Because of its limited treatment choices and high recurrence rates, bladder cancer (BCa) presents a significant clinical issue. As a result, current research is concentrated on creating novel approaches for early diagnosis and more specialized treatments. Nanorobots hold significant potential as precise medicine-delivery systems and as in situ diagnostic vectors within this dynamic environment. Personalized treatments are becoming increasingly feasible thanks to new insights into the molecular pathways driving tumor growth, revealed through studies on exosomes and non-coding RNAs (ncRNAs), however, their true potential lies in integrating these findings. This review analyzes the role of nanorobots, exosomes and ncRNAs in BCa and, more importantly, proposes a synergistic framework where active nanorobots are used for the targeted delivery of therapeutic exosomes (loaded with ncRNAs), overcoming the physiological limitations of intravesical administration. The interplay between nanorobots, exosomes and ncRNAs outlines a coherent and synergistic therapeutic approach with nanorobots enabling active navigation, exosomes offering stable and biocompatible loading, and ncRNAs providing the precision molecular functions required for targeted intervention. Their integration constitutes the core rationale driving this emerging approach and this technological convergence may open new avenues for precision diagnosis and targeted therapy. Incorporating these state-of-the-art technologies could ultimately transform the treatment of BCa and greatly enhance patient outcomes and quality of life. The aim of this review is to evaluate the current evidence on these three technologies and to define an integrated strategy that addresses existing clinical barriers and advances precision medicine in BCa.

Locally advanced head and neck squamous cell carcinoma (LA-HNSCC) remains difficult to treat despite multimodal therapy. Immune checkpoint inhibitors (ICIs) have expanded treatment options, but phase III trials combining ICIs with chemoradiotherapy have demonstrated limited survival benefit due to complex resistance mechanisms. These include immunosuppressive tumor microenvironments, impaired DNA damage responses, hypoxia-driven adaptations, metabolic reprogramming, and oncogenic signaling via the HER receptor family. This review outlines key resistance pathways and emerging strategies to overcome them. Nanotechnology-based approaches may enhance drug delivery and modulate the tumor microenvironment, while dual inhibition of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 3 (HER3), and downstream pathways shows promise in addressing compensatory signaling. Advances in biomarkers, including programmed death-ligand 1 (PD-L1), circulating tumor DNA, metabolic profiling, and radiomics, enable improved patient selection and monitoring. Novel immune checkpoints and adoptive cellular therapies, alongside personalized and adaptive trial designs, offer potential to improve outcomes in LA-HNSCC.

Background: While radical cystectomy is standard for muscle-invasive bladder cancer (MIBC), micrometastasis-related recurrence is common. Cisplatin-based neoadjuvant therapy (NAT) confers modest benefits, while immune checkpoint inhibitors (ICIs) provide new efficacy-enhancing strategies. This study aims to compare the efficacy and safety of ICIs with chemotherapy (NAC-ICI), neoadjuvant chemotherapy (NAC), and no neoadjuvant therapy (NNAT). It also explores potential biomarkers predictive of NAT response and evaluates the real-world efficacy of NAC-IC. Method: This single-center retrospective analysis included 80 radical cystectomy patients, with 51 NNAT group and 29 in the NAT group. Survival outcomes were evaluated by Kaplan-Meier survival curves, with log-rank test and restricted mean survival time (RMST) for comparisons. Pathological responses were assessed by complete response (pCR) and downstaging (pDS). Treatment-related adverse events (TRAEs) and predictive hematological biomarkers were analyzed. Results: Kaplan-Meier curves showed NAT is non-significant survival advantage over NNAT (p = 0.30). The RMST analysis showed the NAC-ICI had significantly longer RMST than the NNAT (56.00 vs. 47.73 months; Δ = +8.27 months; p = 0.0008). Fisher's exact test showed that NAC-ICI had a numerically higher pCR rate (42.10%) than NAC (20.00%), but the difference was non-significant (p = 0.414) ROC analysis showed baseline platelet count (PLT) was a significant negative predictor of pCR after NAC-ICI. Conclusions: This study indicates potential feasibility and safety of NAT for MIBC patients. Chemoimmunotherapy trends toward better pathological and survival outcomes than chemotherapy alone, but no statistically significant differences were observed. Baseline PLT may be a potential prdictive biomarker.

Peripheral blood mononuclear cell (PBMC) immunophenotyping has emerged as a promising non-invasive approach to characterize systemic immune alterations in cancer and to identify biomarkers associated with treatment response and resistance. However, current evidence remains fragmented and predominantly descriptive, with substantial heterogeneity in study design, immunophenotyping methodologies, and patient populations, limiting the identification of robust and clinically translatable immune signatures. In this review, we aim to comprehensively analyze PBMC immune phenotypes across multiple cancer types, with particular emphasis on their association with disease progression, therapeutic outcomes, and the key methodological and translational challenges that currently limit their clinical implementation. Across malignancies, conserved immune features are consistently observed, including T cell exhaustion, regulatory T cell (Treg) expansion, and upregulation of immune checkpoint molecules, reflecting chronic immune activation and dysfunction. In parallel, tumor-specific phenotype, such as peripheral helper T (Tph) cell expansion in non-small cell lung cancer, Vδ1+CD69+ γδ T cells in hepatocellular carcinoma, and T-cell immunoreceptor with Ig and ITIM domains (TIGIT) positive dysfunctional T cells in oral squamous cell carcinoma, highlight the influence of tumor-specific immune contexts. Importantly, this review moves beyond descriptive reporting by integrating mechanistic insights into how PBMC phenotypes contribute to therapeutic resistance. Key mechanisms include immunosuppressive cytokine signaling (e.g., interleukin-10 (IL-10), transforming growth factor-β (TGF-β)), chronic antigen stimulation driving T cell dysfunction, and systemic immune-tumor crosstalk mediated by chemokine axes such as stromal cell-derived factor 1 (SDF-1)/C-X-C motif chemokine receptor 4 (CXCR4). In addition to lymphoid populations, we emphasize the contribution of myeloid cell subsets, including monocytes and myeloid-derived suppressor cells, as central regulators of immune evasion and treatment failure. Despite these advances, significant challenges remain, including the lack of standardized protocols, limited longitudinal and multicenter validation studies, and insufficient integration of multi-omics approaches. Addressing these limitations will be essential for clinical translation. Overall, this review provides a refined conceptual framework that distinguishes conserved and tumor-specific immune signatures and highlights their mechanistic relevance in therapeutic resistance, supporting the development of PBMC immunophenotyping as a tool for personalized cancer immunotherapy.

Backgrounds: Fruquintinib is a selective vascular endothelial growth factor receptor (VEGFR)-1/2/3 inhibitor approved for previously treated metastatic colorectal cancer. As its use expands across gastrointestinal (GI) malignancies and combination regimens, randomized evidence is needed to define the toxicity profile most relevant to clinical monitoring, particularly hypertension, dermatologic toxicity, renal toxicity, bleeding, and thrombotic events. The objective of this study was to synthesize randomized controlled trial evidence to quantify the incidence and relative risk of key toxicities associated with fruquintinib in gastrointestinal malignancies. Methods: MEDLINE, EMBASE, and Cochrane CENTRAL were searched from inception through 1 January 2026 for phase II-III randomized controlled trials of fruquintinib in GI cancers reporting hypertension, proteinuria, hemorrhage, venous thromboembolism (VTE), and hand-foot skin reaction or palmar-plantar erythrodysesthesia (HFSR/PPE). Trial-reported CTCAE adverse events were pooled as risk ratios (RRs) with 95% confidence intervals (CIs) using Mantel-Haenszel random-effects models. Exploratory subgroup analyses were performed in metastatic colorectal cancer (mCRC). Results: Four randomized trials (n = 1872) were included. Fruquintinib significantly increased grade ≥3 hypertension (RR 9.01, 95% CI 4.67-17.40) and grade ≥3 HFSR/PPE (RR 26.00, 95% CI 6.42-105.29). Any-grade proteinuria was also increased (RR 1.89, 95% CI 1.30-2.74). Grade ≥3 hemorrhage occurred at low absolute rates and was numerically higher with fruquintinib, but the pooled estimate did not reach statistical significance (RR 1.82, 95% CI 0.92-3.61). VTE estimates were imprecise because of sparse events (any-grade VTE: RR 1.23, 95% CI 0.53-2.88; grade ≥3 VTE: RR 1.96, 95% CI 0.52-7.36). Conclusions: In randomized evidence across GI malignancies, the principal safety signals associated with fruquintinib are grade ≥3 hypertension and grade ≥3 HFSR/PPE, together with increased any-grade proteinuria. Grade ≥3 hemorrhage was uncommon and numerically higher, whereas VTE estimates remained imprecise. These findings support early blood pressure optimization, proactive dermatologic management, routine urinalysis monitoring, and individualized assessment of bleeding and thrombotic risk when initiating therapy.

Background: Fascin actin-bundling protein 1 (FSCN1) modulates the expression of key lipogenic enzymes fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD1) in colorectal cancer (CRC), but the underlying mechanisms remain elusive. Methods: Bioinformatics analyses were performed to evaluate FSCN1 expression and its prognostic value in CRC. Intracellular lipid levels following FSCN1 knockdown were assessed by Nile Red/DAPI co-staining and triglyceride quantification, and further validated by Oil Red O staining of xenograft tumors. Expression levels of key metabolic enzymes were measured by qRT-PCR and Western blotting. RNA sequencing identified FSCN1-associated pathways, which were functionally investigated using pharmacological inhibitors. Results: FSCN1 was significantly upregulated in CRC (p < 0.001; AUC = 0.796) and was correlated with poorer overall survival (p = 0.018). FSCN1 depletion reduced intracellular lipid accumulation, accompanied by downregulation of lipogenic mediators-sterol regulatory element-binding transcription factor 1 (SREBF1; protein product: SREBP1), FASN, and SCD1-and upregulation of peroxisomal fatty acid oxidation (FAO)-related factors-peroxisome proliferator-activated receptor alpha (PPARA; protein product: PPARα) and acyl-CoA oxidase 1 (ACOX1). Mechanistically, FSCN1 was associated with activation of the protein kinase B/mammalian target of rapamycin (AKT/mTOR) and p38 mitogen-activated protein kinase (p38 MAPK) pathways; pharmacological inhibition with LY294002 or SB203580 phenocopied the lipid-lowering effects of FSCN1 knockdown. Conclusion: Collectively, these findings link FSCN1 to the AKT/mTOR/SREBP1/(FASN/SCD1) lipogenic axis and the p38 MAPK/PPARα/ACOX1 peroxisomal FAO pathway, implicating FSCN1 in lipid metabolic regulation and CRC progression, while suggesting a putative functional regulatory axis and a promising candidate therapeutic target for CRC.

Background: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, with limited treatment options for advanced-stage patients. DNA polymerase theta (POLQ) is overexpressed in various cancers, but its role and underlying mechanisms in CRC remain not fully elucidated. This study aimed to investigate the expression, prognostic value, biological functions, and molecular mechanisms of POLQ in CRC. Methods: POLQ expression was analyzed using public databases and 55 paired clinical samples. Lentivirus-mediated knockdown and overexpression were employed to assess CRC cell proliferation, migration, and invasion. Single-cell transcriptomics and CellChat analysis were used to explore the tumor microenvironment (TME). Western blotting, immunofluorescence, and dual-luciferase reporter assays were performed to verify the Wnt/β-catenin pathway and epithelial-mesenchymal transition (EMT). Results: POLQ was significantly overexpressed in CRC tissues and cell lines, and high POLQ expression was associated with neural invasion, vascular tumor thrombus, lymph node metastasis, advanced TNM stage, and poor prognosis. Single-cell analysis revealed that POLQ was specifically enriched in malignant epithelial cells, which acted as communication hubs with prominent Wnt signaling. Functional experiments demonstrated that POLQ activated the Wnt/β-catenin pathway, induced EMT, promoted β-catenin nuclear translocation and TCF/LEF transcriptional activity, and enhanced CRC cell proliferation, migration, and invasion. The Wnt inhibitor XAV939 reversed the POLQ overexpression-induced malignant phenotype, while the Wnt activator SKL2001 partially rescued the knockdown phenotype. Additionally, single-cell transcriptomics and CellChat analysis generated a computational prediction that POLQ-high cells may be involved in remodeling of the immunosuppressive microenvironment; however, this inference requires direct experimental validation through immune cell profiling in future studies. Conclusions: POLQ promotes CRC progression by activating the Wnt/β-catenin-EMT axis. Bioinformatic inference suggests a potential association with an immunosuppressive microenvironment, but this finding remains correlative and requires experimental confirmation. These findings suggest that POLQ is a potential prognostic biomarker and therapeutic target, though further validation in prospective, multicenter cohorts is warranted.

Breast cancer (BC) has become the most commonly diagnosed malignant tumor among women worldwide, with approximately 70% of patients with advanced BC developing bone metastases. These metastases trigger bone destruction and skeletal-related events (SREs) and significantly reduce patient survival. In recent years, research into the mechanisms underlying BC bone metastasis has advanced rapidly. Molecular biological and genomic studies have revealed that BC bone metastasis is co-regulated by multiple signaling pathways through crosstalk between BC cells and the bone microenvironment. This review analyzes the research progress of signaling pathways involved in BC bone metastasis and systematically elaborates four core cascades: Wingless-related integration site (Wnt)/β-catenin, transforming growth factor-β (TGF-β), RANK/receptor activator of nuclear factor-κB ligand (RANKL)/osteoclastogenesis inhibitory factor (OPG), and phosphatidylinositol 3-Kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR). It explains how each pathway mediates epithelial-mesenchymal transition (EMT), excessive Osteoclast (OC) activation, maintenance of cancer stem cell stemness, and the formation of an immunosuppressive microenvironment. The positive feedback loops and reciprocal crosstalk between these pathways are also summarized, which together fuel the vicious cycle of osteolytic bone metastasis. This paper further consolidates therapeutic strategies targeting the aforementioned signaling pathways and outlines cutting-edge therapeutic approaches and emerging research hotspots. Nevertheless, critical obstacles including complex pathway compensation, drug resistance, and dysregulated bone immunity remain major bottlenecks hindering clinical translation. Future research will leverage single-cell sequencing and multi-omics technologies to identify pivotal molecular targets and develop potent combinatorial therapies. Such advances will facilitate the implementation of precise, individualized treatment for BC bone metastasis and ultimately improve the quality of life and long-term clinical outcomes of patients with advanced bone-metastatic disease.

Chronic lymphocytic leukemia (CLL) is a biologically heterogeneous B cell malignancy in which non-malignant T lymphocytes constitute a critical component of the tumor microenvironment and significantly influence disease evolution and the therapeutic response. Growing evidence suggests that CLL-associated T cells not only participate in the antitumor response but also activate signals that promote the development of CLL subclones. Although novel targeted therapies, such as Bruton's tyrosine kinase (BTK) inhibitors, BTK degraders, B-cell lymphoma 2 (BCL-2) inhibitors, T cell engagers, immune checkpoint inhibitors, and adoptive T cell therapy have different mechanisms of action, they affect the T cell compartment in addition to targeting CLL cells. Therefore, in-depth knowledge of the role of T cells in the development and progression of CLL is essential for proper stratification of the benefit-to-risk ratio with regard to immunotherapeutic strategies. This review comprehensively summarizes current knowledge on alterations within the T cell compartment in CLL and discusses the clinical implications, regarding clinical course and response to immunotherapy.

[This retracts the article DOI: 10.3727/096504018X15180508535835.].

Bladder cancer (BC) is a prevalent malignancy characterized by a high recurrence rate and the necessity for long-term surveillance demands, creating a need for accurate yet practical tools for early detection and monitoring. While current standards including cystoscopy, urinary cytology, and imaging remain indispensable, their clinical utility is constrained by invasiveness, suboptimal sensitivity for selected lesions or low-grade lesions, inter-observer variability, and cumulative costs. Currently, biomarker research has expanded from single protein assays to multi-analyte strategies encompassing DNA, RNA, proteins, extracellular vesicle-associated cargo, and metabolomics signatures. This review synthesizes recent advances in diagnostic, surveillance, prognostic, and treatment-predictive biomarkers, with emphasis on assay principles, analytical platforms and reported performance where available. Furthermore, we delineate critical barriers to translation, including limited prospective multicenter validation, heterogeneous pre-analytical workflows, inconsistent thresholds, and the persistent trade-off between sensitivity and specificity in real-world benign urologic conditions. Ultimately, while emerging biomarkers and multi-omics panels hold transformative potential as non-invasive adjuncts in risk-adapted clinical pathways, their routine adoption is contingent upon rigorous clinical integration and standardized validation.

Objectives: Combretastatin A-4 (CA-4) is a microtubule-disrupting agent with established anti-tumor properties. This study aimed to evaluate the effects of CA-4 on key metastatic traits of cancer cells, including migration, clonogenic potential, cytoskeletal protein expression, and microtentacle (McTN) formation, using multiple cancer cell models, including the colon patient-derived circulating tumor cell line CTC-MCC-41. Methods: H1299 (non-small cell lung cancer), MDA-MB-231 (triple-negative breast cancer), HT-29 (colorectal cancer), and CTC-MCC-41 (derived from the blood of a colon cancer patient) cells were treated with CA-4 (10 μM) for 24 and 48 h. Colony formation was assessed with a clonogenic assay. Migration assays (Boyden chamber) evaluated cell motility, while cell viability was determined via MTT assay. Western blot analysis examined vimentin and α/β-tubulin expression. TetherChip assay analyzed McTN formation using wheat germ agglutinin (WGA) staining. Results: CA-4 treatment significantly reduced cell viability, colony formation, and migration across all tested cancer cell lines. Western blot analysis revealed a marked reduction in vimentin and α/β-tubulin expression after 48 h of treatment, indicating disruption of cytoskeletal integrity. In addition, TetherChip analysis demonstrated a pronounced decrease in McTN formation following CA-4 exposure, suggesting inhibition of cytoskeletal protrusions associated with metastatic dissemination. Conclusions: CA-4 effectively impairs multiple cancer cell functions related to metastatic progression, including proliferation, migration, cytoskeletal organization, and McTN formation. These findings highlight the potential of CA-4 as a microtubule-targeting agent with anti-metastatic activity, particularly in circulating tumor cells.

Background: Collecting duct carcinoma (CDC; Bellini duct carcinoma) is a rare, aggressive renal cancer with no established standard of care, and evidence for immune checkpoint inhibitor (ICI)-based therapy in CDC remains emerging and fragmented. We aimed to systematically synthesise efficacy and safety data on immunotherapy in adult patients with CDC. Methods: PubMed and Web of Science were searched from inception to 29 March 2025, with targeted post-search monitoring of key journals and ClinicalTrials.gov updated on 11 April 2026. Prospective interventional studies, observational cohorts/registries, and case series/reports were eligible. Screening, extraction and risk-of-bias appraisal (Joanna Briggs Institute tools) were performed independently in duplicate; results were narratively synthesised. Results: Overall, ICIs-particularly combinations-showed clinically meaningful activity in a subset of CDC patients. Twenty-four studies met criteria (2 prospective trials, 8 observational cohorts, 14 case-level publications/16 patients). The SUNNIFORECAST randomised phase II trial reported a CDC-specific ORR of 40% with ipilimumab + nivolumab versus 20% with standard of care (n = 9 CDC). Observational evidence yielded ORR ~10-44% and mOS ~13-42 months depending on regimen, with the highest activity seen with ICI plus TKI combinations. Durable complete responses (≥3-6 years) were documented at case level with dual checkpoint blockade and anti-PD-1 monotherapy. Safety was generally manageable, though serious events occurred sporadically (immune-mediated hepatitis; one fatal pneumonia). Conclusions: ICIs-particularly combination strategies-demonstrate clinically meaningful activity in selected patients with CDC, but evidence is limited by small samples, heterogeneity and high risk of bias. Prospective, biomarker-informed CDC-dedicated trials and coordinated registries are needed.

Cholesterol metabolism is central to cancer biology, influencing tumour initiation, progression, and therapeutic response, while contributing to the increased cardiovascular risk observed in cancer patients. Epidemiological studies investigating the relationship between circulating cholesterol levels and cancer risk have yielded conflicting results, reflecting substantial biological heterogeneity, tumour-specific metabolic demands, and methodological biases such as reverse causality. At the cellular level, malignant cells exhibit elevated cholesterol uptake and synthesis to sustain membrane biogenesis, lipid raft-dependent oncogenic signalling, and rapid proliferation. Cholesterol and its oxidized derivatives further modulate inflammation, angiogenesis, immune evasion, and key signalling pathways. Anticancer therapies profoundly disrupt lipid homeostasis; conventional chemotherapies, targeted therapies, hormone-modulating agents, and immunotherapies can induce dyslipidaemia and accelerate atherosclerotic disease, thereby contributing to long-term morbidity in cancer survivors. Conversely, lipid-lowering therapies-particularly statins-have emerged as pivotal tools in cardio-oncology, primarily for cardiovascular protection. Beyond this role, growing evidence suggests potential adjunctive antitumor effects mediated through inhibition of the mevalonate pathway, blockade of oncogenic signalling, and modulation of the tumour microenvironment. Novel agents, including ezetimibe, bempedoic acid, and proprotein convertase subtilisin-kexin type 9 inhibitors, provide additional therapeutic options, with emerging evidence supporting their immunomodulatory and anticancer properties, especially in combination with immune checkpoint inhibitors. Cholesterol metabolism plays a critical role in both CV disease and cancer biology, with growing evidence suggesting a complex bidirectional relationship between lipid homeostasis and tumour development. In addition, several anticancer therapies may profoundly affect lipid metabolism, thereby contributing to CV risk in cancer patients. The aim of this review is to provide a comprehensive overview of the interplay between cholesterol metabolism and cancer, to summarize the lipid-modifying effects of anticancer therapies, and to discuss the potential role of lipid-lowering strategies within the evolving framework of cardio-oncology care.

Programmed cell death regulates the tumor immune microenvironment. A comprehensive synthesis of how multiple programmed cell death pathways collectively orchestrate the remodeling of the urological immune landscape is currently lacking. This review summarizes and discusses how diverse programmed cell death modes, including ferroptosis, pyroptosis, autophagy, PANoptosis, necroptosis and cuproptosis, regulate immune evasion or activation in a context-dependent manner. Current preclinical evidence suggests that necroptosis, pyroptosis, and cuproptosis may enhance anti-tumor immunity by facilitating the release of damage-associated molecular patterns and increasing the infiltration of functional CD8[+] T cells and dendritic cells, thereby potentially improving responses to immunotherapy. At the same time, several programmed cell death pathways display exhibit pronounced context dependence. In renal cell carcinoma, ferroptosis exhibited a functional contradiction: while its induction directly eliminated cancer cells, the resulting lipid peroxidation could simultaneously impair the survival and metabolic fitness of infiltrating immune cells. This dualistic effect necessitated precise, cell-type-specific strategies to ensure that ferroptosis-mediated tumor suppression did not undermine the anti-tumor immune response. Similarly, autophagy in tumor cells facilitated immune evasion via the selective degradation of major histocompatibility complex class I (MHC-I) and stabilizing programmed death-ligand 1, while it also improved the cytotoxic function and cellular longevity of natural killer cells. Consequently, future drug development should consider cell-type-specific modulation to address these contradictory effects across different cells and avoid unintended immunosuppression. Emerging evidence on PANoptosis, which integrates multiple programmed cell death pathways into a synergistic framework, may provide a useful direction for investigating immune therapeutic resistance. Ultimately, targeting the intricate landscape of programmed cell death may inform strategies for improving cancer treatment and urological immunotherapy, but stronger translational evidence is still needed.