Non-small cell lung cancer (NSCLC) is the predominant form of lung cancer. Ferroptosis is a novel therapeutic target against treatment resistance in NSCLC. However, its regulation by m6A RNA modification remains incompletely elucidated. m6A RNA modification mediates mRNA stability, translation, and splicing to target transcripts. Methyltransferase like 7B (METTL7B) has been implicated in tumor progression, but its role in NSCLC ferroptosis via m6A modification have not been reported. We aimed to investigate the mechanism of METTL7B-medaited m6A modification in NSCLC cell ferroptosis. NSCLC cells (SK-MES-1/PC9/H1975/A549) and normal cells (BEAS-2B) were cultured. The expression of METTL7B, long non-coding RNA 02159 (LINC02159), and aryl hydrocarbon receptor nuclear translocator-like 2 (ARNTL2) was determined. After METTL7B knockdown, cell viability was measured by MTT assay; ferroptosis-related factors were analyzed. m6A quantification was performed. m6A enrichment on LINC02159 was analyzed. The interaction between LINC02159 and KAT2A was verified. KAT2A and H3K27ac enrichment on the ARNTL2 promoter was detected. The roles of LINC02159 and ARNTL2 were validated. METTL7B, LINC02159, and ARNTL2 were upregulated in NSCLC cells compared to BEAS-2B cells. METTL7B knockdown increased iron ions, reactive oxygen species, and malondialdehyde levels and decreased cell viability, superoxide dismutase, and glutathione levels. METTL7B potentially upregulate LINC02159 expression through m6A modification. LINC02159 may recruit KAT2A to enhance H3K27ac enrichment on the ARNTL2 promoter, thereby promoting ARNTL2 expression. Overexpression of LINC02159 or ARNTL2 partially reversed the pro-ferroptotic effects of METTL7B knockdown on NSCLC cells. In conclusion, METTL7B inhibits ferroptosis in NSCLC cells via the LINC02159/KAT2A/ARNTL2 axis in an m6A-dependent manner.

Neutrophils are the most abundant circulating leukocytes and are raipidly recruited to inflammatory sites as key effectors of innate immunity. Nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV)-associated epithelial malignancy endemic in Southeast Asia and North Africa, develops within a chronically inflamed and immunologically specialized tumor microenvironment (TME). Current standard therapies (concurrent chemoradiotherapy and induction chemotherapy) face challenges of recurrence and metastasis, highlighting the need to explore the role of neutrophils in NPC progression and potential therapeutic targets. EBV shapes the cytokine/chemokine milieu in the NPC TME, driving neutrophil recruitment and reprogramming into a continuum of tumor-associated neutrophils (TANs) and PMN-MDSC-like states. These neutrophils promote tumor progression via immunosuppression, extracellular matrix remodeling, angiogenesis, and metastasis. Neutrophil extracellular traps (NETs) further mediate immune evasion, thrombosis, and dissemination. Clinically, peripheral inflammatory indices correlate with NPC prognosis but are limited by heterogeneous cutoffs and confounding factors. Neutrophils also exhibit context-dependent anti-tumor effects. Potential therapies include targeting the CXCL8-CXCR1/2 axis, modulating NET formation, and combining with immune checkpoint inhibitors. This review establishes a unifying framework linking EBV-driven inflammation to neutrophil plasticity, NET biology, and NPC progression. Neutrophils are dynamic, targetable components with dual pro-tumor and anti-tumor roles. While neutrophil-related indices hold prognostic value, their clinical translation requires standardization and integration with other biomarkers. Targeting suppressive neutrophil programs and NETs offers promising strategies to improve therapeutic efficacy and overcome treatment resistance in NPC.

High-grade serous ovarian carcinoma (HGSOC) is characterised by profound genomic instability and limited durable responses to standard therapy, leading to poor prognosis. The use of next-generation sequencing technologies has improved understanding of its molecular landscape, revealing consistent Tumour Protein p53 (TP53) mutations, homologous recombination defects, pathway alterations, and epigenetic dysregulation. Such genomic profiling now underpins the classification criteria between the ovarian cancer subtypes described by the Cancer Genome Atlas. Widespread chromosomal instability and pathogenic variants in multiple genes distinguish HGSOC from other subtypes of ovarian cancer and, further, from low-grade serous ovarian cancer. Importantly, the new-found understanding of the genomic landscape of HGSOC guides the use of platinum-based chemotherapies and Poly(ADP-ribose) Polymerase (PARP) inhibitors, with homologous recombination deficiency emerging as a cancer vulnerability that enhances treatment response. A combined multi-omics approach integrates transcriptomics, proteomics, metabolomics, and epigenomics to further the understanding of the characteristics, therapeutic targets and treatment resistance within HGSOC. Despite these advances, major challenges persist, including intratumoural heterogeneity and the poor diversity of genomic datasets. Artificial Intelligence (AI) technology, Clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing, neoantigen-guided immunotherapy and ovarian cancer vaccination indicate a promising future for genomics-guided interventions and support the integration of genomics within multi-omic approaches to improve HGSOC outcomes.

Liquid biopsy (LB) offers a minimally invasive approach to characterizing and monitoring glioblastoma (GB), a tumor marked by extensive heterogeneity, limited surgical accessibility and rapid molecular evolution. By analyzing circulating tumor-derived components such as circulating tumor DNA (ctDNA), extracellular vesicles (EVs), circulating RNA species and circulating tumor cells (CTC), LB provides dynamic molecular information that cannot be captured by neuroimaging or single-site tissue sampling. Cerebrospinal fluid (CSF) currently yields the highest sensitivity for detecting tumor-specific alterations, while plasma enables repeat monitoring despite lower biomarker abundance. EVs have gained particular prominence due to their ability to preserve DNA, RNA, and protein cargo that reflects key genomic changes, treatment resistance mechanisms, and immune evasion. Although advances are substantial, clinical implementation remains constrained by low analyte concentrations, methodological variability, limited standardization and the high cost of testing, which is rarely reimbursed by insurers. This review summarizes current evidence on circulating biomarkers in GB and highlights research priorities essential for integrating LB into future diagnostic and therapeutic workflows.

Existing salvage therapies for recurrent glioblastoma (rGBM) have limited efficacy, with median survival of approximately 9 months. Given the complex molecular heterogeneity of GBM, single-target approaches have consistently failed as a treatment strategy. We conducted a phase 1 clinical trial to assess the feasibility, safety, and efficacy of a genomically-tailored multi-agent regimen in 30 adults with surgically-treated rGBM. Adults with IDH-wildtype glioblastoma (n=29) or grade 4 IDH-mutant astrocytoma (n=1) were consented and underwent clinically-indicated surgery for recurrent disease. Comprehensive genomic profiling was performed on the recurrent tumors, and results for each patient were discussed at an individualized molecular tumor board to determine a personalized treatment regimen combining up to 4 FDA-approved drugs, including one cytotoxic agent as backbone. A total of 12 drugs were used in 18 combinations - the most common regimen was lomustine, afatinib, and abemaciclib (n=8). The most common toxicities included cytopenias, rash, and gastrointestinal symptoms, requiring frequent dose reductions. Measured from surgery at trial enrollment, progression-free survival at 6 months (PFS-6) was 40%, overall survival at 9 months (OS-9) was 73%, and median OS was 12.7 months. After trial therapy, genomic profiling performed on subsequent recurrent tumor specimens identified genetic evolution corresponding to putative treatment resistance mechanisms. Implementation of individualized treatment regimens in a timely fashion was feasible for patients with surgically resectable rGBM. Overall efficacy was not significantly improved compared to a contemporary patient cohort treated without experimental regimens, with full dosing of most combination therapies limited by toxicities.

Oncolytic viruses (OVs) represent a promising strategy in cancer immunotherapy, as they selectively infect and lyse tumor cells while simultaneously triggering robust antitumor immune responses. By inducing immunogenic cell death, OVs enhance tumor antigen presentation and initiate a systemic immune response, effectively transforming the tumor microenvironment from an immune-suppressive state to an immune-permissive state. In addition to exerting direct oncolytic effects, OVs modulate key tumor-associated biological processes, including tumor angiogenesis and extracellular matrix remodeling, disrupting tumor progression and metastasis. Notably, recent advances have highlighted the therapeutic potential of combining OVs with conventional and emerging cancer treatments, such as chemotherapy, radiotherapy, immune checkpoint inhibitors, adoptive cell therapy, and epigenetic-targeted drugs. These combination strategies demonstrate synergistic effects by improving tumor selectivity, increasing antitumor immunity, and overcoming treatment resistance. Nevertheless, persistent challenges, such as viral dissemination dynamics, therapy resistance, and regulatory complexities, impede the broad clinical implementation of oncolytic virus therapy (OVT). In this Review, we illustrate recent advancements and innovative therapeutic strategies in OVT within the context of contemporary cancer treatment paradigms. First, we outline the historical evolution and key milestones in OVT development. We then discuss the classification of OVs and their multimodal mechanisms that target tumorigenesis, metastasis, disease recurrence, and therapy resistance. Finally, we evaluate the clinical research progress of OVT applications, focusing on their integration with other therapies, analyze the translational barriers hindering clinical implementation, and propose evidence-based future directions for optimizing cancer treatment.

Evolutionary therapy (ET) applies principles of evolutionary biology to steer tumour dynamics and forestall or delay treatment resistance, typically guided by data-driven mathematical models. Our aim is to assess whether ET protocols, and specifically Zhang et al.'s protocol proposed for metastatic castrate-resistant prostate cancer, can be theoretically effective for fast-growing metastatic cancers such as stage IV non-small-cell lung cancer (NSCLC). Using longitudinal tumour-burden data from NSCLC patients treated with erlotinib, we systematically evaluate 26 two-population differential-equation models based on classical tumour-growth dynamics, with varying assumptions about density- and frequency-dependent interactions, pharmacokinetics, and treatment-induced death. Previous work by Yin et al. on the same dataset employed an exponential model that omitted density- and frequency-dependent interactions; although it provided a good fit to tumour-burden data, its structure would theoretically lead to poorer outcomes under ET protocols. In contrast, our analysis identifies the minimal model structure required to reproduce the resistance-driven regrowth observed in NSCLC, with the Gompertzian model featuring log-kill dynamics and both density- and frequency-dependent interactions providing the best fit. In this model, Zhang et al.'s protocol prolonged median time-to-progression to 42.3 months compared with 24.8 months under maximum tolerated dose. These results indicate that ET is theoretically a viable treatment strategy for NSCLC. This study offers a practical framework for assessing ET feasibility using clinical data and supports future clinical translation of ET in NSCLC.

Growing evidence highlights the existence and tumor-promoting role of intratumoral bacteria in various types of cancers. However, the mechanisms enabling the intracellular survival of these microorganisms remain poorly understood, impeding the development of microbiota-targeting anticancer strategies. A transcriptomics analysis was used to identify the disease-related bacteria in nasopharyngeal carcinoma (NPC). Cell-bacteria coculture assay, cell viability assay, and mouse xenograft tumor model were used for functional investigation. Immunofluorescence, quantitative PCR analysis, RNA sequencing, immunoblot analysis, co-immunoprecipitation and mass spectrometry were utilized in mechanistic research. Fluorescent in situ hybridization in NPC specimens and clinical data were used for prognosis analysis. We discovered that the Fusobacterium nucleatum (F. nucleatum), especially the C2 clade of F. nucleatum subsp. animalis (Fna C2), acts as an intracellular pathogen and exhibits distinct colonization advantages in NPC by inhibiting autophagy flux in host cells. Mechanistically, the virulence protein FadA of Fna C2 increases the ubiquitination and promotes the degradation of Ras-related protein RAB7A by enhancing the interaction between RAB7A and the E3 ligase TRIM28, which thus impairs the autophagosome-lysosome fusion and the autophagy machinery. The dysfunctional autophagy not only enables the persistent intracellular survival of F. nucleatum but also contributes to the treatment resistance of NPC. Clinically, a high intratumoral F. nucleatum colonization is associated with tumor relapse and poor outcome in NPC patients. Our findings elucidate a key mechanism by which F. nucleatum survives and promotes treatment resistance in NPC, providing a microbiological prognosis indicator for NPC patients.

Ferroptosis, an iron dependent form of regulated cell death driven by lipid peroxidation, has emerged as a pivotal process in prostate cancer biology and therapy. This review summarizes the multifaceted regulation of ferroptosis in prostate cancer from molecular, metabolic, and microenvironmental perspectives. Core regulators such as GPX4, SLC7A11, and ACSL4 coordinate redox balance, glutathione metabolism, and lipid peroxidation, together determining ferroptotic sensitivity. Transcriptional, epigenetic, and post translational mechanisms including STAT3, the JMJD6 ATF4 axis, and TRIM family proteins further refine ferroptosis regulation. Metabolic reprogramming involving APOC1, SLC25A10, and BCAT2, as well as mitochondrial dynamics governed by VSTM2L and RPS6KC1, establishes metabolic dependencies that influence resistance or susceptibility to ferroptosis. Within the tumor microenvironment, cancer-associated fibroblasts and extracellular matrix components modulate ferroptosis through lactate signaling, exosomal microRNAs, and detachment resistance. Clinically, ferroptosis-related gene signatures provide valuable prognostic tools and predict responses to radiotherapy, antiandrogen therapy, and immunotherapy, linking ferroptotic dysregulation with immune suppression and treatment resistance. Emerging therapeutic strategies that inhibit GPX4 or system Xc-, modulate iron metabolism, and employ PSMA-targeted nanoplatforms have shown potent antitumor efficacy, especially in castration resistant disease. Repurposed drugs such as flubendazole and the ezetimibe derivative L14-8, along with natural compounds including evodiamine and luteolin, demonstrate translational potential for ferroptosis induction. Collectively, ferroptosis represents a promising therapeutic vulnerability for precision treatment of advanced prostate cancer.

BackgroundSkin cancers, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), cutaneous melanoma (CM) and acral melanoma (AM), exhibit profound heterogeneity in clinical behaviour and therapeutic response. However, how tumour‐immune ecosystems are remodelled across skin cancer types and disease stages, and how these changes influence immune escape and treatment resistance, remain poorly understood.MethodsHere, we integrate single‐cell transcriptomics data from 102 skin cancer samples (including adjacent normal skin, early‐stage and advanced‐stage tumours), with bulk RNA‐seq prognosis cohorts, immunofluorescence staining and in vitro assays to define clinically relevant immune remodelling patterns.ResultsOur analyses identify a malignant NARS2+NDUFC2+ melanoma cell subpopulation, characterised by reduced MHC‐I expression, enriched in advanced‐stage tumours and associated with worse survival and immunotherapy response. CRISPR screening further showed that NARS2 and NDUFC2 are necessary for the proliferation of melanoma cells, highlighting these genes as potential therapeutic targets. Tumour‐associated macrophages (TAMs) originate from both FCN1+ monocytes and FOLR2+ tissue‐resident macrophages, displaying two polarisation states with distinct prognostic associations. Specifically, pro‐inflammatory CXCL9+CXCL10+ TAMs are enriched in SCC, while tissue‐remodelling SPP1+ TAMs are predominant in melanoma. Immunofluorescence staining confirmed that SPP1+ macrophage accumulation correlates with advanced stage, metastasis and poor prognosis in the melanoma cohort. Immune ecotype analysis reveals a transition from ‘T‐cell‐dominant’ ecotypes to ‘desert’ ecotypes as disease advances in BCC, CM and AM. Cell‒cell communication analysis shows that ‘T‐cell‐dominant’ ecotypes have higher MHC‐I signalling pathways in tumour cells, whereas ‘Desert’ ecotypes have higher SPP1+ macrophage signalling, underlining the role of SPP1 on immune remodelling. Functional assays confirm that melanoma cells could drive M2 polarisation and SPP1 upregulation in macrophages. Knocking down or overexpressing SPP1 correspondingly alters M2 gene expression in macrophages.ConclusionsThis study establishes a pan‐skin cancer immune remodelling framework, providing a foundation for biomarker discovery and the development of new immunotherapy strategies.

Glioblastoma (GB) is the most common and aggressive primary brain tumor in adults, with its significant inter- and intra-tumoral heterogeneity being a major factor in its treatment resistance and overall prognosis. GB diagnosis typically involves magnetic resonance imaging, confirmed by histology after surgical resection or biopsy. Recurrence is almost expected despite adjuvant therapies. Extracellular vesicles (EVs) may represent promising cancer biomarkers for diagnosis, prognosis, and therapeutic monitoring. In this work, we monitored 21GB patients at different time intervals performing a quantitative and dimensional analysis of plasma-derived EVs, with the aim of finding correlations with their clinical course. Our analyses revealed a slight correlation with patients' clinical conditions during follow-up, such as tumor time recurrence over time, but no significant difference in plasma EV concentration in GB patients and healthy control subjects (HC), contrary to previously published data. Although based on a limited number of patients, our methodological study highlights the need for a universal analysis method to compare data from large patient populations in order to use EVs as a biomarker for the diagnosis of recurrence by liquid biopsy, especially in GB, a tumor known for its heterogeneity.

The global obesity crisis requires precision biomarkers to overcome treatment resistance. We investigated circulating multi-omics signatures for predicting and monitoring glucagon-like peptide-1 receptor agonist (GLP-1RA) (GZR18) response, addressing gaps in personalized obesity therapy. We conducted longitudinal multi-omics profiling (proteomics, metabolomics, and lipidomics) of 221 plasma samples from 25 participants (n=25) treated with GZR18 at nine time points over 30 weeks. High-resolution mass spectrometry quantified molecular features alongside clinical body mass index (BMI) trajectories. Theil-Sen regression modeled baseline predictors (BMI slope Z), while linear regression analysis identified longitudinal biomarkers (%BMI change). Significant candidates (P<0.05) underwent gene set enrichment analysis (GSEA; Kyoto Encyclopedia of Genes and Genomes [KEGG] pathways) and STRING network integration, with dual-response biomarkers validated through correlation and trajectory analyses. GZR18-treated obese patients exhibited a dose-dependent reduction in BMI, with 48 mg biweekly producing the steepest declines (Z<-0.4 vs. placebo: Z=-0.22, P<0.001). We identified glycogenin 1 (GYG1) as a dual-function biomarker (coefficient= 2.0 for prediction, P<0.05 for monitoring) and as a central network hub. Lipidomic (phosphatidylinositol 18:2-18:2) and metabolomic (oxoglutaric acid) markers predicted baseline response, while proteomic (insulin like growth factor binding protein 2 [IGFBP2]) and lipidomic (phosphatidylcholine 18:0-20:3) profiles tracked longitudinal efficacy (P<0.05). Adipocytokine signaling governed the initial response (normalized enrichment score >1.8), while starch/sucrose metabolism modulated ongoing efficacy through integrated molecular networks. This study establishes GYG1 as a clinically actionable, dual-function biomarker for GLP-1RA therapy in obesity, linking baseline prediction and real-time monitoring of treatment response through integrated multi-omics profiling. Our findings highlight convergent metabolic pathways driving therapeutic efficacy and provide a precision-medicine framework for optimizing obesity pharmacotherapy through blood-based molecular signatures.

Deep-seated tumors are difficult to treat because of their location, conventional treatment resistance, and limited light penetration during photothermal therapy (PTT). Interstitial PTT with "inside-out" laser irradiation using optical fibers (OFs) offers a promising solution. This study proposes a drug-device integrated platform assisted by a puncture needle combining stimuli-responsive hydrogels with a spherical-tip polymer OF (SPOF) to overcome dual challenges: Inadequate photothermal agent retention and insufficient optical penetration. The injectable thermosensitive hydrogel (SW8@Gel), composed of Pluronic F127 and aza-boron-dipyrromethene-derived SW8 nanoparticles, rapidly undergoes sol-gel transition at 38°C, facilitating localized and sustained delivery of the photothermal agent. The flexible low-bending-loss SPOF emits 360° divergent near-infrared II (1064nm) light from its spherical tip, allowing single-fiber illumination of deep-seated tumors (penetration >10cm) in complex biological environments. Integrating these components enables depth-adaptive tumor ablation. Compared to other methods, the SPOF/SW8@Gel combination demonstrates the lowest frequency and shortest duration for PTT of deep-seated tumors and achieves superior efficacy, with a 90% tumor regression rate in mice models and no off-target damage due to enhanced heating uniformity and reduced systemic toxicity. This platform offers a transformative clinically viable solution for precise ablation of deep malignancies, bridging advanced photonics and targeted oncotherapy.

Ovarian cancer is a deadly gynecological malignancy, often detected late with frequent recurrence and treatment resistance. Non-coding RNAs, particularly long non-coding RNAs (lncRNAs), are now recognized as crucial regulators of cancer pathogenesis. This review synthesizes current literature to elucidate the molecular and functional roles of the lncRNA HAGLROS in ovarian cancer, focusing on its interactions within competing endogenous RNA (ceRNA) networks. HAGLROS, located at 2q31.1, is an oncogenic lncRNA that promotes ovarian cancer progression. It drives enhanced cell proliferation, metastasis, and chemotherapy resistance while inhibiting apoptosis. Its oncogenic activity is primarily mediated through intricate sponging interactions with microRNAs (miRNAs), disrupting post-transcriptional gene regulation and influencing epigenetic and transcriptional processes. The dysregulation of HAGLROS underscores its significant role in ovarian tumorigenesis. Its ability to modulate key cancer hallmarks via miRNA interactions reveals complex regulatory axes central to the disease's pathogenesis. HAGLROS represents a promising candidate for early diagnostic biomarkers and novel therapeutic interventions. Further investigation into the HAGLROS-miRNA-mRNA network is essential for defining its clinical utility and developing targeted treatments for ovarian cancer.

To determine the safety and efficacy of taselisib, a selective PI3K-inhibitor, in combination with tamoxifen. POSEIDON is a phaseII, randomized, placebo-controlled trial conducted from June 2016 to March 2020. Eligible patients were refractory upon prior endocrine therapy. Prior treatment with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and everolimus was allowed. Patients were randomized (1:1) to receive either taselisib (4mg) + tamoxifen (20mg) or placebo + tamoxifen. The primary endpoint of the trial was investigator-assessed progression-free survival (PFS) in the intention-to-treat (ITT) population (two-sided alpha 0.2, 90% power). Exploratory biomarker analysis with regards to prognosis and treatment resistance were conducted in circulating tumor (ct)DNA. POSEIDON met its primary endpoint, where patients treated with taselisib + tamoxifen had improved PFS compared to patients treated with placebo + tamoxifen in the ITT population (median PFS 4.8 months versus. 3.2 months; stratified hazard ratio 0.69, 80% CI 0.49-0.98, p=0.17). However, toxicity of taselisib was significant with diarrhea (40% any grade) as most common adverse event. Exploratory analyses indicated that high tumor fraction determined in ctDNA at baseline is associated with worse PFS and OS (p<0.0001). Our findings suggest efficacy of PI3K inhibition + tamoxifen beyond second-line treatment and after prior targeted therapies, including CDK4/6 inhibition in metastatic HR+/HER2- breast cancer although the magnitude of benefit did not outweigh the tolerability of this combination. Exploratory biomarker analysis indicates that tumor fraction determined in ctDNA differentiates patients based on prognosis and may help to optimize patient selection for targeted treatment strategies.

Extrachromosomal DNAs (ecDNAs) are acentric circular DNA elements that frequently mediate oncogene amplification and genomic rearrangements in human cancers. Found across diverse adult and paediatric malignancies, ecDNA drives rapid tumour evolution, metabolic adaptation and treatment resistance. Its presence in precancerous lesions and association with poor outcome underscore the need for improved detection and therapeutic targeting. Recent advances have substantially expanded our understanding of ecDNA biology, revealing mechanisms underlying oncogene plasticity and treatment failure. This Review synthesizes key findings on ecDNA biology, the challenges faced by current therapeutic and detection approaches and the recent discoveries that point to emerging therapeutic vulnerabilities. We propose future directions to ecDNA-focused therapeutic development, including the utility of chemical proteomics approaches, and discuss efforts required to integrate ecDNA diagnostics into the clinic, presenting a roadmap from bench to bedside.

Platinum-based chemotherapy is commonly used for non-small cell lung cancer (NSCLC) and high-grade serous ovarian cancer (HGSOC) treatments, yet clinical outcomes remain poor. Cellular senescence and its associated secretory phenotype (SASP) can have multiple tumor-promoting activities, but both are largely unexplored in these cancers. In this study, using xenograft, orthotopic and KrasG12V-driven murine NSCLC models, we demonstrate that cisplatin-induced senescence strongly promotes malignant phenotypes and tumor progression, which is stimulated by aging. Mechanistically, we found that a transforming growth factor-beta (TGFβ)-enriched SASP drives pro-proliferative effects through TGFBR1 and AKT/mTOR. TGFBR1 inhibition with galunisertib or senolytic treatment reduces tumor progression driven by cisplatin-induced senescence, and concomitant use of TGFBR1 inhibitors with platinum-based chemotherapy reduces tumor burden and improves survival. Finally, we validate the translational relevance of tumor-promoting TGFβ-enriched SASP using clinical NSCLC and HGSOC samples from patients who received neoadjuvant platinum-based chemotherapy. Together, our findings identify a potential cancer therapy resistance mechanism and provide preclinical proof of concept for future trials.

Plasticity of cancer, including epithelial-mesenchymal transition (EMT), cancer stem cell (CSC) self-renewal, and microenvironmental adaptation, drives metastasis, therapy resistance, and poor outcomes in prostate cancer (PCa). Ion channels and extrachromosomal DNA (ecDNA) have emerged as key drivers of such adaptive processes by influencing signaling, metabolism, and immune interactions. We evaluated available evidence on ion channel biology, ecDNA dynamics, and their roles in tumor plasticity and drug resistance in PCa. Further, we analyzed two publicly accessible single-cell RNA-sequencing (scRNA-seq) datasets (primary PCa and castration-resistant PCa) to determine ion channel and transporter expression profiles in tumor and stromal cell populations. Our analysis showed cell type-specific expression of many ion channels, including KCNJ10, CACNA1H, and CLIC1, and identification of six transporters (SLC25A1, SLC25A10, SLC25A33, SLC25A42, SLC29A2, SLC7A11) strongly enriched in luminal tumor cells. The discovered genes regulate mitochondrial metabolism, redox homeostasis, nucleotide biosynthesis, immune modulation, and resistance to ferroptosis, all contributing to tumor growth. ecDNA facilitates oncogene amplification (e.g., MYC, EGFR), induction of EMT, and immune evasion, driving intratumoral heterogeneity and therapy-resistant clones. Ion channels and ecDNA are central to the disease progression and treatment resistance of PCa through regulation of EMT, CSC phenotype, and tumor microenvironment (TME) interactions. Targeting the drivers-through ion channel modulators, ferroptosis induction, and ecDNA-targeting interventions (BET/HDAC inhibitors, CRISPR-based methods) offers a promising way to overcome resistance. Integration of multi-omics, and combination treatments will be key to construct precision medicine strategies and improve clinical outcomes in advanced PCa.

Iron homeostasis and ferroptosis: a converging axis in cancer therapy.

Epithelial ovarian cancer (EOC) represents the most lethal gynecologic malignancy, characterized by extensive tumor heterogeneity that contributes to treatment resistance and high recurrence rates. Recently, we developed SAIL66, a CLDN6-targeting T-cell engager currently in clinical evaluation for CLDN6-positive solid cancers including EOC. While CLDN6 is considered an attractive target for cancer therapy due to its cancer specificity, its biology remains poorly understood. In this study, we investigated the biological characteristics of CLDN6-positive EOC to identify its significance as a therapeutic target for ovarian cancer (OC) treatment. We demonstrated heterogeneous CLDN6 expression in xenograft and clinical tumors. In vitro cultured OC cell lines showed reversible changes in CLDN6 expression depending on cell density, accompanied by alterations in EMT-related and stemness-related genes. Spatial transcriptomic analysis of clinical specimens revealed that CLDN6-positive areas formed both solid regions and dispersed small clusters within the same tumors, with differential expression of EMT-related and cell-matrix remodeling genes between these areas, consistent with our in vitro observations at varying cell densities. Furthermore, carboplatin treatment increased CLDN6 expression, accompanied by changes in EMT-related genes. Leveraging these biological characteristics of CLDN6, we discovered that significant tumor regression was observed in mice treated with SAIL66 following carboplatin pretreatment. Post-carboplatin analysis revealed increased CLDN6 expression, EMT-related gene changes, and enhanced T-cell infiltration, which were associated with the synergistic effect of SAIL66. Our study provides insights into the biology and plasticity of CLDN6-positive cells in EOC heterogeneity and highlights the clinical significance of CLDN6-targeting therapies for ovarian cancer treatment.