Tumor-associated macrophages (TAMs) are considered to be one of the most attractive targets in cancer therapy but attempts to target them have produced variable and often contradictory results. Their phenotype and function are shaped by developmental origin, spatial niche, metabolic conditions, immune context, and treatment history. For this reason, TAM-directed therapy should not be approached as a simple problem of depletion or repolarization, but as a problem of function and timing. This framework integrates converging evidence from multiple independently reported studies of stage-, sequence-, and context-dependent macrophage targeting into a single decision structure, rather than proposing a new biological mechanism. We discuss here recurrent macrophage functions in solid tumors, including vascular support, matrix remodeling, immune exclusion, tumor-cell survival, antigen presentation, and tissue repair after therapy. We then consider how these functions affect the choice between depletion, recruitment blockade, reprogramming, and activation, and why the same intervention may be beneficial, ineffective, or harmful depending on lesion state and treatment sequence. Particular attention is given to therapeutic windows, biomarker-guided personalization, and adverse consequences of TAM intervention, including toxicity, compensatory myeloid substitution, loss of protective immune functions, repair-driven relapse, and the selection of inflammation-adapted or macrophage-resistant tumor cells. Effective TAM therapy will require functional precision, temporal precision, dynamic reassessment, and explicit attention to macrophage plasticity as both an opportunity and a source of risk.

Long-established prostate cancer cell lines provide limited insight into how contemporary early prostate cancer evolves into drug-resistant and neuroendocrine-like refractory disease. Patient-derived three-dimensional (3D) ex vivo models may better preserve this transition. Here, we found that 8 of 10 magnetic resonance imaging-guided biopsy specimens from patients with early-stage prostate cancer generated sustained 3D tumor spheroid cultures. After 12 weeks of enzalutamide selection, only one patient-derived culture acquired a resistant phenotype with treatment-emergent neuroendocrine prostate cancer (t-NEPC)-like features, including increased chromogranin A (CgA) and synaptophysin (SYP); reduced androgen receptor (AR), prostate-specific antigen (PSA), and prostate-specific membrane antigen (PSMA); and conversion from compact spheroids into irregular resistant aggregates. During this transition, WD repeat and SOCS box-containing protein 1 (WSB1) increased, whereas PSMA progressively decreased. WSB1 silencing restored PSMA, AR, and PSA expression and reduced neuroendocrine-associated features. A similar WSB1 dependency was observed in enzalutamide-resistant LNCaP cells, the castration-resistant prostate cancer model 22Rv1, and the neuroendocrine/small-cell prostate cancer model NCI-H660. Mechanistically, WSB1 functioned as a SOCS box-dependent E3 ubiquitin ligase adaptor that promoted PSMA ubiquitination and degradation. SOCS box deletion or T380A mutation impaired this process, while Aurora kinase A (AURKA) inhibition reduced WSB1-dependent PSMA ubiquitination. WSB1 depletion, AURKA inhibition with alisertib, and combined AURKA inhibition with EZH2 suppression reduced resistant aggregate growth and increased apoptosis-associated markers in patient-derived enzalutamide-resistant neuroendocrine-like spheroids and related models. These findings nominate the AURKA-WSB1-PSMA axis as a therapeutic vulnerability in refractory prostate cancer.

Gliomas are the most common group of primary brain tumors, among which glioblastoma multiforme (GBM) is characterized by a particularly poor prognosis and the limited effectiveness of available treatments. Ophiobolin A (OP-A), a natural sesterterpenoid, exhibits promising anticancer properties, including the ability to cross the blood-brain barrier and induce paraptosis-like cell death. However, the molecular mechanisms underlying its action, especially in the early phase of the cellular response, remain not fully understood. The aim of this study was to analyze early changes in the expression of genes associated with apoptosis, ferroptosis, and antioxidant mechanisms in T98G and U118MG glioma cells exposed to OP-A. Gene expression was assessed by RT-qPCR, apoptosis was evaluated using Annexin V/PI staining and flow cytometry, and treatment-induced morphological changes were documented by brightfield microscopy. Statistical analysis was performed using the Mann-Whitney U test. Descriptive Annexin V/PI analysis showed a lower proportion of viable cells and a higher proportion of early apoptotic cells in the analyzed OP-A-treated T98G and U118MG samples compared with the corresponding vehicle-control samples. These preliminary observations were based on technical replicates from a single biological experiment and require confirmation in independent biological replicates. Transcriptional profiling revealed a shift toward a pro-apoptotic phenotype, characterized by increased BAX and FAS expression together with a trend toward reduced BCL2 expression, whereas ferroptosis-associated genes remained largely unchanged. Notably, SLC7A11 upregulation suggested activation of compensatory antioxidant mechanisms in response to OP-A treatment. In T98G cells, OP-A induced a distinct and reproducible transcriptional signature that enabled accurate discrimination from control conditions (AUC = 0.833). Feature importance and SHAP analyses identified BAX as the most informative predictor, followed by SLC7A11 and FAS, with bootstrap validation confirming BAX as a stable marker. Pathway analysis demonstrated selective activation of apoptosis- and cysteine metabolism-related pathways, while hierarchical clustering revealed that OP-A generated a transcriptional profile distinct from oxidative stress-inducing agents. The predictive performance of this molecular signature was cell-line dependent, showing weaker discrimination in U118MG cells.Short-term OP-A exposure in T98G and U118MG cells was associated with exploratory trends in apoptosis- and redox-related gene expression and a higher proportion of Annexin V-positive cells. The machine-learning analyses identified candidate discriminatory features within this limited dataset but should be regarded as hypothesis-generating. Larger studies with independent biological replication, additional GBM models, different exposure conditions, and functional validation are required to confirm these observations and clarify the mechanism of OP-A action.

Tumor-associated macrophages are key components of the tumor microenvironment in oral carcinogenesis; however, their role is not yet fully understood. We aimed to characterize the expression of macrophage (M) markers across the spectrum of oral carcinogenesis, including oral leukoplakias (OL) and oral squamous cell carcinomas (OSCCs). This immunohistochemical study analyzed the macrophage density (cells/mm2) based on the expression of CD68 (pan-macrophage), CD163 (M2), and CD80 (M1) in 81 samples, including healthy mucosa (n = 16), OL (n = 30), and OSCC (n = 35), in both epithelial and subepithelial compartments. All markers showed a progressive increase across the study groups, with significantly higher densities in OSCC than in healthy mucosa (p < 0.001), consistently higher in the subepithelial compartment. CD163 was the most expressed marker (increasing from 78.96 cells/mm2 in healthy mucosa to 300.56 cells/mm2 in OSCC), whereas CD80 was the least abundant, particularly in OSCC (35.66 cells/mm2 in healthy tissue to 188.49 cells/mm2 in OSCC). No significant associations were observed between biomarker expression and clinicopathological variables. These results support the involvement of macrophages during oral carcinogenesis, particularly CD163+ (M2) cells, and highlight the potential prognostic and therapeutic relevance of these markers.

Reactive oxygen species (ROS) are central regulators of cancer biology and represent a double-edged target in oncology. At physiological levels, ROS support signal transduction, proliferation, differentiation, and immune responses, whereas sustained ROS imbalance promotes DNA damage, genomic instability, metabolic reprogramming, and remodeling of the tumor microenvironment, thereby contributing to tumor initiation, progression, metastasis, and therapy resistance. Conversely, because many cancer cells operate close to the limit of tolerable oxidative stress, further ROS elevation can trigger apoptosis, ferroptosis, immunogenic cell death, and other cytotoxic programs. This review summarizes the major intracellular and microenvironmental sources of ROS, the mechanisms by which redox signaling shapes malignant transformation and tumor adaptation, and the antioxidant systems that buffer oxidative stress in cancer cells. We further discuss current therapeutic approaches based on both ROS suppression and ROS amplification, including redox-modulating small molecules, radiotherapy, photodynamic and sonodynamic therapy, catalytic nanomaterials, and ROS-responsive prodrugs and drug delivery systems. Particular attention is given to the context-dependent effects of ROS, the antioxidant paradox, tumor heterogeneity, hypoxia, off-target toxicity, and the need for robust redox biomarkers. A deeper understanding of tumor-specific redox vulnerabilities will be essential for developing precise and clinically effective ROS-oriented cancer therapies.

Inadequate supply of oxygen causing hypoxic cellular stress drives metabolic reprograming across diverse physiological conditions, including cancer. The activation of hypoxia-inducible factors (HIFs) to facilitate adaptation to low oxygen environments is well-characterized; however, post-transcriptional regulation by microRNAs (miRNAs) is poorly understood. Here, we investigated the mRNA and miRNA response in hypoxia-mediating reduced growth and cellular metabolism. Next-generation sequencing revealed the impact of hypoxia in cultured human hepatocellular carcinoma cells and identified over 400 mRNAs and 140 miRNAs that were differentially expressed. Hypoxia upregulated mRNA transcripts associated with glycolysis, DNA replication and the PI3K (phosphoinositide 3-kinase)-Akt pathway, which promote anaerobic metabolism for energy production, decreased cell proliferation and genomic instability, respectively. Upregulated miRNAs included miR-197-3p and miR-766-3p, targeting genes involved in lipid biosynthesis and metabolism. Downregulated miRNAs included miR-33a-5p and miR-15a-5p, targeting genes involved in glycolysis and lactate metabolism. Notably, miR-6834 emerged as a potential regulator of mechanistic target of rapamycin (mTOR) signaling and insulin-like growth factor binding protein-1 (IGFBP-1) signaling; miR-6834 overexpression altered 4E-BP1 phosphorylation levels and IGFBP-1 secretion. These findings provide critical insights into miRNA-mRNA regulation of metabolic adaptation and highlight miRNAs as potential targets for interventions with relevance to tumor biology and other hypoxia-associated conditions.

Mismatch repair deficiency (MMRd) is a critical biomarker in endometrial cancer (EC) for prognostication, Lynch syndrome screening, and immunotherapy eligibility. This study aimed to determine the prevalence of MMRd and its correlation with clinicopathological characteristics in EC. This prospective observational cohort included 93 patients with EC undergoing primary surgical treatment, managed as per the European Society of Gynaecological Oncology (ESGO) guidelines. MLH1, PMS2, MSH2, and MSH6 expression was assessed through immunohistochemistry (IHC) on formalin-fixed, paraffin-embedded hysterectomy specimens. Associations between mismatch repair (MMR) status and histology, grade, lymphovascular space invasion (LVSI), myometrial invasion, FIGO 2023 stage, nodal status, recurrence, and survival were analyzed. The median age was 66 years. Most tumors were endometrioid (86%), 29% were grade 3, 45.2% showed deep myometrial invasion, and 23.7% had substantial LVSI. MMRd was identified in 41.9% of cases, with MLH1 and PMS2 loss being most frequent, and was significantly associated with endometrioid histology (p = 0.027) and deep myometrial invasion (p = 0.011). No significant correlations were found with grade, LVSI, FIGO stage, nodal involvement, recurrence, or overall survival. Routine MMR assessment may refine risk stratification and guide individualized treatment decisions.

Ewing sarcoma is a highly malignant tumor whose histological appearance often overlaps with that of other undifferentiated round-cell and ovoid-cell tumors, making accurate diagnosis challenging. Selecting the most appropriate immunohistochemical and molecular tests is critical, particularly when only limited core biopsy material is available and tissue preservation for additional molecular or biomarker testing is required. Artificial intelligence (AI)-based histopathological image analysis is emerging as a promising diagnostic tool in oncology. This study evaluated the potential of AI-based histopathological analysis to assist pathologists in the morphologic classification of Ewing sarcoma and selected histological mimics using tissue microarrays (TMAs), rather than to identify or predict molecular alterations. We analyzed 1926 digitized histological cores, from 729 patients, assembled into 45 tissue microarrays. The dataset comprised 517 Ewing sarcomas (ESs), 367 rhabdomyosarcomas (RMSs), 187 chondrosarcomas (CHSs), 138 gastrointestinal stromal tumors (GISTs), and 124 synovial sarcomas (SSs). A weakly supervised multiple-instance learning (MIL) framework with transformer-based aggregation was developed using only core-level diagnostic labels. The model achieved classification accuracies of 97.1% for Ewing sarcoma, 80.0% for rhabdomyosarcoma, 85.7% for gastrointestinal stromal tumors, 80.0% for chondrosarcoma, and 76.0% for synovial sarcoma. The overall classification accuracy was 91.6%, with no misclassifications between Ewing sarcoma and rhabdomyosarcoma. These findings highlight the model's robustness in distinguishing tumor entities that present a well-recognized diagnostic challenge in routine pathology. The AI algorithm demonstrated strong potential as a diagnostic adjunct for assisting pathologists in the morphologic classification of Ewing sarcoma and selected tumor entities based on histopathological features. Although these tumor entities are characterized by specific molecular alterations, the model was not designed to identify or predict molecular alterations directly. Instead, it supports clinical decision-making by recognizing morphologic patterns associated with diagnostically defined tumor entities. The integration of AI-based histopathological analysis with immunohistochemistry and contemporary molecular diagnostic techniques has the potential to improve diagnostic accuracy, optimize the use of ancillary testing, enhance our understanding of genotype-phenotype relationships, and ultimately support more effective patient management.

Glioblastoma (GB), the most prevalent and aggressive brain tumor, remains one of the most lethal challenges in modern oncology. Standard therapy remains largely ineffective, mainly due to limited therapeutic penetration across the blood-brain barrier (BBB) and adaptive tumor resistance. Consequently, there is an urgent need for innovative strategies to enhance therapeutic precision and efficacy. To address these limitations, we engineered a targeted peptide-based co-delivery system using the WRAP5 cell-penetrating peptide functionalized with a transferrin receptor (TfR)-targeting T7 peptide (sequence: HAIYPRH), enabling simultaneous delivery of temozolomide (TMZ) and a p53-encoding plasmid DNA. The resulting peptide-based TMZ/p53 nanocomplexes exhibited favorable physicochemical properties, enhanced TfR-mediated cellular uptake, and targeted antitumor activity mediated through p53-induced apoptosis in two-dimensional (2D) U87 MG cell cultures. To better reproduce the structural and cellular complexity of the tumor microenvironment, a three-dimensional U87 MG spheroid model was established and optimized using a Design of Experiments (DoE) approach to improve reproducibility and physiological relevance. The developed WRAP5-based nanocomplexes induced a significant dose-dependent inhibition of growth and morphological alterations in the U87 MG spheroid model, accompanied by deep penetration and cell death throughout the spheroid. Collectively, these findings highlight the potential of this targeted and tailored nanosystem to enhance cellular transfection, enable drug/gene co-delivery, restore p53 function, and promote apoptosis, representing a promising therapeutic strategy for GB treatment.

Bladder cancer (BC) remains a major clinical challenge owing to limited therapeutic options and high recurrence rates. Oridonin (ORI), a natural diterpenoid derived from Rabdosia plants, exhibits promising anti-tumor activity, but its effects and mechanisms in BC remain poorly defined. We evaluated the anti-BC potential of ORI in vitro and in vivo using proliferation, migration, invasion, cell-cycle, and apoptosis assays, integrated transcriptomic and proteomic analyses, Western blotting, and a 5637 xenograft model. ORI dose- and time-dependently inhibited 5637 and T24 cell proliferation, induced S-phase arrest (from 23.37% to 42.12% in 5637 and from 31.87% to 50.28% in T24; p < 0.01), and reduced migration (from 53.39% to 13.77% and from 59.81% to 12.49%; p < 0.0001) and invasion (from 74.42% to 25.43% and from 67.03% to 30.12%; p < 0.001). Multi-omics analyses revealed widespread changes enriched in apoptosis- and cell-cycle-related pathways. Consistently, ORI promoted apoptosis and necrosis, up-regulating BAX, CASP3, BID, and CYCS and down-regulating BCL2, validating the omics findings. In vivo, ORI (20 mg/kg, daily gavage) significantly suppressed xenograft growth (p < 0.001) without obvious toxicity, indicating that ORI inhibits BC growth and metastasis by inducing S-phase arrest and apoptosis and is a promising candidate for BC therapy.

We report the first documented case of extreme, intact parathyroid hormone (PTH)-independent hypercalcemia mediated by a rare non-osteoclastic bone remodeling mechanism in a 65-year-old Puerto Rican woman, detected within 24 h of the second dose of the Moderna mRNA-1273 COVID-19 vaccine and leading to the diagnosis of high-risk biclonal IgA plasma cell myeloma (R-ISS Stage III). Peak serum calcium reached 17.4 mg/dL with concurrent hyperphosphatemia, normal lactate dehydrogenase (LDH), and without marrow osteoclasts or osteolytic lesions, findings inconsistent with classical cancer-associated hypercalcemia. Hypercalcemia resolved within eight days with supportive treatment alone, remaining durably normal nine months later. The temporal proximity to vaccination, together with the biochemical-histopathological profile, generates the hypothesis, without implying causation, that a vaccine-induced innate immune response triggered a rare inflammatory osteocytic perilacunar/canalicular remodeling. The biclonal gammopathy, Clone-1 (normal karyotype, CD33+, OCT-2+, MYC-, CD19+, PAX5-) and Clone-2 (complex high-risk karyotype, OCT-2-, MYC+low, CD19-), suggests epigenetic rather than genomic drivers in the predominant clone. This case proposes a novel mechanistic hypothesis for vaccine-associated hypercalcemia and generates testable questions that warrant prospective investigation.

Dynamic transcriptomic remodeling of epithelial cells represents a critical hallmark of lung adenocarcinoma (LUAD) progression, yet epithelial-cell progression signatures (ECPSs) linked to this process remain incompletely characterized, impeding our understanding of malignant LUAD transformation. Here, we performed a multi-resolution multi-omics study and identified two functionally opposing ECPSs: a Cancer-Promoting Signature (CPS) and a Cancer-Suppressing Signature (CSS). The CPS was progressively upregulated from normal to early- and advanced-stage lesions, while the CSS was gradually downregulated, and both were validated by multi-resolution transcriptomic data. Both the CPS and CSS demonstrated robust diagnostic value for LUAD, particularly in early-stage detection (median AUC > 0.95). In seven independent validation cohorts, the CPS and CSS served as robust prognostic risk and protective factors, respectively. Their combination could better stratify LUAD patients into distinct prognostic subgroups, with the CPShigh-CSSlow subgroup showing the worst prognosis, accompanied by high genomic instability, an immunosuppressive tumor microenvironment, and resistance to chemotherapy. Notably, the CPS and CSS exhibited broad translational value in other epithelium-derived cancers. HMGA1, a key CPS gene, showed epithelium- and advanced-stage-specific high expression, which was significantly associated with poor prognosis, genomic instability, and immune escape. Collectively, our study identifies the CPS and CSS as clinically reliable ECPSs, providing valuable biomarkers for clinical application to LUAD.

Bladder cancer (BLCA) is a common and heterogeneous malignancy in which disease progression is driven not only by tumor-intrinsic alterations but also by dynamic interactions within the tumor microenvironment (TME). Increasing evidence positions the extracellular matrix (ECM) as a critical regulator of these processes. Matricellular proteins (MCPs), a group of nonstructural ECM-associated molecules, have emerged as key modulators of tumor-stroma communication. In BLCA, MCPs have been reported to display divergent, and in some cases opposing, associations or functions, with the same protein participating in both tumor promotion and suppression. Here, we review current evidence on the function of MCPs in BLCA and synthesize their bidirectional roles in carcinogenesis. MCPs contribute to tumor progression by promoting invasion, epithelial-mesenchymal transition (EMT), angiogenesis, and metastatic niche formation. At the same time, MCPs can restrain tumor growth by inhibiting angiogenesis, stabilizing ECM organization, inducing cell cycle arrest, and maintaining epithelial integrity. A key concept emerging from this body of evidence is the context-dependent functional plasticity of MCPs. We propose that MCP-associated phenotypes in BLCA may be influenced by contextual factors, including isoform diversity arising from alternative splicing and post-translational modifications, spatial compartmentalization within tumor and stromal niches, tumor microenvironmental composition, and molecular subtype. However, the level of supporting evidence differs substantially among MCPs, and direct BLCA-specific mechanistic evidence remains limited for many proposed relationships. These factors, therefore, provide a framework for interpreting divergent findings rather than representing universally established determinants of MCP function. Recognizing MCPs as context-sensitive regulators rather than fixed tumor-promoting or tumor-suppressing entities provides a unifying framework for understanding their roles in BLCA. This could be an important step for therapeutic targeting, encouraging effective strategies to consider and incorporate the molecular and microenvironmental context in which MCPs operate.

Bone metastasis is often treated clinically as a late complication of advanced cancer, yet accumulating evidence indicates that it is also a spatial evolutionary process shaped by clonal selection, niche adaptation, dormancy, and reseeding. This review examines BoM through a phylogeographic framework that links tumor ancestry with anatomical location and time. We discuss how heterogeneous primary tumors generate bone-tropic subclones, how circulating tumor cells pass through dissemination bottlenecks, and how disseminated tumor cells enter perivascular and endosteal niches that either maintain dormancy or support early micrometastatic outgrowth. We then compare clonal architectures across breast, prostate, lung, and renal cell carcinomas, emphasizing both lineage-specific programs and convergent bone-adaptive states, including osteomimicry, immune evasion, metabolic plasticity, and epigenetic remodeling. Methodological platforms such as multiregion sequencing, single-cell and spatial transcriptomics, lineage tracing, and liquid biopsy are evaluated with attention to the technical limitations imposed by mineralized tissue. Finally, we consider how bone lesions may function as reservoirs for secondary dissemination and how evolutionary thinking could improve biomarker development, dormancy prediction, trial design, and therapy selection. Viewing BoM as an evolving ecosystem may help shift the field from reactive skeletal management toward earlier, biology-informed intervention.

Breast cancer (BC) progression is strongly influenced by the extracellular matrix (ECM), whose remodelling regulates tumour growth, invasion, metastasis, immune modulation, and therapeutic response. Among ECM components, collagens have emerged as both structural proteins and active mediators of mechanotransduction, stromal interactions, and tumour cell behaviour. This narrative review analyses collagen families and collagen-associated proteins implicated in BC, integrating evidence on their expression patterns, biological functions, clinical significance, and translational potential. We examine fibrillar and non-fibrillar collagens, including fibril-associated collagens with interrupted triple helices (FACITs), membrane-associated collagens with interrupted triple helices (MACITs), basement membrane (BM) collagens, and multiplexins, together with their interactions with cancer-associated fibroblasts (CAFs), immune cells, and signalling pathways involved in tumour progression. Alterations in collagen composition, organization, crosslinking, and degradation regulate ECM stiffness, epithelial-mesenchymal transition (EMT), invasion, metastatic dissemination, and therapy resistance. Several collagen types and collagen-derived fragments also show promise as prognostic biomarkers and therapeutic targets, particularly in aggressive BC subtypes such as human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC). Overall, this review highlights the collagenome as a dynamic component of the breast tumour microenvironment (TME) and supports collagen-informed strategies for improved patient stratification and targeted therapies.

Estrogen receptor (ER)-positive breast cancer (BrCa) accounts for two-thirds of all BrCa cases worldwide. Therefore, ER-targeted endocrine therapy is the standard treatment for this disease. There has been a recent trend towards developing combination therapies using molecularly targeted drugs to improve outcomes. This study aimed to identify therapeutic targets demonstrating efficacy when combined with fulvestrant (a selective ER downregulator/degrader). We generated microRNA (miRNA) signatures from fulvestrant-treated MCF-7 cells by RNA sequencing. From the signature, we evaluated miR-374b-5p because its expression was elevated by fulvestrant treatment in MCF-7 cells. Also, in expression analysis by subtype of BrCa patients, miR-374b-5p expression was suppressed only in luminal BrCa. Ectopic expression assays revealed that miR-374b-5p attenuated the malignant phenotypes of MCF-7 cells. We searched for genes regulated by miR-374b-5p and discovered that 11 (NEK2, NUF2, HMMR, DEPDC1B, FOXM1, ELOVL6, KIF20A, NCAPH, CENPK, FAM83D, and KIAA0101) are closely involved in BrCa molecular pathogenesis. Among these target genes, we focused on forkhead box M1 (FOXM1), a transcription factor regulating cell cycle progression and division. Notably, combination therapy with fulvestrant and a FOXM1 inhibitor significantly suppressed MCF-7 cell proliferation. From the miRNA signature established in this study, we identified antitumor miR-374b-5p and its target genes and used these findings to explore candidate drugs with potential efficacy when combined with fulvestrant.

Small cell carcinoma of the cervix (SCCC) is a rare yet highly aggressive subtype of cervical cancer (CC), characterized by early invasion, high metastatic potential, frequent recurrence, and extremely poor prognosis, which severely impairs women's physical and mental health. Currently, high-risk human papillomavirus (hr-HPV, particularly HPV18) infection is recognized as one of the core drivers underlying the initiation and progression of SCCC. Malignant evolution is not triggered by a single infection event but is cooperatively regulated at multiple molecular levels, including HPV genome integration, critical gene mutations, and aberrant activation of multiple signaling pathways. In addition, SCCC exhibits an HPV-independent oncogenic pathway mainly mediated by somatic mutations in tumor protein 53 (TP53) and retinoblastoma 1 (RB1), thus forming a dual pathogenic mechanism. Based on current clinical understanding and molecular mechanisms, this paper reviews the molecular pathogenesis and subtypes of SCCC, reveals the associations between tumor heterogeneity, therapeutic resistance, and metastasis, and proposes potential novel targets for the treatment of SCCC. This study innovatively presents a closed-loop model of two-way empowerment between basic research and clinical application. It emphasizes that basic research should be oriented toward real clinical problems and highlights the reciprocal feedback of clinical practice on basic research, thereby achieving dynamic iteration and collaborative breakthroughs in both fields.

The prognosis of glioblastoma (GBM) patients remains dismal due to chemoresistance. Repurposing of natural and endogenous compounds, such as the pineal hormone melatonin (MLT) and minor phytocannabinoids like cannabinol (CBN) or cannabigerol (CBG), represents a promising strategy. This study investigates the cytotoxic potential of combining these phytocannabinoids with MLT, evaluating their efficacy both alone and synergistically with temozolomide (TMZ) to overcome drug resistance. To achieve this, cytotoxicity, synergy (Bliss model), and selectivity were evaluated in U87, T98, and U251 GBM lines and normal astrocytes. Mechanisms of damage were characterized via Western blot (γH2AX and PARP-1), flow cytometry using fluorescent dyes/probes (DCFDA, JC-1, MitoBright, BODIPY, PI, and Annexin-V), or the protein marker COX IV and confocal analysis. The results demonstrated that CBN-MLT and CBG-MLT regimens exerted synergistic cytotoxicity while sparing healthy astrocytes. Notably, combining these regimens (U87: MLT 0.3 mg/mL + CBN 25 µM; MLT 0.2 mg/mL + CBG 15 µM. T98: MLT 0.7 mg/mL + CBN 25 µM; MLT 0.6 mg/mL + CBG 30 µM. U251: MLT 0.4 mg/mL + CBN 20 µM; MLT 0.5 mg/mL + CBG 35 µM) with TMZ significantly enhanced chemotherapeutic efficacy, overcoming baseline effects of TMZ in these cell lines. The combinations induced necrotic cell death characterized by severe double-strand DNA damage. This was driven by an early accumulation of intracellular ROS, which triggered mitochondrial depolarization, loss of organelle mass, and lipid peroxidation. CBN combinations consistently triggered more robust biochemical alterations than CBG-based treatments. Taken together, this study provides a strong preclinical basis for utilizing minor cannabinoids combined with MLT in GBM management. Crucially, this co-treatment emerges as a promising approach to potentiate TMZ efficacy, offering a novel and potentially effective therapeutic strategy to counter GBM resilience.

Liquid-liquid phase separation (LLPS) has attracted considerable attention in cell biology as a potentially widespread organizing principle in the cellular environment. LLPS involving proteins and nucleic acids participates in a wide range of cellular processes, including regulation of genome activity, modulation of enzymatic activity, and control of subcellular compartmentalization. Emerging evidence supports the idea that aberrant LLPS behavior is associated with various diseases, including cancer and infectious diseases. These findings suggest that LLPS provides a new framework for understanding complex regulatory phenomena in cells. In this review, we provide a comprehensive overview of LLPS, focusing on the biophysical mechanisms underlying condensate formation, the molecular composition of biomolecular condensates, and current experimental approaches used to study this process. In particular, we highlight the role of LLPS in aberrant transcriptional regulation, with a specific focus on its regulatory functions and underlying molecular mechanisms in tumor cells. Collectively, this review provides an updated perspective on the functional and mechanistic roles of LLPS in physiological and pathological contexts, particularly in tumor biology.

Colorectal cancer (CRC) remains a major cause of cancer mortality worldwide, highlighting the need for novel molecular targets and alternative therapeutic strategies. TYRO3, a member of the TAM receptor tyrosine kinase family, has been associated with tumor progression and poor prognosis in CRC. In this study, the effects of the natural compounds Meleagrin and Cucurbitacin B on TYRO3 expression and CRC cell behavior were investigated in HCT-116 and HT-29 cells. Cell proliferation, apoptosis, migration, and TYRO3 expression were evaluated using functional and expression-based analyses. Both compounds modulated TYRO3 expression and suppressed proliferation and wound closure dynamics in CRC cells. Cucurbitacin B exerted more pronounced antiproliferative and pro-apoptotic effects, whereas Meleagrin demonstrated antiproliferative activity with comparatively lower effects on normal colon epithelial cells (CCD 841 CoN), suggesting a potentially more favorable selectivity profile. Collectively, these findings support further mechanistic investigation of TYRO3-modulating natural compounds as potential therapeutic candidates for CRC.