictive and prognostic markers. Some have been validated in breast cancer. Due to their seemingly active roles in breast cancer progression, some of the haemostatic proteins are being developed as diagnostic tools in the management of breast cancer. They are equally seen as potential targets for the development of novel therapies in breast cancer or repurposing drugs in current use for the same gain. This review highlights the role haemostatic proteins play in breast cancer progression, and their diagnostic and therapeutic relevance.
DOI: https://doi.org/10.37349/etat.2026.1002361
This article belongs to the special issue Breaking Boundaries in Breast Cancer Care: Emerging Controversies and Innovation in Surgical and Medical Approaches
Background:
Docetaxel is a cornerstone chemotherapy for metastatic hormone-sensitive and castration-resistant prostate cancer. Although the standard triweekly regimen is widely used, weekly and biweekly schedules are often employed to improve tolerability, particularly in elderly or frail patients. The comparative efficacy and safety of these dosing strategies remain unclear. This study aimed to systematically compare weekly, biweekly, and triweekly docetaxel regimens using a network meta-analysis.
Methods:
MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception to February 2025. Randomized controlled trials and observational retrospective studies comparing weekly, biweekly, and triweekly docetaxel regimens were included. Outcomes assessed were prostate-specific antigen (PSA) response rate, time to treatment failure or progression, and adverse events. A frequentist random-effects network meta-analysis was conducted using R software.
Results:
Eleven studies involving 1,238 patients were included. PSA response rates did not differ significantly among regimens; triweekly docetaxel showed a numerically lower response compared with weekly dosing (RR = 0.79, 95% CI 0.52–1.22; I2 = 41.1%). Time to treatment failure was significantly longer with triweekly dosing compared with weekly dosing (mean difference = 10.91 months, 95% CI 6.94–14.87; I2 = 96.8%). Biweekly and triweekly regimens were associated with significantly higher hepatotoxicity compared with weekly dosing (RR = 3.71 and RR = 3.21, respectively; I2 = 0%). Vomiting was more frequent with triweekly docetaxel (RR = 2.47, 95% CI 1.31–4.63). No significant differences were observed for overall adverse events, hematologic toxicity, neuropathy, fatigue, febrile neutropenia, nausea, anorexia, or diarrhea.
Discussion:
Docetaxel dosing schedules show comparable PSA response rates. Triweekly dosing prolongs time to treatment failure but is associated with greater toxicity, whereas weekly dosing offers better tolerability. Treatment decisions should balance efficacy and safety based on individual patient characteristics.
Background:
Docetaxel is a cornerstone chemotherapy for metastatic hormone-sensitive and castration-resistant prostate cancer. Although the standard triweekly regimen is widely used, weekly and biweekly schedules are often employed to improve tolerability, particularly in elderly or frail patients. The comparative efficacy and safety of these dosing strategies remain unclear. This study aimed to systematically compare weekly, biweekly, and triweekly docetaxel regimens using a network meta-analysis.
Methods:
MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception to February 2025. Randomized controlled trials and observational retrospective studies comparing weekly, biweekly, and triweekly docetaxel regimens were included. Outcomes assessed were prostate-specific antigen (PSA) response rate, time to treatment failure or progression, and adverse events. A frequentist random-effects network meta-analysis was conducted using R software.
Results:
Eleven studies involving 1,238 patients were included. PSA response rates did not differ significantly among regimens; triweekly docetaxel showed a numerically lower response compared with weekly dosing (RR = 0.79, 95% CI 0.52–1.22; I2 = 41.1%). Time to treatment failure was significantly longer with triweekly dosing compared with weekly dosing (mean difference = 10.91 months, 95% CI 6.94–14.87; I2 = 96.8%). Biweekly and triweekly regimens were associated with significantly higher hepatotoxicity compared with weekly dosing (RR = 3.71 and RR = 3.21, respectively; I2 = 0%). Vomiting was more frequent with triweekly docetaxel (RR = 2.47, 95% CI 1.31–4.63). No significant differences were observed for overall adverse events, hematologic toxicity, neuropathy, fatigue, febrile neutropenia, nausea, anorexia, or diarrhea.
Discussion:
Docetaxel dosing schedules show comparable PSA response rates. Triweekly dosing prolongs time to treatment failure but is associated with greater toxicity, whereas weekly dosing offers better tolerability. Treatment decisions should balance efficacy and safety based on individual patient characteristics.
DOI: https://doi.org/10.37349/etat.2026.1002360
Acquired middle-ear cholesteatoma is a histologically benign keratinizing squamous epithelial lesion that paradoxically exhibits locally destructive, recurrent, and invasive behavior, often resulting in ossicular erosion, hearing loss, labyrinthine fistula, and, rarely, intracranial complications. Surgical excision remains the primary management strategy; however, recurrence is common due to persistent microenvironmental drivers. Recent mechanistic studies—including single-cell transcriptomics, spatial proteomics, and epigenetic profiling—reveal a multifactorial pathogenesis orchestrated by chronic inflammation, proteolytic extracellular-matrix remodeling, osteoclast activation via RANKL and activin A, epithelial plasticity with partial epithelial-to-mesenchymal transition (EMT), and a dysbiotic, biofilm-forming microbiome. Emerging evidence further implicates oxidative stress, RNA and epigenetic modifications, miRNA dysregulation, and immune cell infiltration as central modulators of lesion chronicity and bone resorption. Collectively, these processes establish a self-sustaining pro-osteolytic microenvironment that drives bone erosion and postoperative recurrence. Cholesteatoma recapitulates several features of malignant lesions—hyperproliferation, local invasion, and stromal/immune cell recruitment—yet remains fundamentally benign, lacking metastatic potential and genomic instability. Its aggression is ecological rather than genetic, highlighting the potential for microenvironment-directed, precision-based strategies. Adjunctive approaches may include local delivery of modulatory agents, targeted interference with inflammatory, proteolytic, osteoclastogenic, and microbial axes, and biomarker-guided patient stratification. Preclinical and early-phase experimental studies assessing target engagement, radiologic stabilization, and molecular surrogates of efficacy could inform safer, mechanism-driven interventions that complement surgery, reduce recurrence, and preserve hearing. Integrating molecular pathobiology with clinical strategy positions cholesteatoma as a model for benign yet locally aggressive, microenvironment-driven disease, providing a roadmap for translational therapies with direct relevance to surgical practice.
Acquired middle-ear cholesteatoma is a histologically benign keratinizing squamous epithelial lesion that paradoxically exhibits locally destructive, recurrent, and invasive behavior, often resulting in ossicular erosion, hearing loss, labyrinthine fistula, and, rarely, intracranial complications. Surgical excision remains the primary management strategy; however, recurrence is common due to persistent microenvironmental drivers. Recent mechanistic studies—including single-cell transcriptomics, spatial proteomics, and epigenetic profiling—reveal a multifactorial pathogenesis orchestrated by chronic inflammation, proteolytic extracellular-matrix remodeling, osteoclast activation via RANKL and activin A, epithelial plasticity with partial epithelial-to-mesenchymal transition (EMT), and a dysbiotic, biofilm-forming microbiome. Emerging evidence further implicates oxidative stress, RNA and epigenetic modifications, miRNA dysregulation, and immune cell infiltration as central modulators of lesion chronicity and bone resorption. Collectively, these processes establish a self-sustaining pro-osteolytic microenvironment that drives bone erosion and postoperative recurrence. Cholesteatoma recapitulates several features of malignant lesions—hyperproliferation, local invasion, and stromal/immune cell recruitment—yet remains fundamentally benign, lacking metastatic potential and genomic instability. Its aggression is ecological rather than genetic, highlighting the potential for microenvironment-directed, precision-based strategies. Adjunctive approaches may include local delivery of modulatory agents, targeted interference with inflammatory, proteolytic, osteoclastogenic, and microbial axes, and biomarker-guided patient stratification. Preclinical and early-phase experimental studies assessing target engagement, radiologic stabilization, and molecular surrogates of efficacy could inform safer, mechanism-driven interventions that complement surgery, reduce recurrence, and preserve hearing. Integrating molecular pathobiology with clinical strategy positions cholesteatoma as a model for benign yet locally aggressive, microenvironment-driven disease, providing a roadmap for translational therapies with direct relevance to surgical practice.
DOI: https://doi.org/10.37349/etat.2026.1002359
Glioblastoma (GBM) is a complex condition with a poorly understood pathophysiology and no effective treatment to date. The present article highlights the role of canonical and non-canonical signal transducer and activator of transcription 3 (STAT3) interactions with nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the modulation of the mitochondrial melatonergic pathway in GBM microenvironment pathophysiology. The capacity of STAT3 and NF-κB to interact to upregulate the mitochondrial melatonergic pathway is suppressed systemically over the course of aging, thereby attenuating the capacity to achieve inflammation resolution. The suppressed capacity to induce the mitochondrial melatonergic pathway systemically is partly driven by the dramatic 10-fold decrease in pineal melatonin over aging. The attenuation of pineal melatonin in the first half of sleep over aging and aging-accelerating conditions disinhibits the effects of cortisol in the second half of sleep. This decrease in the melatonin/cortisol ratio alters the nature of night-time dampening and resetting in preparation for the coming day by altering cellular and intercellular homeostatic interactions. Aging and aging-accelerating conditions, by impacting the night-time melatonin/cortisol ratio, also suppress the capacity of the vagal nerve to resolve inflammation. This further contributes to systemic changes that influence GBM pathoetiology and ongoing pathophysiology. Aging-associated changes in night-time dampening and resetting provide a novel framework on which many previously disparate bodies of data on GBM pathophysiology can be collated. This has numerous future research, prevention, and treatment implications.
Glioblastoma (GBM) is a complex condition with a poorly understood pathophysiology and no effective treatment to date. The present article highlights the role of canonical and non-canonical signal transducer and activator of transcription 3 (STAT3) interactions with nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the modulation of the mitochondrial melatonergic pathway in GBM microenvironment pathophysiology. The capacity of STAT3 and NF-κB to interact to upregulate the mitochondrial melatonergic pathway is suppressed systemically over the course of aging, thereby attenuating the capacity to achieve inflammation resolution. The suppressed capacity to induce the mitochondrial melatonergic pathway systemically is partly driven by the dramatic 10-fold decrease in pineal melatonin over aging. The attenuation of pineal melatonin in the first half of sleep over aging and aging-accelerating conditions disinhibits the effects of cortisol in the second half of sleep. This decrease in the melatonin/cortisol ratio alters the nature of night-time dampening and resetting in preparation for the coming day by altering cellular and intercellular homeostatic interactions. Aging and aging-accelerating conditions, by impacting the night-time melatonin/cortisol ratio, also suppress the capacity of the vagal nerve to resolve inflammation. This further contributes to systemic changes that influence GBM pathoetiology and ongoing pathophysiology. Aging-associated changes in night-time dampening and resetting provide a novel framework on which many previously disparate bodies of data on GBM pathophysiology can be collated. This has numerous future research, prevention, and treatment implications.
DOI: https://doi.org/10.37349/etat.2026.1002358
Machine learning (ML) and deep learning (DL) models applied to electronic health records (EHRs) have substantial potential to improve oncology care across diagnosis, prognosis, treatment selection, and trial recruitment. However, opacity of many high-performing models limits clinician trust, regulatory acceptance, and safe deployment. Explainable artificial intelligence (XAI) methods aim to make model behavior understandable and actionable in clinical contexts. The present perspective summarizes current XAI approaches applied to EHR-based oncology tasks, identifies key challenges in evaluation, reproducibility, clinical utility, and equity, and proposes pragmatic recommendations and research directions to accelerate safe adoption in oncology. Common XAI categories used with EHR data include feature importance/interaction methods, intrinsically interpretable models, attention mechanisms, dimensionality reduction, and knowledge distillation or rule extraction. Tree-based models with SHapley Additive exPlanations (SHAP) explanations dominate recent EHR studies. Other interpretable strategies, such as generalized additive models and rule sets, appear in settings where transparency is prioritized. Gaps include inconsistent reporting, scarce formal evaluation of explanations for clinical utility, limited reproducibility for data and code availability, inadequate external validation, and insufficient consideration of fairness and equity that these issues are particularly important in oncology, where heterogeneity and stakes are high. Overall, integrating XAI with EHR-driven oncology models is promising but underdeveloped, which requires further progress by multi-stakeholder evaluation frameworks, reproducible pipelines, prospective and multicenter validations, and equity-aware design. The field should prioritize clinically meaningful explanations beyond ranking features and study how explanations affect clinician decision-making and patient outcomes.
Machine learning (ML) and deep learning (DL) models applied to electronic health records (EHRs) have substantial potential to improve oncology care across diagnosis, prognosis, treatment selection, and trial recruitment. However, opacity of many high-performing models limits clinician trust, regulatory acceptance, and safe deployment. Explainable artificial intelligence (XAI) methods aim to make model behavior understandable and actionable in clinical contexts. The present perspective summarizes current XAI approaches applied to EHR-based oncology tasks, identifies key challenges in evaluation, reproducibility, clinical utility, and equity, and proposes pragmatic recommendations and research directions to accelerate safe adoption in oncology. Common XAI categories used with EHR data include feature importance/interaction methods, intrinsically interpretable models, attention mechanisms, dimensionality reduction, and knowledge distillation or rule extraction. Tree-based models with SHapley Additive exPlanations (SHAP) explanations dominate recent EHR studies. Other interpretable strategies, such as generalized additive models and rule sets, appear in settings where transparency is prioritized. Gaps include inconsistent reporting, scarce formal evaluation of explanations for clinical utility, limited reproducibility for data and code availability, inadequate external validation, and insufficient consideration of fairness and equity that these issues are particularly important in oncology, where heterogeneity and stakes are high. Overall, integrating XAI with EHR-driven oncology models is promising but underdeveloped, which requires further progress by multi-stakeholder evaluation frameworks, reproducible pipelines, prospective and multicenter validations, and equity-aware design. The field should prioritize clinically meaningful explanations beyond ranking features and study how explanations affect clinician decision-making and patient outcomes.
DOI: https://doi.org/10.37349/etat.2026.1002357
DOI: https://doi.org/10.37349/etat.2026.1002356
The evolution of nanocarrier-based drug delivery systems has transformed the paradigm of cancer therapeutics, advancing from conventional cytotoxic formulations to intelligent, adaptive nanosystems capable of precision targeting. Early-generation nanocarriers exploited the enhanced permeability and retention (EPR) effect for passive tumor accumulation, yet their therapeutic efficiency remained constrained by tumor heterogeneity, limited penetration, and off-target toxicity. Emerging nanotechnologies now integrate active targeting, stimuli-responsive components, and biomimetic strategies to achieve spatiotemporal control over drug release and tumor-selective action. These “intelligent” nanocarriers are designed to recognize molecular signatures, respond dynamically to tumor microenvironmental cues such as pH, redox gradients, hypoxia, and enzymatic activity, and even engage in real-time feedback through imaging or biosensing modules. In addition, hybrid and multifunctional platforms—combining liposomes, micelles, dendrimers, polymeric nanoparticles, and inorganic systems—offer programmable functionality and synergistic delivery of chemotherapeutic, gene-editing, and immunomodulatory agents. This review delineates the mechanistic basis of passive and active targeting, highlights recent innovations in stimuli-responsive and biomimetic nanocarriers, and explores translational and regulatory perspectives shaping their clinical journey. By integrating nanotechnology with systems biology and artificial intelligence, next-generation nanocarriers promise to redefine the landscape of precision antitumor therapy.
The evolution of nanocarrier-based drug delivery systems has transformed the paradigm of cancer therapeutics, advancing from conventional cytotoxic formulations to intelligent, adaptive nanosystems capable of precision targeting. Early-generation nanocarriers exploited the enhanced permeability and retention (EPR) effect for passive tumor accumulation, yet their therapeutic efficiency remained constrained by tumor heterogeneity, limited penetration, and off-target toxicity. Emerging nanotechnologies now integrate active targeting, stimuli-responsive components, and biomimetic strategies to achieve spatiotemporal control over drug release and tumor-selective action. These “intelligent” nanocarriers are designed to recognize molecular signatures, respond dynamically to tumor microenvironmental cues such as pH, redox gradients, hypoxia, and enzymatic activity, and even engage in real-time feedback through imaging or biosensing modules. In addition, hybrid and multifunctional platforms—combining liposomes, micelles, dendrimers, polymeric nanoparticles, and inorganic systems—offer programmable functionality and synergistic delivery of chemotherapeutic, gene-editing, and immunomodulatory agents. This review delineates the mechanistic basis of passive and active targeting, highlights recent innovations in stimuli-responsive and biomimetic nanocarriers, and explores translational and regulatory perspectives shaping their clinical journey. By integrating nanotechnology with systems biology and artificial intelligence, next-generation nanocarriers promise to redefine the landscape of precision antitumor therapy.
DOI: https://doi.org/10.37349/etat.2025.1002355
Immune checkpoint inhibitor (ICI) therapy has revolutionized metastatic melanoma treatment, yet only a subset of patients respond effectively, and the treatment can induce a variety of immune-related adverse events (irAEs), including colitis. The gut microbiome plays a critical role in determining patient responses to immunotherapy, prompting exploration of gut-modifying strategies such as prebiotics, probiotics, and fecal microbiota transplantation (FMT) to overcome both primary and acquired resistance and improve treatment outcomes. Prebiotics, defined as dietary substrates that selectively support the growth and/or activity of beneficial gut microorganisms, represent a feasible and safe strategy for microbiome reshaping. Plant-derived prebiotics like castalagin, inulin, fructooligosaccharides, galactooligosaccharides, mushroom extract, kale extract, and konjac glucomannan offer unique advantages over synthetic or animal-derived alternatives due to their natural fiber content alongside their ability to enhance gut microbial diversity. Prebiotics are known to achieve health benefits by selectively stimulating beneficial gut bacteria, producing short-chain fatty acids (SCFAs) that modulate the host immune system, suppressing pathogenic microbes, enhancing mucin production, and modulating systemic and gut-associated immune responses. SCFAs generated through prebiotic fermentation influence host innate and adaptive immunity and regulate metabolic activity via inhibition of histone deacetylases (HDACs), influencing mTOR/MAPK signaling and cytokine production. They also act as ligands for G-protein-coupled receptors (GPCRs), altering intracellular calcium and cAMP to modulate immune cell gene expression. However, the specific mechanisms by which individual prebiotics interact with host genetics, beneficial gut bacteria, and their metabolites are not very well understood. This is crucial to optimize their therapeutic potential in cancer immunotherapy. This review synthesizes current evidence on plant-derived prebiotics, highlighting the impact of beneficial gut bacteria and their metabolites. Given their established safety for human consumption, prebiotics represent a promising, low-risk option to improve gut microbiome composition and potentially enhance immunotherapy and clinical outcomes in cancer.
Immune checkpoint inhibitor (ICI) therapy has revolutionized metastatic melanoma treatment, yet only a subset of patients respond effectively, and the treatment can induce a variety of immune-related adverse events (irAEs), including colitis. The gut microbiome plays a critical role in determining patient responses to immunotherapy, prompting exploration of gut-modifying strategies such as prebiotics, probiotics, and fecal microbiota transplantation (FMT) to overcome both primary and acquired resistance and improve treatment outcomes. Prebiotics, defined as dietary substrates that selectively support the growth and/or activity of beneficial gut microorganisms, represent a feasible and safe strategy for microbiome reshaping. Plant-derived prebiotics like castalagin, inulin, fructooligosaccharides, galactooligosaccharides, mushroom extract, kale extract, and konjac glucomannan offer unique advantages over synthetic or animal-derived alternatives due to their natural fiber content alongside their ability to enhance gut microbial diversity. Prebiotics are known to achieve health benefits by selectively stimulating beneficial gut bacteria, producing short-chain fatty acids (SCFAs) that modulate the host immune system, suppressing pathogenic microbes, enhancing mucin production, and modulating systemic and gut-associated immune responses. SCFAs generated through prebiotic fermentation influence host innate and adaptive immunity and regulate metabolic activity via inhibition of histone deacetylases (HDACs), influencing mTOR/MAPK signaling and cytokine production. They also act as ligands for G-protein-coupled receptors (GPCRs), altering intracellular calcium and cAMP to modulate immune cell gene expression. However, the specific mechanisms by which individual prebiotics interact with host genetics, beneficial gut bacteria, and their metabolites are not very well understood. This is crucial to optimize their therapeutic potential in cancer immunotherapy. This review synthesizes current evidence on plant-derived prebiotics, highlighting the impact of beneficial gut bacteria and their metabolites. Given their established safety for human consumption, prebiotics represent a promising, low-risk option to improve gut microbiome composition and potentially enhance immunotherapy and clinical outcomes in cancer.
DOI: https://doi.org/10.37349/etat.2025.1002354
Fibroblast growth factor receptor 1 (FGFR1) is crucial in the progression of various cancers, participating in the processes of cell proliferation, survival, and differentiation. FGFR1 plays a role in the resistance to immune checkpoint inhibitors (ICIs) such as pembrolizumab and nivolumab. Therefore, using monoclonal antibodies and tyrosine kinase inhibitors to target FGFR1 and enhancing ICIs by modifying the tumor microenvironment and combating immune suppression represents a potential therapeutic strategy. Based on the FGFR1-related research and the active targeting strategy, we believe that modifying the surface of nanomedicines with anti-FGFR1 antibodies (such as OM-RCA-01) is an effective targeted treatment method for tumors with high expression of FGFR1. Although there have been relevant studies confirming the feasibility of this approach, there are challenges in clinical application, especially in terms of maintaining uniform quality during large-scale production. Therefore, we suggest conducting further optimization studies in the future to accelerate the clinical application of such drug delivery systems and provide more efficient and cost-effective options for tumor treatment.
Fibroblast growth factor receptor 1 (FGFR1) is crucial in the progression of various cancers, participating in the processes of cell proliferation, survival, and differentiation. FGFR1 plays a role in the resistance to immune checkpoint inhibitors (ICIs) such as pembrolizumab and nivolumab. Therefore, using monoclonal antibodies and tyrosine kinase inhibitors to target FGFR1 and enhancing ICIs by modifying the tumor microenvironment and combating immune suppression represents a potential therapeutic strategy. Based on the FGFR1-related research and the active targeting strategy, we believe that modifying the surface of nanomedicines with anti-FGFR1 antibodies (such as OM-RCA-01) is an effective targeted treatment method for tumors with high expression of FGFR1. Although there have been relevant studies confirming the feasibility of this approach, there are challenges in clinical application, especially in terms of maintaining uniform quality during large-scale production. Therefore, we suggest conducting further optimization studies in the future to accelerate the clinical application of such drug delivery systems and provide more efficient and cost-effective options for tumor treatment.
DOI: https://doi.org/10.37349/etat.2025.1002353
Radiation exposure to the eye during cancer treatment can lead to ocular radiation injury (ORI), a devastating condition that can have a profound and permanent impact on vision-related quality of life. Rodent models do not have adequate ocular anatomy to accurately simulate human ORI, and modeling in non-human primates is limited by logistical and ethical concerns. To improve future translational research investigating ways to treat or prevent ORI, we developed protocols for a tree shrew model of ORI. Northern tree shrews (Tupaia belangeri) were obtained by our laboratory. Custom housing and handling methods were developed, including custom body suits to maintain the tree shrew’s body temperature during procedures. Radiation delivery was optimized to accurately deliver radiation, and imaging was performed to observe fundus changes from ORI. Optimization of tree shrew handling, housing, anesthesia approaches, radiation delivery, and clinically-relevant ocular imaging permitted successful induction and assessment of ORI in tree shrews. With these protocols, tree shrews can be used as a highly relevant model organism with key anatomic features similar to humans to study ORI.
Radiation exposure to the eye during cancer treatment can lead to ocular radiation injury (ORI), a devastating condition that can have a profound and permanent impact on vision-related quality of life. Rodent models do not have adequate ocular anatomy to accurately simulate human ORI, and modeling in non-human primates is limited by logistical and ethical concerns. To improve future translational research investigating ways to treat or prevent ORI, we developed protocols for a tree shrew model of ORI. Northern tree shrews (Tupaia belangeri) were obtained by our laboratory. Custom housing and handling methods were developed, including custom body suits to maintain the tree shrew’s body temperature during procedures. Radiation delivery was optimized to accurately deliver radiation, and imaging was performed to observe fundus changes from ORI. Optimization of tree shrew handling, housing, anesthesia approaches, radiation delivery, and clinically-relevant ocular imaging permitted successful induction and assessment of ORI in tree shrews. With these protocols, tree shrews can be used as a highly relevant model organism with key anatomic features similar to humans to study ORI.
DOI: https://doi.org/10.37349/etat.2025.1002352
Colorectal cancer (CRC) is a significant global health problem, ranking as the third most common cancer and the second leading cause of cancer deaths in the world. The highest incidence of CRC is found in developed regions, thus underlining its characterization as a Western disease. Major risk factors for CRC include an unhealthy diet, lack of physical exercise, and cigarette smoking. The gut microbiota refers to the complex community of microorganisms inhabiting the digestive tract and plays a crucial role in the maintenance of host health and modulation of immune responses. Gut dysbiosis can be caused by poor diet and alcohol consumption, increasing CRC risk. Specific bacteria, such as Fusobacterium nucleatum and Escherichia coli, may have a close relationship with CRC development, while the beneficial bacteria are frequently depleted in CRC patients. This paper will discuss the mechanisms of colorectal carcinogenesis, focusing on the effects of bacterial genotoxins, immune evasion, inflammation, and diet. Additionally, it reviews preventative strategies including short-chain fatty acids (SCFAs), prebiotics, probiotics, synbiotic supplements, and the method of fecal microbiota transplantation (FMT), showing their potential to improve overall gut health and reduce the risk for CRC. Understanding these mechanisms and implementing specific preventative strategies could significantly enhance clinical interventions and reduce the global burden of CRC.
Colorectal cancer (CRC) is a significant global health problem, ranking as the third most common cancer and the second leading cause of cancer deaths in the world. The highest incidence of CRC is found in developed regions, thus underlining its characterization as a Western disease. Major risk factors for CRC include an unhealthy diet, lack of physical exercise, and cigarette smoking. The gut microbiota refers to the complex community of microorganisms inhabiting the digestive tract and plays a crucial role in the maintenance of host health and modulation of immune responses. Gut dysbiosis can be caused by poor diet and alcohol consumption, increasing CRC risk. Specific bacteria, such as Fusobacterium nucleatum and Escherichia coli, may have a close relationship with CRC development, while the beneficial bacteria are frequently depleted in CRC patients. This paper will discuss the mechanisms of colorectal carcinogenesis, focusing on the effects of bacterial genotoxins, immune evasion, inflammation, and diet. Additionally, it reviews preventative strategies including short-chain fatty acids (SCFAs), prebiotics, probiotics, synbiotic supplements, and the method of fecal microbiota transplantation (FMT), showing their potential to improve overall gut health and reduce the risk for CRC. Understanding these mechanisms and implementing specific preventative strategies could significantly enhance clinical interventions and reduce the global burden of CRC.
DOI: https://doi.org/10.37349/etat.2025.1002351
Therapeutic cancer vaccines harness the adaptive immune system to eradicate malignancies by targeting tumor-specific antigens. This review charts the evolution of cancer vaccine platforms—from shared tumor-associated antigens (TAAs) and dendritic cell (DC) vaccines to next-generation neoantigen-messenger ribonucleic acid (mRNA) vaccines—highlighting advances in vaccine delivery, antigen discovery, computational prediction, and translational efficacy. We explore cutting-edge clinical data, including long-lived T-cell memory and promising outcomes in various cancer types, including pancreatic ductal adenocarcinoma (PDAC), melanoma, head and neck cancers, renal cell carcinoma (RCC), and others. We address critical challenges, including tumor heterogeneity, manufacturing scalability, biomarker development, and regulatory frameworks, and propose an integrated translational ecosystem to accelerate the adoption of personalized cancer vaccines.
Therapeutic cancer vaccines harness the adaptive immune system to eradicate malignancies by targeting tumor-specific antigens. This review charts the evolution of cancer vaccine platforms—from shared tumor-associated antigens (TAAs) and dendritic cell (DC) vaccines to next-generation neoantigen-messenger ribonucleic acid (mRNA) vaccines—highlighting advances in vaccine delivery, antigen discovery, computational prediction, and translational efficacy. We explore cutting-edge clinical data, including long-lived T-cell memory and promising outcomes in various cancer types, including pancreatic ductal adenocarcinoma (PDAC), melanoma, head and neck cancers, renal cell carcinoma (RCC), and others. We address critical challenges, including tumor heterogeneity, manufacturing scalability, biomarker development, and regulatory frameworks, and propose an integrated translational ecosystem to accelerate the adoption of personalized cancer vaccines.
DOI: https://doi.org/10.37349/etat.2025.1002350
This article belongs to the special issue Cancer Vaccines: From Basic Innovations to Clinical Translation
The convergence of DNA nanotechnology with nanofluidics has catalyzed a transformative shift in precision drug delivery. DNA origami, a self-assembled nanoscale architecture constructed via programmable base pairing, offers atomically precise control over size, shape, and function—making it an ideal scaffold for site-specific therapeutic cargo loading and release. When integrated into nanofluidic systems, these origami nanostructures form intelligent platforms capable of navigating biological barriers, sensing intracellular cues, and delivering payloads in a spatially and temporally controlled manner. This review explores the fabrication principles, design strategies, and intracellular trafficking mechanisms that underpin the efficacy of these smart nanofluidic DNA origami systems. We highlight key stimuli-responsive features such as pH-triggered unfolding, enzyme-cleavable hinges, redox-sensitive disassembly, and light-mediated gate release. Case studies from preclinical models demonstrate their superiority in overcoming drug resistance, enhancing tumor selectivity, and minimizing systemic toxicity compared to conventional nanocarriers. We also evaluate methods for surface modification, channel integration, and stimulus modulation using electron-beam lithography and soft lithography techniques. Additional biosafety and scalability challenges are discussed, alongside regulatory and immunogenicity considerations. The review concludes by outlining future directions involving AI-assisted DNA origami design, microfluidic diagnostics, and digital therapeutics. The synthesis of programmable nanocarriers with smart fluidic control represents a new frontier in targeted therapy, combining modularity, precision, and adaptability. As such, nanofluidic DNA origami systems hold immense promise for next-generation therapeutics in oncology, gene therapy, and personalized medicine, paving the way for dynamic and autonomous intracellular delivery platforms with real-world translational potential.
The convergence of DNA nanotechnology with nanofluidics has catalyzed a transformative shift in precision drug delivery. DNA origami, a self-assembled nanoscale architecture constructed via programmable base pairing, offers atomically precise control over size, shape, and function—making it an ideal scaffold for site-specific therapeutic cargo loading and release. When integrated into nanofluidic systems, these origami nanostructures form intelligent platforms capable of navigating biological barriers, sensing intracellular cues, and delivering payloads in a spatially and temporally controlled manner. This review explores the fabrication principles, design strategies, and intracellular trafficking mechanisms that underpin the efficacy of these smart nanofluidic DNA origami systems. We highlight key stimuli-responsive features such as pH-triggered unfolding, enzyme-cleavable hinges, redox-sensitive disassembly, and light-mediated gate release. Case studies from preclinical models demonstrate their superiority in overcoming drug resistance, enhancing tumor selectivity, and minimizing systemic toxicity compared to conventional nanocarriers. We also evaluate methods for surface modification, channel integration, and stimulus modulation using electron-beam lithography and soft lithography techniques. Additional biosafety and scalability challenges are discussed, alongside regulatory and immunogenicity considerations. The review concludes by outlining future directions involving AI-assisted DNA origami design, microfluidic diagnostics, and digital therapeutics. The synthesis of programmable nanocarriers with smart fluidic control represents a new frontier in targeted therapy, combining modularity, precision, and adaptability. As such, nanofluidic DNA origami systems hold immense promise for next-generation therapeutics in oncology, gene therapy, and personalized medicine, paving the way for dynamic and autonomous intracellular delivery platforms with real-world translational potential.
DOI: https://doi.org/10.37349/etat.2025.1002349
The realization that the composition and functionality of gut microbiota have an impact on the outcome of immune checkpoint inhibition (ICI) therapy of cancer has initiated research into the potential of microbiota management as adjunctive therapy. Fecal microbiota transplantation can improve the outcome of ICI, but for optimal donor selection, safety, and large-scale implementation, there remain bottlenecks. Alternative strategies, such as the use of selected bacterial species, require fundamental knowledge of the underlying mechanisms governing the interaction between (intestinal) microbiota and the immune system. Gut microbiota also appears to be able to colonize the tumor microenvironment. Some bacterial species directly or indirectly promote tumor growth. Other defined species have tumoricidal properties. These findings and insights are now being used to further optimize the functionality of the immune system and shape the tumor microenvironment in order to improve the outcome of ICI.
The realization that the composition and functionality of gut microbiota have an impact on the outcome of immune checkpoint inhibition (ICI) therapy of cancer has initiated research into the potential of microbiota management as adjunctive therapy. Fecal microbiota transplantation can improve the outcome of ICI, but for optimal donor selection, safety, and large-scale implementation, there remain bottlenecks. Alternative strategies, such as the use of selected bacterial species, require fundamental knowledge of the underlying mechanisms governing the interaction between (intestinal) microbiota and the immune system. Gut microbiota also appears to be able to colonize the tumor microenvironment. Some bacterial species directly or indirectly promote tumor growth. Other defined species have tumoricidal properties. These findings and insights are now being used to further optimize the functionality of the immune system and shape the tumor microenvironment in order to improve the outcome of ICI.
DOI: https://doi.org/10.37349/etat.2025.1002348
Immune checkpoint inhibitors (ICIs) are established treatments for various malignancies, including lung, kidney, and colorectal cancers. However, their broad use has led to an increase in immune-related adverse events (irAEs), with thyroiditis, colitis, and pneumonitis being the most common. Hemophagocytic lymphohistiocytosis (HLH) is a rare but severe irAE characterized by excessive immune activation, leading to systemic inflammation and multi-organ dysfunction. We present three cases of ICI-induced HLH in patients with lung cancer who were treated with ICIs. All patients showed elevated inflammatory markers and responded to high-dose corticosteroids without the addition of etoposide. These cases underscore the importance of early recognition and treatment of HLH in patients receiving ICIs to mitigate morbidity and mortality. Large-scale studies are needed to establish standardized guidelines for diagnosing and managing ICI-induced HLH.
Immune checkpoint inhibitors (ICIs) are established treatments for various malignancies, including lung, kidney, and colorectal cancers. However, their broad use has led to an increase in immune-related adverse events (irAEs), with thyroiditis, colitis, and pneumonitis being the most common. Hemophagocytic lymphohistiocytosis (HLH) is a rare but severe irAE characterized by excessive immune activation, leading to systemic inflammation and multi-organ dysfunction. We present three cases of ICI-induced HLH in patients with lung cancer who were treated with ICIs. All patients showed elevated inflammatory markers and responded to high-dose corticosteroids without the addition of etoposide. These cases underscore the importance of early recognition and treatment of HLH in patients receiving ICIs to mitigate morbidity and mortality. Large-scale studies are needed to establish standardized guidelines for diagnosing and managing ICI-induced HLH.
DOI: https://doi.org/10.37349/etat.2025.1002347
Cancer is one of the leading global causes of mortality and morbidity, so it needs early diagnosis and therapies. Traditional diagnostic and therapeutic strategies are inadequate due to several limitations, such as poor specificity, systemic toxicity, and delays, while metal-grafted Gr nanostructures have emerged as promising theranostic platforms due to their unique electronic, optical, and structural properties. Metals such as Fe3O4, Au, Ag, TiO2, Pd, Pt, Bi, ZnO, and Cu grafted onto the Gr surface impart electronic modulation, enhance surface area, flexibility, conductivity, reactivity, biomolecular interactions, and biosensing, thereby enabling precise biomarker detection, targeted drug delivery, imaging, and photothermal/photodynamic therapy (PTT/PDT). Eco-friendly synthesis using plant extracts and microbes offers a sustainable and biocompatible alternative to conventional chemical synthesis. However, challenges remain, such as homogenous doping, synthetic complexity, long-term safety, and clinical scalability. Innovations such as scalable, cost-effective, biocompatible nanofibers, nanopapers, microfluidic, and wearable biosensors are being explored by incorporating AI and advanced diagnostic tools for advanced biomedical devices. In vitro, half maximum inhibitory concentrations (IC50) studies show that size- and dose-dependent nanohybrids such as Fe3O4-Gr, γ-Fe2O3-Gr, Au-Gr, and Bi-Gr exhibited safer responses at lower concentrations 10–200 µg/mL across HBE, MCF-7, HeLa B, and LNCaP cell lines. Bi-Gr was tested on human liver cancer (HepG2) cell line, which exhibits higher reactivity despite a safer profile of Bi at ~53–88 µg/mL. Pd-Gr and Pt-Gr significantly reduced viability in prostate and ovarian cancer cells at 10–50 µg/mL, while ZnO-Gr, Ag-Gr, and Cu-Gr showed safer activity at lower concentrations on MCF-7. In vivo studies remain limited; median lethal dose (LD50) values for Fe3O4-Gr and γ-Fe2O3-Gr were determined to be associated with rapid lethal biodistribution observed in the liver, lungs, and spleen. Metal-grafted Gr nanohybrids demonstrate immense potential for multifunctional cancer theranostics, though systematic in vivo toxicity studies still need to be explored by the intravenously administered route to lower the LD50 of nanohybrids for their clinical translation.
Cancer is one of the leading global causes of mortality and morbidity, so it needs early diagnosis and therapies. Traditional diagnostic and therapeutic strategies are inadequate due to several limitations, such as poor specificity, systemic toxicity, and delays, while metal-grafted Gr nanostructures have emerged as promising theranostic platforms due to their unique electronic, optical, and structural properties. Metals such as Fe3O4, Au, Ag, TiO2, Pd, Pt, Bi, ZnO, and Cu grafted onto the Gr surface impart electronic modulation, enhance surface area, flexibility, conductivity, reactivity, biomolecular interactions, and biosensing, thereby enabling precise biomarker detection, targeted drug delivery, imaging, and photothermal/photodynamic therapy (PTT/PDT). Eco-friendly synthesis using plant extracts and microbes offers a sustainable and biocompatible alternative to conventional chemical synthesis. However, challenges remain, such as homogenous doping, synthetic complexity, long-term safety, and clinical scalability. Innovations such as scalable, cost-effective, biocompatible nanofibers, nanopapers, microfluidic, and wearable biosensors are being explored by incorporating AI and advanced diagnostic tools for advanced biomedical devices. In vitro, half maximum inhibitory concentrations (IC50) studies show that size- and dose-dependent nanohybrids such as Fe3O4-Gr, γ-Fe2O3-Gr, Au-Gr, and Bi-Gr exhibited safer responses at lower concentrations 10–200 µg/mL across HBE, MCF-7, HeLa B, and LNCaP cell lines. Bi-Gr was tested on human liver cancer (HepG2) cell line, which exhibits higher reactivity despite a safer profile of Bi at ~53–88 µg/mL. Pd-Gr and Pt-Gr significantly reduced viability in prostate and ovarian cancer cells at 10–50 µg/mL, while ZnO-Gr, Ag-Gr, and Cu-Gr showed safer activity at lower concentrations on MCF-7. In vivo studies remain limited; median lethal dose (LD50) values for Fe3O4-Gr and γ-Fe2O3-Gr were determined to be associated with rapid lethal biodistribution observed in the liver, lungs, and spleen. Metal-grafted Gr nanohybrids demonstrate immense potential for multifunctional cancer theranostics, though systematic in vivo toxicity studies still need to be explored by the intravenously administered route to lower the LD50 of nanohybrids for their clinical translation.
DOI: https://doi.org/10.37349/etat.2025.1002346
This article belongs to the special issue Potential Clinical Applications of Inorganic Nanomaterials in Cancer
