Previous
A functional immune system is a key antagonist of cancer cell growth. Cytokines such as interferons (IFNs) promote the onset of inflammation, turn cells into an anti-viral state, and shape the dynamic tumor-immune cell interactome. Recent work illustrates how type I IFNs contribute to the resolution of inflammatory conditions. This involves macrophage-mediated efferocytosis for the clearance of apoptotic cells and the intrinsic capacity of type I IFNs to restrict their own autocrine signaling loops via the IFN-stimulated gene 15 (ISG15) protein. We discuss how this may affect tumor cells and how acetylation-dependent processes can affect the phosphorylation-dependent signaling cascades that augment IFN-dependent gene expression.
A functional immune system is a key antagonist of cancer cell growth. Cytokines such as interferons (IFNs) promote the onset of inflammation, turn cells into an anti-viral state, and shape the dynamic tumor-immune cell interactome. Recent work illustrates how type I IFNs contribute to the resolution of inflammatory conditions. This involves macrophage-mediated efferocytosis for the clearance of apoptotic cells and the intrinsic capacity of type I IFNs to restrict their own autocrine signaling loops via the IFN-stimulated gene 15 (ISG15) protein. We discuss how this may affect tumor cells and how acetylation-dependent processes can affect the phosphorylation-dependent signaling cascades that augment IFN-dependent gene expression.
DOI: https://doi.org/10.37349/etat.2026.1002399
Breast cancer management increasingly hinges on decisions made in “grey zones” where tissue sampling is scarce, and tumour biology evolves under therapeutic pressure. This narrative review synthesises evidence on how whole-body imaging biomarkers and circulating tumour DNA (ctDNA) can support response-adaptive pathways at the interface of surgical and systemic care. Four clinically actionable domains are discussed. (a) 16α-[18F]fluoro-17β-estradiol ([18F]FES) positron emission tomography/computed tomography (PET/CT) enables non-invasive, whole-body mapping of functional oestrogen receptor (ER) expression to address receptor discordance, heterogeneous metastases, and selection of endocrine-based strategies. (b) Human epidermal growth factor receptor 2 (HER2)-targeted PET (notably 89Zr-trastuzumab, with emerging alternatives) provides whole-body receptor assessment to uncover actionable HER2-positive disease despite HER2-negative primaries, informing anti-HER2 treatment selection when repeat biopsy is infeasible. (c) In triple-negative breast cancer treated with immune checkpoint inhibitors, 18F-fluorodeoxyglucose (18F-FDG) PET/CT offers quantitative response and whole-body burden assessment but requires immunotherapy-aware interpretation (e.g., confirmation strategies for apparent early progression) to mitigate pseudoprogression and dissociated responses, while simultaneously visualising immune-related adverse events. (d) Pairing early metabolic change on FDG PET/CT with ctDNA kinetics is presented as a biologically complementary approach for response monitoring and risk stratification, with potential to inform trial-embedded response-adaptive hypotheses, with ctDNA offering a rapid systemic trajectory and PET providing lesion-level localisation in heterogeneous or oligoprogressive disease. Overall, these tools add value only when linked to prespecified clinical questions and consensus actions; prospective studies are needed to validate standardised, outcome-improving response-adaptive algorithms that integrate imaging and liquid biopsy. Key implementation challenges include tracer availability, harmonised acquisition/reconstruction, threshold definition, and avoiding overtesting. Near-term impact may be greatest in problem-solving and in trial-embedded decision rules that operationalise biomarker-guided care.
Breast cancer management increasingly hinges on decisions made in “grey zones” where tissue sampling is scarce, and tumour biology evolves under therapeutic pressure. This narrative review synthesises evidence on how whole-body imaging biomarkers and circulating tumour DNA (ctDNA) can support response-adaptive pathways at the interface of surgical and systemic care. Four clinically actionable domains are discussed. (a) 16α-[18F]fluoro-17β-estradiol ([18F]FES) positron emission tomography/computed tomography (PET/CT) enables non-invasive, whole-body mapping of functional oestrogen receptor (ER) expression to address receptor discordance, heterogeneous metastases, and selection of endocrine-based strategies. (b) Human epidermal growth factor receptor 2 (HER2)-targeted PET (notably 89Zr-trastuzumab, with emerging alternatives) provides whole-body receptor assessment to uncover actionable HER2-positive disease despite HER2-negative primaries, informing anti-HER2 treatment selection when repeat biopsy is infeasible. (c) In triple-negative breast cancer treated with immune checkpoint inhibitors, 18F-fluorodeoxyglucose (18F-FDG) PET/CT offers quantitative response and whole-body burden assessment but requires immunotherapy-aware interpretation (e.g., confirmation strategies for apparent early progression) to mitigate pseudoprogression and dissociated responses, while simultaneously visualising immune-related adverse events. (d) Pairing early metabolic change on FDG PET/CT with ctDNA kinetics is presented as a biologically complementary approach for response monitoring and risk stratification, with potential to inform trial-embedded response-adaptive hypotheses, with ctDNA offering a rapid systemic trajectory and PET providing lesion-level localisation in heterogeneous or oligoprogressive disease. Overall, these tools add value only when linked to prespecified clinical questions and consensus actions; prospective studies are needed to validate standardised, outcome-improving response-adaptive algorithms that integrate imaging and liquid biopsy. Key implementation challenges include tracer availability, harmonised acquisition/reconstruction, threshold definition, and avoiding overtesting. Near-term impact may be greatest in problem-solving and in trial-embedded decision rules that operationalise biomarker-guided care.
DOI: https://doi.org/10.37349/etat.2026.1002398
This article belongs to the special issue Breaking Boundaries in Breast Cancer Care: Emerging Controversies and Innovation in Surgical and Medical Approaches
Precision oncology has revolutionized cancer care in high-income countries, but its implementation in Latin American low-resource settings faces profound bioethical dilemmas. This study analyzes these challenges through the lens of social justice and equity. An integrative review was conducted following the Whittemore and Knafl framework. A systematic search was performed across PubMed, Scopus, SciELO, and LILACS (2015–2025). Thematic synthesis was applied to integrate empirical data with normative bioethical theories. Four major analytical themes were identified: 1) The innovation paradox and financial toxicity, where prohibitive pricing (exceeding 100,000 USD/year) violates distributive justice and leads to a biological penalty in survival; 2) Infrastructure deficits and epistemic injustice, highlighted by a 9.4% access rate to next-generation sequencing (NGS) and the risks of applying Eurocentric genomic data to admixed LA populations; 3) Research vulnerability, where clinical trials serve as survival strategies, compromising autonomy and informed consent; and 4) The judicialization dilemma, where individual court orders for high-cost drugs threaten systemic sustainability and equity. To prevent a genomic apartheid, Latin America must transition toward genomic sovereignty and frugal precision oncology. Bioethical frameworks in the region must prioritize protection ethics and social justice to ensure that scientific innovation does not exacerbate existing health inequities.
Precision oncology has revolutionized cancer care in high-income countries, but its implementation in Latin American low-resource settings faces profound bioethical dilemmas. This study analyzes these challenges through the lens of social justice and equity. An integrative review was conducted following the Whittemore and Knafl framework. A systematic search was performed across PubMed, Scopus, SciELO, and LILACS (2015–2025). Thematic synthesis was applied to integrate empirical data with normative bioethical theories. Four major analytical themes were identified: 1) The innovation paradox and financial toxicity, where prohibitive pricing (exceeding 100,000 USD/year) violates distributive justice and leads to a biological penalty in survival; 2) Infrastructure deficits and epistemic injustice, highlighted by a 9.4% access rate to next-generation sequencing (NGS) and the risks of applying Eurocentric genomic data to admixed LA populations; 3) Research vulnerability, where clinical trials serve as survival strategies, compromising autonomy and informed consent; and 4) The judicialization dilemma, where individual court orders for high-cost drugs threaten systemic sustainability and equity. To prevent a genomic apartheid, Latin America must transition toward genomic sovereignty and frugal precision oncology. Bioethical frameworks in the region must prioritize protection ethics and social justice to ensure that scientific innovation does not exacerbate existing health inequities.
DOI: https://doi.org/10.37349/etat.2026.1002397
Primary bone sarcomas are rare and biologically heterogeneous malignancies for which therapeutic progress remains limited, particularly in metastatic and recurrent disease. Advances in genomic and molecular profiling have revealed substantial inter- and intratumoral heterogeneity across the major subtypes, including osteosarcoma, Ewing sarcoma and chondrosarcoma, challenging conventional histology-driven treatment strategies. Precision medicine approaches are being increasingly explored to better capture this biological complexity and guide individualized therapeutic decision-making. This review examines emerging precision oncology strategies in bone sarcomas, including molecular diagnostics, targeted therapeutic approaches, three-dimensional functional modeling systems, and liquid biopsy technologies for dynamic disease monitoring. Together, these platforms provide biologically informed frameworks for patient-specific treatment and longitudinal assessment of tumor evolution. However, clinical implementation remains limited by genomic complexity, small patient cohorts, and methodological variability across experimental platforms. The integration of multi-layered precision models combining genomic stratification, functional drug sensitivity testing and circulating biomarker monitoring may enable more adaptive and individualized management strategies. Such approaches have the potential to improve therapeutic selection and ultimately advance outcomes for patients with primary bone sarcomas.
Primary bone sarcomas are rare and biologically heterogeneous malignancies for which therapeutic progress remains limited, particularly in metastatic and recurrent disease. Advances in genomic and molecular profiling have revealed substantial inter- and intratumoral heterogeneity across the major subtypes, including osteosarcoma, Ewing sarcoma and chondrosarcoma, challenging conventional histology-driven treatment strategies. Precision medicine approaches are being increasingly explored to better capture this biological complexity and guide individualized therapeutic decision-making. This review examines emerging precision oncology strategies in bone sarcomas, including molecular diagnostics, targeted therapeutic approaches, three-dimensional functional modeling systems, and liquid biopsy technologies for dynamic disease monitoring. Together, these platforms provide biologically informed frameworks for patient-specific treatment and longitudinal assessment of tumor evolution. However, clinical implementation remains limited by genomic complexity, small patient cohorts, and methodological variability across experimental platforms. The integration of multi-layered precision models combining genomic stratification, functional drug sensitivity testing and circulating biomarker monitoring may enable more adaptive and individualized management strategies. Such approaches have the potential to improve therapeutic selection and ultimately advance outcomes for patients with primary bone sarcomas.
DOI: https://doi.org/10.37349/etat.2026.1002396
This article belongs to the special issue Precision Oncology: Molecular Classification, Efficacy Prediction, and Treatment Decision-Making
Aim:
The aim of our study was to evaluate the safety and efficacy of delivering systemic treatments concurrently with whole-brain radiotherapy (WBRT).
Methods:
A single-institution, prospective observational study was conducted in Athens, Greece, including 99 patients treated with WBRT for brain metastases from September 2017 until October 2019, and with a follow-up period extending to March 2025. The study endpoints included overall survival (OS) for all causes of death, time to intracranial progression (TTICP), and serious acute toxicities.
Results:
The median OS from all causes of death was 6 months [95% confidence interval (CI): 4.7–7.3]. Concomitant systemic therapy reduced the risk of death (p = 0.005), and the presence of systemic metastases (p = 0.009) increased the risk of death for patients with brain metastases treated with whole brain radiotherapy. The median TTICP was 10 months (95% CI: 3.3–16.6), with a more protracted fractionation and a larger number of brain metastases being prognostic of an increase in the TTICP. Acute severe toxicity was observed in 16.2% of patients, with no statistically significant difference between concurrent and no systemic therapy groups, and with no treatment interruptions in patients treated concurrently.
Conclusions:
This study showed that there is no serious toxicity from the combination of systemic therapy with WBRT, and that the OS and the TTICP are not compromised with their concurrent delivery.
Aim:
The aim of our study was to evaluate the safety and efficacy of delivering systemic treatments concurrently with whole-brain radiotherapy (WBRT).
Methods:
A single-institution, prospective observational study was conducted in Athens, Greece, including 99 patients treated with WBRT for brain metastases from September 2017 until October 2019, and with a follow-up period extending to March 2025. The study endpoints included overall survival (OS) for all causes of death, time to intracranial progression (TTICP), and serious acute toxicities.
Results:
The median OS from all causes of death was 6 months [95% confidence interval (CI): 4.7–7.3]. Concomitant systemic therapy reduced the risk of death (p = 0.005), and the presence of systemic metastases (p = 0.009) increased the risk of death for patients with brain metastases treated with whole brain radiotherapy. The median TTICP was 10 months (95% CI: 3.3–16.6), with a more protracted fractionation and a larger number of brain metastases being prognostic of an increase in the TTICP. Acute severe toxicity was observed in 16.2% of patients, with no statistically significant difference between concurrent and no systemic therapy groups, and with no treatment interruptions in patients treated concurrently.
Conclusions:
This study showed that there is no serious toxicity from the combination of systemic therapy with WBRT, and that the OS and the TTICP are not compromised with their concurrent delivery.
DOI: https://doi.org/10.37349/etat.2026.1002395
Breast cancer remains one of the leading causes of cancer-related mortality worldwide, and despite considerable advances in therapeutic strategies, the absence of reliable, minimally invasive diagnostic tools continues to limit early detection and real-time disease monitoring. Liquid biopsy has emerged as a transformative paradigm in oncology, offering the capacity to integrate tumor biology through the analysis of tumor-derived materials that circulate in peripheral blood and other biofluids. This review provides a comprehensive overview of the key analytes employed in liquid biopsy, including circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), microRNAs (miRNAs), extracellular vesicles (EVs), and protein biomarkers with particular emphasis on their translational relevance in breast cancer. Drawing on landmark clinical trials and foundational molecular studies, we highlight how these biomarkers capture spatial and temporal tumor heterogeneity in ways that conventional tissue biopsy cannot. Finally, we address the technical, clinical, and ethical challenges that still impede widespread adoption of liquid biopsy, and we outline a forward-looking research agenda oriented toward multi-omics integration and point-of-care diagnostics. Taken together, this review underscores the potential of liquid biopsy to complement existing diagnostic standards and improve how we screen for, monitor, and treat breast cancer across disease stages.
Breast cancer remains one of the leading causes of cancer-related mortality worldwide, and despite considerable advances in therapeutic strategies, the absence of reliable, minimally invasive diagnostic tools continues to limit early detection and real-time disease monitoring. Liquid biopsy has emerged as a transformative paradigm in oncology, offering the capacity to integrate tumor biology through the analysis of tumor-derived materials that circulate in peripheral blood and other biofluids. This review provides a comprehensive overview of the key analytes employed in liquid biopsy, including circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), microRNAs (miRNAs), extracellular vesicles (EVs), and protein biomarkers with particular emphasis on their translational relevance in breast cancer. Drawing on landmark clinical trials and foundational molecular studies, we highlight how these biomarkers capture spatial and temporal tumor heterogeneity in ways that conventional tissue biopsy cannot. Finally, we address the technical, clinical, and ethical challenges that still impede widespread adoption of liquid biopsy, and we outline a forward-looking research agenda oriented toward multi-omics integration and point-of-care diagnostics. Taken together, this review underscores the potential of liquid biopsy to complement existing diagnostic standards and improve how we screen for, monitor, and treat breast cancer across disease stages.
DOI: https://doi.org/10.37349/etat.2026.1002394
This article belongs to the special issue Breaking Boundaries in Breast Cancer Care: Emerging Controversies and Innovation in Surgical and Medical Approaches
Aim:
Breast cancer remains a major cause of cancer-related mortality in women, particularly in advanced stages where therapeutic options are limited. While immune checkpoint inhibitors (ICIs) have improved outcomes in a subset of patients, many do not respond, highlighting the need for alternative immunotherapeutic strategies. This study evaluated the effect of dendritic cell (DC)-based immunotherapy on tumor growth and on the inflammatory profile of peritoneal myeloid cells in a 4T1 murine breast cancer model.
Methods:
BALB/c mice bearing 4T1 breast tumors were treated with bone marrow-derived DC-based immunotherapy. Tumor volume was monitored over time, and CD14+ cells obtained from peritoneal lavage were analyzed by flow cytometry for the cytokines IL-12, IL-17, and TNF-α and the transcription factors RORγT and GATA3.
Results:
DC-based immunotherapy was associated with a non-significant trend toward reduced tumor volume and a marked suppression of key proinflammatory cytokines: IL-12 (P < 0.0005), IL-17 (P < 0.0001), and TNF-α (P < 0.0001). Expression of the transcription factors RORγT and GATA3, associated with Th17 and Th2 differentiation, was also downregulated (P < 0.0001). These immunological effects were observed in CD14+ myeloid cells from the peritoneal compartment.
Conclusions:
DC-based immunotherapy modulates the systemic/peritoneal inflammatory profile and attenuates tumor-promoting inflammation. This strategy may offer therapeutic benefit for patients with breast cancer who are unresponsive to conventional or ICI-based treatments and supports its further evaluation in translational studies.
Aim:
Breast cancer remains a major cause of cancer-related mortality in women, particularly in advanced stages where therapeutic options are limited. While immune checkpoint inhibitors (ICIs) have improved outcomes in a subset of patients, many do not respond, highlighting the need for alternative immunotherapeutic strategies. This study evaluated the effect of dendritic cell (DC)-based immunotherapy on tumor growth and on the inflammatory profile of peritoneal myeloid cells in a 4T1 murine breast cancer model.
Methods:
BALB/c mice bearing 4T1 breast tumors were treated with bone marrow-derived DC-based immunotherapy. Tumor volume was monitored over time, and CD14+ cells obtained from peritoneal lavage were analyzed by flow cytometry for the cytokines IL-12, IL-17, and TNF-α and the transcription factors RORγT and GATA3.
Results:
DC-based immunotherapy was associated with a non-significant trend toward reduced tumor volume and a marked suppression of key proinflammatory cytokines: IL-12 (P < 0.0005), IL-17 (P < 0.0001), and TNF-α (P < 0.0001). Expression of the transcription factors RORγT and GATA3, associated with Th17 and Th2 differentiation, was also downregulated (P < 0.0001). These immunological effects were observed in CD14+ myeloid cells from the peritoneal compartment.
Conclusions:
DC-based immunotherapy modulates the systemic/peritoneal inflammatory profile and attenuates tumor-promoting inflammation. This strategy may offer therapeutic benefit for patients with breast cancer who are unresponsive to conventional or ICI-based treatments and supports its further evaluation in translational studies.
DOI: https://doi.org/10.37349/etat.2026.1002393
Aim:
Oligoprogressive disease (OPD) has emerged as a clinically relevant and common scenario in oncology, reflecting progression in a limited number of metastatic sites while systemic therapy continues to control the majority of disease. Despite its increasing recognition, the definition, diagnostic approach, and management of OPD remain poorly standardized.
Methods:
A multidisciplinary expert panel from Kazakhstan and international faculty, including ten medical oncologists, radiation, and surgical oncologists, participated in a structured survey. The questionnaire consisted of 15 items divided into three domains: definition of OPD, diagnostic evaluation, and treatment strategies. Responses were analyzed, and consensus was defined as ≥ 70% agreement, relative agreement as 50–69%, and lack of consensus as < 50%.
Results:
Consensus was reached that OPD is defined as progression in a limited number of lesions while other sites remain controlled, regardless of lesion size or localization. No consensus was achieved regarding the maximum number of progressive lesions, with experts divided between “≤ 5 lesions” and “any number amenable to local therapy.” Imaging with CT or PET-CT was considered sufficient. Biopsy and molecular testing were recommended only in selected contexts. Systemic therapy continuation during OPD was endorsed if effective, with strong support for local therapy, particularly stereotactic ablative radiotherapy (SBRT/SABR). Divergence remained regarding the management of repeat OPD.
Conclusions:
This Kazakhstan Cancer Society consensus defines the fundamental clinical features of OPD and provides practical recommendations for diagnosis and treatment. Comparison with international guidelines reveals broad alignment on systemic continuation and local therapy, as well as persistent variation regarding lesion number, biopsy, and repeat OPD management.
Aim:
Oligoprogressive disease (OPD) has emerged as a clinically relevant and common scenario in oncology, reflecting progression in a limited number of metastatic sites while systemic therapy continues to control the majority of disease. Despite its increasing recognition, the definition, diagnostic approach, and management of OPD remain poorly standardized.
Methods:
A multidisciplinary expert panel from Kazakhstan and international faculty, including ten medical oncologists, radiation, and surgical oncologists, participated in a structured survey. The questionnaire consisted of 15 items divided into three domains: definition of OPD, diagnostic evaluation, and treatment strategies. Responses were analyzed, and consensus was defined as ≥ 70% agreement, relative agreement as 50–69%, and lack of consensus as < 50%.
Results:
Consensus was reached that OPD is defined as progression in a limited number of lesions while other sites remain controlled, regardless of lesion size or localization. No consensus was achieved regarding the maximum number of progressive lesions, with experts divided between “≤ 5 lesions” and “any number amenable to local therapy.” Imaging with CT or PET-CT was considered sufficient. Biopsy and molecular testing were recommended only in selected contexts. Systemic therapy continuation during OPD was endorsed if effective, with strong support for local therapy, particularly stereotactic ablative radiotherapy (SBRT/SABR). Divergence remained regarding the management of repeat OPD.
Conclusions:
This Kazakhstan Cancer Society consensus defines the fundamental clinical features of OPD and provides practical recommendations for diagnosis and treatment. Comparison with international guidelines reveals broad alignment on systemic continuation and local therapy, as well as persistent variation regarding lesion number, biopsy, and repeat OPD management.
DOI: https://doi.org/10.37349/etat.2026.1002392
Aim:
Breast cancer is the most prevalent malignant tumor among women. Human papillomavirus (HPV) has been detected in breast tumors since the 1990s, and beyond its oncogenic potential, therapy resistance driven by viral immune evasion in non-anogenital tumors, such as oropharyngeal cancers, highlights the need to investigate viral activity in breast tissues. Among high-risk HPV types, HPV16 is one of the most prevalent and exhibits the highest carcinogenic potential. Therefore, this study aimed to evaluate the expression of HPV16 oncogenes E5, E6, and E7 in breast tumors, as well as the modulation of the PI3K/AKT/mTOR signaling pathway associated with viral activity.
Methods:
A total of 92 breast cancer patients were included after Ethics Committee approval. Clinical data were obtained from medical records. RNA was extracted from formalin-fixed, paraffin-embedded tissues and reverse-transcribed into cDNA. Transcripts of HPV oncogenes (E5, E6, and E7), components of the PI3K/AKT/mTOR pathway, and regulatory genes (EGFR and PTEN) were quantified by RT-qPCR. Gene expression levels were calculated using the ΔCt method.
Results:
Forty-eight samples met RNA quality criteria and were included in the expression analysis. Among these, 77.08% showed expression of at least one viral oncogene, with E5 being the most frequently expressed. The PI3K/AKT/mTOR pathway was modulated in HPV-positive samples, with increased PI3K expression and decreased mTOR expression. Notably, the high expression of E5—associated with immune evasion—combined with reduced mTOR expression suggests that HPV16 status may influence therapeutic response in breast cancer patients.
Conclusions:
These findings reinforce the importance of further studies investigating HPV activity in breast tumors to better understand its biological and clinical impact.
Aim:
Breast cancer is the most prevalent malignant tumor among women. Human papillomavirus (HPV) has been detected in breast tumors since the 1990s, and beyond its oncogenic potential, therapy resistance driven by viral immune evasion in non-anogenital tumors, such as oropharyngeal cancers, highlights the need to investigate viral activity in breast tissues. Among high-risk HPV types, HPV16 is one of the most prevalent and exhibits the highest carcinogenic potential. Therefore, this study aimed to evaluate the expression of HPV16 oncogenes E5, E6, and E7 in breast tumors, as well as the modulation of the PI3K/AKT/mTOR signaling pathway associated with viral activity.
Methods:
A total of 92 breast cancer patients were included after Ethics Committee approval. Clinical data were obtained from medical records. RNA was extracted from formalin-fixed, paraffin-embedded tissues and reverse-transcribed into cDNA. Transcripts of HPV oncogenes (E5, E6, and E7), components of the PI3K/AKT/mTOR pathway, and regulatory genes (EGFR and PTEN) were quantified by RT-qPCR. Gene expression levels were calculated using the ΔCt method.
Results:
Forty-eight samples met RNA quality criteria and were included in the expression analysis. Among these, 77.08% showed expression of at least one viral oncogene, with E5 being the most frequently expressed. The PI3K/AKT/mTOR pathway was modulated in HPV-positive samples, with increased PI3K expression and decreased mTOR expression. Notably, the high expression of E5—associated with immune evasion—combined with reduced mTOR expression suggests that HPV16 status may influence therapeutic response in breast cancer patients.
Conclusions:
These findings reinforce the importance of further studies investigating HPV activity in breast tumors to better understand its biological and clinical impact.
DOI: https://doi.org/10.37349/etat.2026.1002391
This article belongs to the special issue Breaking Boundaries in Breast Cancer Care: Emerging Controversies and Innovation in Surgical and Medical Approaches
Tumor heterogeneity and cellular plasticity are major drivers of therapeutic failure across many cancer types. While precision oncology has largely focused on static genomic alterations, growing evidence indicates that tumors behave as dynamic biological systems that continuously adapt during treatment. Tumor cell populations can transition between distinct functional states under therapeutic pressure, including transient drug-tolerant phenotypes that may precede stabilization of genetically or epigenetically resistant clones. These transitions are shaped by mechanisms such as epigenetic reprogramming, stress-response signaling, metabolic rewiring, and microenvironmental interactions. This review synthesizes findings from tumor plasticity, drug-tolerant persister biology, therapy-induced vulnerabilities, clonal evolution, and adaptive therapy to examine how temporal tumor dynamics influence treatment response. Emerging evidence suggests that some tumors may pass through short-lived phases of cellular instability during therapy in which molecular dependencies, stress-response programs, or adaptive survival states are altered before resistance becomes genetically or epigenetically stabilized. However, such transition states should be considered therapeutically actionable only when linked to functional evidence of altered drug sensitivity, pathway dependence, immune susceptibility, or clinical response. Advances in single-cell transcriptomics, epigenomic profiling, serial circulating tumor deoxyribonucleic acid (ctDNA)/cfDNA analysis, multi-omics integration, and dynamic imaging are enabling longitudinal monitoring of tumor state transitions and may facilitate identification of transient biological states preceding stable resistance. Integrating temporal tumor biology with therapeutic sequencing strategies, adaptive treatment schedules, and biomarker-guided monitoring may therefore help test whether specific adaptive states can be therapeutically exploited and may refine precision oncology approaches.
Tumor heterogeneity and cellular plasticity are major drivers of therapeutic failure across many cancer types. While precision oncology has largely focused on static genomic alterations, growing evidence indicates that tumors behave as dynamic biological systems that continuously adapt during treatment. Tumor cell populations can transition between distinct functional states under therapeutic pressure, including transient drug-tolerant phenotypes that may precede stabilization of genetically or epigenetically resistant clones. These transitions are shaped by mechanisms such as epigenetic reprogramming, stress-response signaling, metabolic rewiring, and microenvironmental interactions. This review synthesizes findings from tumor plasticity, drug-tolerant persister biology, therapy-induced vulnerabilities, clonal evolution, and adaptive therapy to examine how temporal tumor dynamics influence treatment response. Emerging evidence suggests that some tumors may pass through short-lived phases of cellular instability during therapy in which molecular dependencies, stress-response programs, or adaptive survival states are altered before resistance becomes genetically or epigenetically stabilized. However, such transition states should be considered therapeutically actionable only when linked to functional evidence of altered drug sensitivity, pathway dependence, immune susceptibility, or clinical response. Advances in single-cell transcriptomics, epigenomic profiling, serial circulating tumor deoxyribonucleic acid (ctDNA)/cfDNA analysis, multi-omics integration, and dynamic imaging are enabling longitudinal monitoring of tumor state transitions and may facilitate identification of transient biological states preceding stable resistance. Integrating temporal tumor biology with therapeutic sequencing strategies, adaptive treatment schedules, and biomarker-guided monitoring may therefore help test whether specific adaptive states can be therapeutically exploited and may refine precision oncology approaches.
DOI: https://doi.org/10.37349/etat.2026.1002390
Aim:
Minimally invasive approaches for radical cystectomy (RC) have been increasingly adopted; however, comparative evidence regarding surgical quality and perioperative outcomes among open (ORC), laparoscopic (LRC), and robot-assisted RC (RARC) remains limited. This study evaluated these three modalities using standardized composite metrics, trifecta and pentafecta, and inverse probability of treatment weighting.
Methods:
We retrospectively analyzed 192 patients who underwent RC with ileal conduit or neobladder reconstruction between 2006 and 2023. Inverse probability of treatment weighting was applied using comprehensive clinicopathological covariates. Trifecta and pentafecta achievements, perioperative parameters, and postoperative complications were compared among the ORC (n = 110), LRC (n = 38), and RARC (n = 44) groups.
Results:
RARC achieved the most favorable perioperative and surgical outcomes. Specifically, RARC showed significantly higher rates of several trifecta and pentafecta components than ORC, including fewer positive soft tissue surgical margins (0.0% vs. 5.2%, P < 0.01), reduced major complication rates within 90 days (16.1% vs. 44%, P < 0.05), and fewer urinary diversion–related sequelae within 12 months (1.5% vs. 13.5%, P < 0.05). RARC was also associated with significantly lower blood loss than ORC (380 ± 513 mL vs. 2,913 ± 2,997 mL, P < 0.01), as well as lower rates of pelvic abscess, gastrointestinal anastomotic leakage, and obstructive ileus (all P < 0.01) than ORC. In contrast, LRC was not superior to ORC in terms of major complications or diversion-related outcomes. Local pelvic recurrence within 12 months did not differ significantly among the three modalities.
Conclusions:
RARC may be a favorable surgical option for reducing perioperative morbidity in patients with high-grade bladder cancer, with comparable 12-month local recurrence rates among surgical approaches.
Aim:
Minimally invasive approaches for radical cystectomy (RC) have been increasingly adopted; however, comparative evidence regarding surgical quality and perioperative outcomes among open (ORC), laparoscopic (LRC), and robot-assisted RC (RARC) remains limited. This study evaluated these three modalities using standardized composite metrics, trifecta and pentafecta, and inverse probability of treatment weighting.
Methods:
We retrospectively analyzed 192 patients who underwent RC with ileal conduit or neobladder reconstruction between 2006 and 2023. Inverse probability of treatment weighting was applied using comprehensive clinicopathological covariates. Trifecta and pentafecta achievements, perioperative parameters, and postoperative complications were compared among the ORC (n = 110), LRC (n = 38), and RARC (n = 44) groups.
Results:
RARC achieved the most favorable perioperative and surgical outcomes. Specifically, RARC showed significantly higher rates of several trifecta and pentafecta components than ORC, including fewer positive soft tissue surgical margins (0.0% vs. 5.2%, P < 0.01), reduced major complication rates within 90 days (16.1% vs. 44%, P < 0.05), and fewer urinary diversion–related sequelae within 12 months (1.5% vs. 13.5%, P < 0.05). RARC was also associated with significantly lower blood loss than ORC (380 ± 513 mL vs. 2,913 ± 2,997 mL, P < 0.01), as well as lower rates of pelvic abscess, gastrointestinal anastomotic leakage, and obstructive ileus (all P < 0.01) than ORC. In contrast, LRC was not superior to ORC in terms of major complications or diversion-related outcomes. Local pelvic recurrence within 12 months did not differ significantly among the three modalities.
Conclusions:
RARC may be a favorable surgical option for reducing perioperative morbidity in patients with high-grade bladder cancer, with comparable 12-month local recurrence rates among surgical approaches.
DOI: https://doi.org/10.37349/etat.2026.1002389
Aim:
Despite advances with immune checkpoint inhibitor (ICI)-based regimens in the past decade, patients with metastatic urothelial cancer (mUC) face a poor prognosis with few approved options. Platinum-based chemotherapy with paclitaxel and carboplatin (TC) +/– ICI may be a feasible choice.
Methods:
We generated an IRB-approved, HIPAA-compliant retrospective database of patients at Mayo Clinic Cancer Center with mUC who started TC +/– ICI after disease progression on ICI from January 2018 through December 2024. Baseline demographics, clinicopathologic features, and treatment outcomes were extracted from the electronic health record. Kaplan-Meier method was used to calculate median duration of response (DOR), progression-free survival (PFS) and overall survival (OS).
Results:
There were 32 patients who fit inclusion criteria, including 31 patients who had disease progression on ICI in the metastatic setting and 1 patient who developed metastatic disease on adjuvant nivolumab. Patients received a median of 4 cycles (range 1–14) of TC over median 12 weeks (range 3–53). Overall, 81% of patients received TC concurrently with an ICI, and 28% continued maintenance ICI after TC discontinuation (at the treating oncologist’s discretion due to adequate response or toxicity). The best objective response rate was 41% and disease control rate was 75%, with median DOR of 4.8 months (IQR 2.7–10.4), median PFS of 4.6 months (IQR 3.3–10.2), and median OS of 9.4 months (IQR 6.3–15.9). Some patients in this series had very durable responses with PFS > 12 months and OS > 24 months. TC +/– ICI was overall well tolerated with expected type and severity of adverse events.
Conclusions:
Strategies to overcome ICI resistance are needed, and TC +/– ICI after disease progression on an ICI shows promising tolerability and efficacy in this setting for patients with mUC. Our series was notable for some patients having a durable response. Validation in larger cohorts is warranted.
Aim:
Despite advances with immune checkpoint inhibitor (ICI)-based regimens in the past decade, patients with metastatic urothelial cancer (mUC) face a poor prognosis with few approved options. Platinum-based chemotherapy with paclitaxel and carboplatin (TC) +/– ICI may be a feasible choice.
Methods:
We generated an IRB-approved, HIPAA-compliant retrospective database of patients at Mayo Clinic Cancer Center with mUC who started TC +/– ICI after disease progression on ICI from January 2018 through December 2024. Baseline demographics, clinicopathologic features, and treatment outcomes were extracted from the electronic health record. Kaplan-Meier method was used to calculate median duration of response (DOR), progression-free survival (PFS) and overall survival (OS).
Results:
There were 32 patients who fit inclusion criteria, including 31 patients who had disease progression on ICI in the metastatic setting and 1 patient who developed metastatic disease on adjuvant nivolumab. Patients received a median of 4 cycles (range 1–14) of TC over median 12 weeks (range 3–53). Overall, 81% of patients received TC concurrently with an ICI, and 28% continued maintenance ICI after TC discontinuation (at the treating oncologist’s discretion due to adequate response or toxicity). The best objective response rate was 41% and disease control rate was 75%, with median DOR of 4.8 months (IQR 2.7–10.4), median PFS of 4.6 months (IQR 3.3–10.2), and median OS of 9.4 months (IQR 6.3–15.9). Some patients in this series had very durable responses with PFS > 12 months and OS > 24 months. TC +/– ICI was overall well tolerated with expected type and severity of adverse events.
Conclusions:
Strategies to overcome ICI resistance are needed, and TC +/– ICI after disease progression on an ICI shows promising tolerability and efficacy in this setting for patients with mUC. Our series was notable for some patients having a durable response. Validation in larger cohorts is warranted.
DOI: https://doi.org/10.37349/etat.2026.1002387
This article belongs to the special issue Emerging Innovation in Surgical and Medical Approaches on the Horizon for Urogenital Malignancies
Aim:
The aim was to determine the transcriptomic features of tumor and stromal cells in direct contact within tumor nodules in luminal and triple-negative breast cancer.
Methods:
Spatial transcriptomic profiling was performed using the Visium 10x platform on FFPE tumor tissue sections from 10 patients with luminal breast cancer and 9 patients with triple-negative breast cancer. Manual morphological annotation of spots and evaluation of differentially expressed genes (DEGs) in identified spot clusters were performed using Loupe Browser v8.0.0 (10X Genomics, USA). Activated biological processes were assessed using the Enrichr online resource and the GO Biological Process 2025 database. Ligand-receptor pairs were identified using the CellChat package (v2.0) in R (v4.4.2).
Results:
In luminal breast cancer, mixed cluster (tumor cells colocalized with stromal cells) was characterized by overexpression of genes encoding S100A family Ca2+-binding proteins (S100A4, S100A8, S100A9), matrix metalloproteinases (MMP2, MMP7, MMP14), cytokeratins (KRT5, KRT7, KRT15, KRT23, KRT81), the mesenchymal marker VIM, and epithelial-mesenchymal transition (EMT)-associated genes (ICAM1, PRRX1) compared to tumor-only cluster. In triple-negative breast cancer, mixed cluster showed overexpression of S100A2, S100A8, S100A9, the epithelial gene KRT6B, the cancer stem cell marker CD44, and NOTCH2, which is associated with negative regulation of EMT. In both breast cancer subtypes, mixed cluster showed transcriptomic enrichment of gene sets associated with regulation of the ERK/MAPK cascade, apoptosis, and cell adhesion and migration. Ligand-receptor pairs associated with cell-cell contact, EMT, and immune response were also detected in colocalized cells, with a broader spectrum of these pairs observed in luminal breast cancer.
Conclusions:
This study assessed the transcriptomic characteristics of directly contacting tumor and stromal cells and identified the spectrum of ligand-receptor pairs mediating their interactions. Characterizing the properties of cells at the tumor-stroma interface helps unravel mechanisms of breast cancer progression and identify novel diagnostic markers and therapeutic targets.
Aim:
The aim was to determine the transcriptomic features of tumor and stromal cells in direct contact within tumor nodules in luminal and triple-negative breast cancer.
Methods:
Spatial transcriptomic profiling was performed using the Visium 10x platform on FFPE tumor tissue sections from 10 patients with luminal breast cancer and 9 patients with triple-negative breast cancer. Manual morphological annotation of spots and evaluation of differentially expressed genes (DEGs) in identified spot clusters were performed using Loupe Browser v8.0.0 (10X Genomics, USA). Activated biological processes were assessed using the Enrichr online resource and the GO Biological Process 2025 database. Ligand-receptor pairs were identified using the CellChat package (v2.0) in R (v4.4.2).
Results:
In luminal breast cancer, mixed cluster (tumor cells colocalized with stromal cells) was characterized by overexpression of genes encoding S100A family Ca2+-binding proteins (S100A4, S100A8, S100A9), matrix metalloproteinases (MMP2, MMP7, MMP14), cytokeratins (KRT5, KRT7, KRT15, KRT23, KRT81), the mesenchymal marker VIM, and epithelial-mesenchymal transition (EMT)-associated genes (ICAM1, PRRX1) compared to tumor-only cluster. In triple-negative breast cancer, mixed cluster showed overexpression of S100A2, S100A8, S100A9, the epithelial gene KRT6B, the cancer stem cell marker CD44, and NOTCH2, which is associated with negative regulation of EMT. In both breast cancer subtypes, mixed cluster showed transcriptomic enrichment of gene sets associated with regulation of the ERK/MAPK cascade, apoptosis, and cell adhesion and migration. Ligand-receptor pairs associated with cell-cell contact, EMT, and immune response were also detected in colocalized cells, with a broader spectrum of these pairs observed in luminal breast cancer.
Conclusions:
This study assessed the transcriptomic characteristics of directly contacting tumor and stromal cells and identified the spectrum of ligand-receptor pairs mediating their interactions. Characterizing the properties of cells at the tumor-stroma interface helps unravel mechanisms of breast cancer progression and identify novel diagnostic markers and therapeutic targets.
DOI: https://doi.org/10.37349/etat.2026.1002388
We aimed to evaluate the suitability of archival ureteroscopic (URS) biopsy specimens for fibroblast growth factor receptor 3 (FGFR3) biomarker analysis in upper urinary tract urothelial carcinoma. Thirty-six patients with upper urinary tract urothelial carcinoma who underwent diagnostic URS and radical nephroureterectomy (RNU) were included. Among the 36 RNU-derived tissue specimens, 33 (92%) yielded valid FGFR3 RNA test results; the remaining three (8.3%) showed test failure because of undetectable amplification by reverse transcriptase-polymerase chain reaction. Of the 33 RNU specimens with valid amplification, eight (24%) had FGFR3 alterations. Of these eight specimens, two (25%) were valid for FGFR3 RNA testing; one showed positive concordance with the paired RNU specimen, whereas the other did not. The remaining six specimens (75%) showed test failure. Correlation analysis of FGFR3 immunohistochemical staining scores demonstrated a moderate positive correlation between RNU and paired URS specimens (Spearman’s ρ = 0.47, P = 0.004). Our findings indicate that URS biopsy specimens are unsuitable for FGFR3 RNA testing but may be useful for protein-based biomarker analysis when RNU specimens are unavailable.
We aimed to evaluate the suitability of archival ureteroscopic (URS) biopsy specimens for fibroblast growth factor receptor 3 (FGFR3) biomarker analysis in upper urinary tract urothelial carcinoma. Thirty-six patients with upper urinary tract urothelial carcinoma who underwent diagnostic URS and radical nephroureterectomy (RNU) were included. Among the 36 RNU-derived tissue specimens, 33 (92%) yielded valid FGFR3 RNA test results; the remaining three (8.3%) showed test failure because of undetectable amplification by reverse transcriptase-polymerase chain reaction. Of the 33 RNU specimens with valid amplification, eight (24%) had FGFR3 alterations. Of these eight specimens, two (25%) were valid for FGFR3 RNA testing; one showed positive concordance with the paired RNU specimen, whereas the other did not. The remaining six specimens (75%) showed test failure. Correlation analysis of FGFR3 immunohistochemical staining scores demonstrated a moderate positive correlation between RNU and paired URS specimens (Spearman’s ρ = 0.47, P = 0.004). Our findings indicate that URS biopsy specimens are unsuitable for FGFR3 RNA testing but may be useful for protein-based biomarker analysis when RNU specimens are unavailable.
DOI: https://doi.org/10.37349/etat.2026.1002385
This article belongs to the special issue Emerging Innovation in Surgical and Medical Approaches on the Horizon for Urogenital Malignancies
Aim:
Transurethral laser ablation (TULA) for recurrent bladder cancer is a less invasive treatment method for patients. We report here our initial clinical experience with TULA for recurrent bladder cancer.
Methods:
This retrospective study analyzed 48 patients. Twenty-four cases were treated with TULA and another 24 cases were treated with transurethral resection of bladder tumor (TURBT) from Feb 2024 to Mar 2025 at Kochi Medical School Hospital. Intraoperative and postoperative outcomes and recurrence-free survival (RFS) were analyzed between TULA and TURBT.
Results:
This study showed that TULA using a 980-nm diode laser was significantly shorter than TURBT in terms of perioperative results: operative time, hospital stay, catheterization, bladder irrigation, and postoperative hospital stay. Regarding the occurrence of complications, TULA was observed to be less prevalent than TURBT in all cases. Kaplan-Meier curves showed that TULA was significantly associated with longer RFS compared to TURBT (hazard ratio 4.739; 95% confidence interval, 1.272–17.65; p = 0.02039).
Conclusions:
Our preliminary results showed that TULA for recurrent bladder cancer is feasible and safe.
Aim:
Transurethral laser ablation (TULA) for recurrent bladder cancer is a less invasive treatment method for patients. We report here our initial clinical experience with TULA for recurrent bladder cancer.
Methods:
This retrospective study analyzed 48 patients. Twenty-four cases were treated with TULA and another 24 cases were treated with transurethral resection of bladder tumor (TURBT) from Feb 2024 to Mar 2025 at Kochi Medical School Hospital. Intraoperative and postoperative outcomes and recurrence-free survival (RFS) were analyzed between TULA and TURBT.
Results:
This study showed that TULA using a 980-nm diode laser was significantly shorter than TURBT in terms of perioperative results: operative time, hospital stay, catheterization, bladder irrigation, and postoperative hospital stay. Regarding the occurrence of complications, TULA was observed to be less prevalent than TURBT in all cases. Kaplan-Meier curves showed that TULA was significantly associated with longer RFS compared to TURBT (hazard ratio 4.739; 95% confidence interval, 1.272–17.65; p = 0.02039).
Conclusions:
Our preliminary results showed that TULA for recurrent bladder cancer is feasible and safe.
DOI: https://doi.org/10.37349/etat.2026.1002386
This article belongs to the special issue Emerging Innovation in Surgical and Medical Approaches on the Horizon for Urogenital Malignancies
The molecular pathogenesis of oral squamous cell carcinoma (OSCC) is a complex process involving genetic alterations that accumulate over time. The clinical presentation and management of patients vary according to several pathological factors, but lymph node involvement is a key consideration in this context. Accurate lymph node staging in the neck is challenging because metastases may be present at an early stage of oral cancer. This narrative review assesses the evolution of imaging techniques over the last five years, distinguishing between research and established methods in order to address specific clinical questions. Conventional imaging techniques, including ultrasonography, contrast-enhanced computed tomography, contrast-enhanced magnetic resonance imaging and fluorine-18 fluorodeoxyglucose positron emission tomography, are reviewed and compared with several noteworthy developments in optical and fluorescence imaging. In this scenario, various position papers and guidelines strongly suggest using scintigraphy for sentinel node biopsy. However, its use in clinical practice is not widespread. This is a direct result of unrelenting advances in imaging accuracy, treatment options and new diagnostic approaches. All these approaches are considered here, but none emerges as a universal solution. Overall, no single technique currently emerges as a universal solution. The most realistic strategy is an integrated, multidisciplinary pathway. Multimodal imaging integration framework and AI-assisted diagnostic strategy could provide a novel clinical decision-making pathway for cervical lymph node staging in T1–T2 stage OSCC patients.
The molecular pathogenesis of oral squamous cell carcinoma (OSCC) is a complex process involving genetic alterations that accumulate over time. The clinical presentation and management of patients vary according to several pathological factors, but lymph node involvement is a key consideration in this context. Accurate lymph node staging in the neck is challenging because metastases may be present at an early stage of oral cancer. This narrative review assesses the evolution of imaging techniques over the last five years, distinguishing between research and established methods in order to address specific clinical questions. Conventional imaging techniques, including ultrasonography, contrast-enhanced computed tomography, contrast-enhanced magnetic resonance imaging and fluorine-18 fluorodeoxyglucose positron emission tomography, are reviewed and compared with several noteworthy developments in optical and fluorescence imaging. In this scenario, various position papers and guidelines strongly suggest using scintigraphy for sentinel node biopsy. However, its use in clinical practice is not widespread. This is a direct result of unrelenting advances in imaging accuracy, treatment options and new diagnostic approaches. All these approaches are considered here, but none emerges as a universal solution. Overall, no single technique currently emerges as a universal solution. The most realistic strategy is an integrated, multidisciplinary pathway. Multimodal imaging integration framework and AI-assisted diagnostic strategy could provide a novel clinical decision-making pathway for cervical lymph node staging in T1–T2 stage OSCC patients.
DOI: https://doi.org/10.37349/etat.2026.1002384
Aim:
This study aims to investigate the expression and function of antisense long non-coding RNA (lncRNA) STEAP3-AS1 in breast cancer (BC). Additionally, it explores STEAP3’s regulatory relationship with STEAP3-AS1 and potential signaling pathways to provide a theoretical foundation for identifying novel therapeutic targets.
Methods:
Database prediction and collection of tissue samples were employed alongside a cell proliferation assay and Transwell migration and invasion assay to examine STEAP3-AS1 expression levels in BC tissues and cell lines, as well as its impact on cellular functions. Statistical analyses were performed, including two-tailed Student’s t-test, Mann-Whitney U test and analysis of variance (ANOVA).
Results:
Both database and 9 paired clinical tissue sample results demonstrate that STEAP3-AS1 expression was significantly downregulated in BC compared with normal breast tissues (P < 0.05). Compared with the estrogen receptor/progesterone receptor (ERPR)-negative (–)/human epidermal growth factor receptor-2 (Her2)-positive (+) subtype, the ERPR(+)/Her2(−) and ERPR(−)/Her2(−) subtypes exhibited a significantly lower expression level of STEAP3-AS1 (P < 0.05). Overexpression of STEAP3-AS1 markedly suppressed the proliferation, migration, and invasion capabilities of MDA-MB-231 and MCF-7 cells compared with negative controls (P < 0.05). Furthermore, STEAP3-AS1 exhibited a positive synergistic effect with its sense strand STEAP3, inhibiting BC cell migration and invasion.
Conclusions:
This study is the first to demonstrate the tumor-suppressive role of STEAP3-AS1 in BC. These findings provide novel insights into the mechanisms underlying BC progression and offer critical theoretical support for the development of new therapeutic strategies.
Aim:
This study aims to investigate the expression and function of antisense long non-coding RNA (lncRNA) STEAP3-AS1 in breast cancer (BC). Additionally, it explores STEAP3’s regulatory relationship with STEAP3-AS1 and potential signaling pathways to provide a theoretical foundation for identifying novel therapeutic targets.
Methods:
Database prediction and collection of tissue samples were employed alongside a cell proliferation assay and Transwell migration and invasion assay to examine STEAP3-AS1 expression levels in BC tissues and cell lines, as well as its impact on cellular functions. Statistical analyses were performed, including two-tailed Student’s t-test, Mann-Whitney U test and analysis of variance (ANOVA).
Results:
Both database and 9 paired clinical tissue sample results demonstrate that STEAP3-AS1 expression was significantly downregulated in BC compared with normal breast tissues (P < 0.05). Compared with the estrogen receptor/progesterone receptor (ERPR)-negative (–)/human epidermal growth factor receptor-2 (Her2)-positive (+) subtype, the ERPR(+)/Her2(−) and ERPR(−)/Her2(−) subtypes exhibited a significantly lower expression level of STEAP3-AS1 (P < 0.05). Overexpression of STEAP3-AS1 markedly suppressed the proliferation, migration, and invasion capabilities of MDA-MB-231 and MCF-7 cells compared with negative controls (P < 0.05). Furthermore, STEAP3-AS1 exhibited a positive synergistic effect with its sense strand STEAP3, inhibiting BC cell migration and invasion.
Conclusions:
This study is the first to demonstrate the tumor-suppressive role of STEAP3-AS1 in BC. These findings provide novel insights into the mechanisms underlying BC progression and offer critical theoretical support for the development of new therapeutic strategies.
DOI: https://doi.org/10.37349/etat.2026.1002380
This article belongs to the special issue Breaking Boundaries in Breast Cancer Care: Emerging Controversies and Innovation in Surgical and Medical Approaches
In recent years, immunotherapy has modified the treatment landscape of advanced and recurrent endometrial cancer (a/rEC), particularly for patients with defective mismatch repair and microsatellite instability-high (dMMR/MSI-H), significantly improving their outcomes. Its success in later treatment lines has led to its investigation and adoption as a first-line therapy, alone or with chemotherapy. However, despite the high and long-lasting efficacy of immune checkpoint inhibitors (ICIs) in dMMR/MSI-H EC, not all patients benefit from this treatment, and reasons underscoring primary resistance in this setting remain poorly understood and are not yet incorporated into clinical decision-making. Additionally, the correlation between ICI response, tumor mutational burden (TMB), and PD-L1 expression, well-documented in other tumors, appears inconsistent in EC. While proficient mismatch repair and microsatellite stable (MMRp/MSS) EC remain an unmet medical need, some patients within this group still respond to ICIs. Although several biomarkers, including TP53, BRCA, and homologous recombination deficiency (HRD), have been investigated, none have proven to be definitively predictive. This review examines the relevant trials with ICIs as a single agent or in combination in EC and explores the available evidence on potential predictive biomarkers.
In recent years, immunotherapy has modified the treatment landscape of advanced and recurrent endometrial cancer (a/rEC), particularly for patients with defective mismatch repair and microsatellite instability-high (dMMR/MSI-H), significantly improving their outcomes. Its success in later treatment lines has led to its investigation and adoption as a first-line therapy, alone or with chemotherapy. However, despite the high and long-lasting efficacy of immune checkpoint inhibitors (ICIs) in dMMR/MSI-H EC, not all patients benefit from this treatment, and reasons underscoring primary resistance in this setting remain poorly understood and are not yet incorporated into clinical decision-making. Additionally, the correlation between ICI response, tumor mutational burden (TMB), and PD-L1 expression, well-documented in other tumors, appears inconsistent in EC. While proficient mismatch repair and microsatellite stable (MMRp/MSS) EC remain an unmet medical need, some patients within this group still respond to ICIs. Although several biomarkers, including TP53, BRCA, and homologous recombination deficiency (HRD), have been investigated, none have proven to be definitively predictive. This review examines the relevant trials with ICIs as a single agent or in combination in EC and explores the available evidence on potential predictive biomarkers.
DOI: https://doi.org/10.37349/etat.2026.1002381
Reactive oxygen species (ROS) are important regulators of cancer biology, acting as tumor-promoting signaling mediators and inducers of oxidative cell death. Oncogenic signaling, mitochondrial dysfunction, metabolic rewiring, and microenvironmental stress lead to increased basal ROS levels in cancer cells, resulting in a state of chronic oxidative pressure. Tumors develop adaptive antioxidant programs such as glutathione and thioredoxin, NADPH regeneration pathways, and sustained activation of the Nrf2–Keap1 axis to adapt to these conditions, leading to redox plasticity and “Nrf2 addiction” in some cancers. This adaptive rewiring allows malignant cells to sustain proliferative signaling while evading ROS-induced cytotoxicity and contributes substantially to therapeutic resistance. Despite the great promise of ROS-targeted therapies in preclinical studies, their translation into the clinic has been challenging for decades. Large antioxidant trials failed or even increased cancer risk. Many pro-oxidant therapies have limited efficacy due to a narrow therapeutic window, systemic toxicity, poor tumor selectivity, and a dynamic ability of tumors to reprogram antioxidant defenses. The significant intra-tumoral and spatial heterogeneity of redox status further complicates these constraints, where different tumor regions and cellular subpopulations exhibit different metabolic states, ROS thresholds, and sensitivities to ferroptosis. Emerging evidence indicates that ferroptosis, an iron-dependent cell death triggered by lipid peroxidation, is a significant therapeutic liability of redox-adapted tumors, particularly when antioxidant buffering systems like GPX4, system Xc–, FSP1, or DHODH are impaired. This review discusses the molecular functions of ROS in tumor initiation, progression, immune regulation, metabolic adaptation, and therapeutic resistance and critically analyzes the reasons for clinical challenges in redox-targeted interventions despite extensive research. The review highlights the importance of adaptive antioxidant rewiring, redox-dependent metabolic flexibility, and the complexity of the tumor microenvironment in determining the therapeutic outcome. Finally, novel strategies in precision redox oncology are discussed, including biomarker-driven patient stratification, real-time redox profiling, ferroptosis-targeted therapies, and rational combination approaches with the aim to exploit tumor-specific redox vulnerabilities while minimizing toxicity to healthy tissues.
Reactive oxygen species (ROS) are important regulators of cancer biology, acting as tumor-promoting signaling mediators and inducers of oxidative cell death. Oncogenic signaling, mitochondrial dysfunction, metabolic rewiring, and microenvironmental stress lead to increased basal ROS levels in cancer cells, resulting in a state of chronic oxidative pressure. Tumors develop adaptive antioxidant programs such as glutathione and thioredoxin, NADPH regeneration pathways, and sustained activation of the Nrf2–Keap1 axis to adapt to these conditions, leading to redox plasticity and “Nrf2 addiction” in some cancers. This adaptive rewiring allows malignant cells to sustain proliferative signaling while evading ROS-induced cytotoxicity and contributes substantially to therapeutic resistance. Despite the great promise of ROS-targeted therapies in preclinical studies, their translation into the clinic has been challenging for decades. Large antioxidant trials failed or even increased cancer risk. Many pro-oxidant therapies have limited efficacy due to a narrow therapeutic window, systemic toxicity, poor tumor selectivity, and a dynamic ability of tumors to reprogram antioxidant defenses. The significant intra-tumoral and spatial heterogeneity of redox status further complicates these constraints, where different tumor regions and cellular subpopulations exhibit different metabolic states, ROS thresholds, and sensitivities to ferroptosis. Emerging evidence indicates that ferroptosis, an iron-dependent cell death triggered by lipid peroxidation, is a significant therapeutic liability of redox-adapted tumors, particularly when antioxidant buffering systems like GPX4, system Xc–, FSP1, or DHODH are impaired. This review discusses the molecular functions of ROS in tumor initiation, progression, immune regulation, metabolic adaptation, and therapeutic resistance and critically analyzes the reasons for clinical challenges in redox-targeted interventions despite extensive research. The review highlights the importance of adaptive antioxidant rewiring, redox-dependent metabolic flexibility, and the complexity of the tumor microenvironment in determining the therapeutic outcome. Finally, novel strategies in precision redox oncology are discussed, including biomarker-driven patient stratification, real-time redox profiling, ferroptosis-targeted therapies, and rational combination approaches with the aim to exploit tumor-specific redox vulnerabilities while minimizing toxicity to healthy tissues.
DOI: https://doi.org/10.37349/etat.2026.1002383
Aim:
The purpose is to explore the mechanism and new therapeutic strategy of lethal 3 malignant brain tumor like 4 (L3MBTL4) gene in pancreatic ductal adenocarcinoma (PDAC).
Methods:
Immunoprecipitation, siRNA knockdown, immunohistochemistry, homologous recombination (HR) and non-homologous end joining (NHEJ) reporter assays, comet assays, and a xenograft mouse model were employed.
Results:
L3MBTL4 was methylated in 16.3% (7/43) of intraductal papillary mucinous neoplasms, 19.0% (4/21) of mucinous cystic neoplasm, and 28.2% (84/298) of PDAC, and its expression was regulated by promoter region methylation. L3MBTL4 methylation was significantly associated with tumor differentiation and tumor size. The expression of L3MBTL4 inhibited cell proliferation, colony formation, and induced apoptosis and G1/S phase arrest. L3MBTL4 activated ATM/CHK2 and inhibited NHEJ signaling by interacting with Ku70. Loss of L3MBTL4 increased the sensitivity of PDAC cells to NU7441 both in vitro and in vivo.
Conclusions:
L3MBTL4 is a new component of NHEJ signaling and epigenetic silencing of L3MBTL4 sensitizes PDAC cells to DNA-PK inhibitors, providing a potential new therapeutic strategy.
Aim:
The purpose is to explore the mechanism and new therapeutic strategy of lethal 3 malignant brain tumor like 4 (L3MBTL4) gene in pancreatic ductal adenocarcinoma (PDAC).
Methods:
Immunoprecipitation, siRNA knockdown, immunohistochemistry, homologous recombination (HR) and non-homologous end joining (NHEJ) reporter assays, comet assays, and a xenograft mouse model were employed.
Results:
L3MBTL4 was methylated in 16.3% (7/43) of intraductal papillary mucinous neoplasms, 19.0% (4/21) of mucinous cystic neoplasm, and 28.2% (84/298) of PDAC, and its expression was regulated by promoter region methylation. L3MBTL4 methylation was significantly associated with tumor differentiation and tumor size. The expression of L3MBTL4 inhibited cell proliferation, colony formation, and induced apoptosis and G1/S phase arrest. L3MBTL4 activated ATM/CHK2 and inhibited NHEJ signaling by interacting with Ku70. Loss of L3MBTL4 increased the sensitivity of PDAC cells to NU7441 both in vitro and in vivo.
Conclusions:
L3MBTL4 is a new component of NHEJ signaling and epigenetic silencing of L3MBTL4 sensitizes PDAC cells to DNA-PK inhibitors, providing a potential new therapeutic strategy.
DOI: https://doi.org/10.37349/etat.2026.1002382
This article belongs to the special issue Cancer Epigenetics: Implications for Novel Therapeutic Strategies
