Search Results (4,326)

Despite advances in multimodal treatment, head and neck squamous cell carcinoma (HNSCC) remains a major clinical problem owing to its high recurrence rate and frequent development of treatment resistance. Abnormal histone modifications, particularly lysine methylation regulated by methyltransferases (KMTs) and demethylases (KDMs), have emerged as key drivers of HNSCC initiation, progression, and cellular plasticity. This review aims to comprehensively evaluate the role of selected KMTs and KDMs in HNSCC biology, with a focus on their contribution to resistance to immunotherapy, radiotherapy, and cytotoxic chemotherapy. We summarize and critically analyze preclinical and clinical studies investigating histone methylation dynamics in HNSCC, with particular emphasis on enzymes such as KMT2C/D, EZH2, NSD1/NSD2, SMYD3, G9a/EHMT2, LSD1, KDM2A/B, KDM3, KDM4, KDM5, KDM6, KDM7, and KDM8. Attention is given particularly to pharmacological approaches targeting these proteins: we discuss small-molecule inhibitors of EZH2, LSD1, KDM4/5/6, and other KMT/KDMs that are currently in preclinical development or in early clinical trials, and we highlight completed and ongoing studies testing EZH1/2 inhibitors and epigenetic combinations in patients with recurrent and metastatic HNSCC. The deregulation of specific KMTs and KDMs reshapes histone methylation at key residues, thereby controlling cell cycle progression, epithelial–mesenchymal transition (EMT), stem cell phenotypes, DNA damage responses, and multiple interactions with the immune system in HNSCC. Targeting disrupted histone methylation pathways may partially reverse the epigenetic reprogramming of HNSCC cells and represents a promising strategy to improve treatment efficacy in patients with advanced disease. We also summarize the preclinical evidence and the currently limited clinical data on targeting histone methylation dynamics in HNSCC and discuss their therapeutic implications. Full article

Peritoneal metastasis (PM) is the most frequent and lethal pattern of dissemination in gastrointestinal malignancies. Despite advances in systemic chemotherapy, outcomes remain poor because the unique biology of PM, characterized by poor vascularization and the peritoneal–plasma barrier (PPB), limits drug penetration and contributes to treatment resistance. To address these challenges, several locoregional treatment strategies have been developed, including cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC). However, their widespread adoption is constrained by invasiveness, strict patient selection, and inconsistent survival benefits. Normothermic intraperitoneal and systemic treatment (NIPS) has emerged as a practical and less invasive alternative, particularly in East Asia. Through an implanted intraperitoneal port, NIPS enables repeated drug administration, providing sustained regional exposure while imposing minimal procedural burden. Importantly, it can be readily integrated with systemic chemotherapy, making it suitable for long-term multimodal treatment. Among available agents, paclitaxel (PTX) is particularly well suited for intraperitoneal administration because of its prolonged retention within the peritoneal cavity and limited systemic absorption. These pharmacokinetic properties allow high local drug concentrations with relatively low systemic toxicity. Consequently, PTX-based NIPS represents a biologically rational and clinically feasible treatment strategy for PM. This review summarizes the pharmacological rationale, clinical evidence, and emerging innovations in drug formulation and delivery that may further enhance the efficacy of PTX-based intraperitoneal chemotherapy for this challenging disease. Full article

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by limited treatment options and poor prognosis. Gemcitabine is a commonly used chemotherapy; however, gemcitabine resistance in PDAC poses a critical barrier to effective treatment, as the underlying mechanisms are not yet fully understood. Methods: This study employs an exploratory untargeted metabolomics approach to investigate metabolic differences in PDAC cells in the presence and absence of gemcitabine treatment. HPAF-II, MIA PaCa-2, and BxPC-3 cell lines were used as models for gemcitabine-resistant, moderately responsive, and permissive PDAC cells, respectively. Results: MTT assay results revealed that BxPC-3 cells are highly sensitive to gemcitabine treatment, HPAF-II cells are the most resistant, and MIA PaCa-2 cells exhibit moderate sensitivity. Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA) of the metabolomics data demonstrated clear differentiation of gemcitabine-treated and untreated (control) cells. When comparing the treated vs. control conditions, 170 metabolites matched to an in-house library of standards were significant (p < 0.05 or fold change ≥ 2 or VIP ≥ 1) differentiators in HPAF-II cells, whereas MIA PaCa-2 and BxPC-3 cells had 178 and 218 differentiating metabolites, respectively. HPAF-II cells treated with gemcitabine had significantly higher levels of N-acetylneuraminic acid and 7-dehydrocholesterol compared with the control group. In contrast, these metabolites were significantly lower or non-significant in BxPC-3 treated cells. Pathway analysis revealed that the steroid biosynthesis pathway was significantly perturbed in HPAF-II cells, whereas amino sugar and nucleotide sugar metabolism was predominantly altered in BxPC-3 cells. Conclusions: Overall, this exploratory study reveals metabolic differences between treated and untreated cells to derive targeted therapeutic strategies that could be used in the future to improve treatment outcomes for PDAC patients. Full article

Cancer immunotherapy has reshaped oncology, yet durable benefit remains limited for many patients because antitumor responses are constrained by multiple biological and clinical barriers. A targeted narrative review was conducted using peer-reviewed literature indexed in PubMed, Scopus, and Web of Science from January 2020 to April 2026, with additional landmark studies from earlier years included for essential mechanistic context. Priority was given to clinical, translational, and high-impact review articles examining combination strategies built on immune checkpoint blockade and related immune platforms. The evidence was synthesized by the main barriers each strategy aims to overcome, including poor immune priming, immune exclusion, immunosuppressive tumor microenvironments, adaptive resistance, and limited treatment durability. Across recent studies, combination immunotherapy is increasingly moving away from empiric regimen construction toward biologically rational approaches that integrate checkpoint blockade with chemotherapy, radiotherapy, antiangiogenic therapy, targeted agents, antibody–drug conjugates, bispecific antibodies, vaccines, and cellular platforms. Increasing emphasis has also been placed on integrated biomarkers that combine tumor-intrinsic, immune, spatial, and dynamic features to improve patient selection. At the same time, growing regimen complexity continues to raise challenges related to overlapping toxicity, sequencing, polypharmacy, and multidisciplinary implementation. Overall, the field is evolving toward mechanism-matched, biomarker-guided, and clinically manageable strategies that may broaden and refine the benefit of cancer immunotherapy. Full article

Ovarian cancer (OVC) is a leading cause of gynecological cancer mortality due to late-stage diagnosis and chemoresistance. Among the multiple molecular mediators, oncogenic epidermal growth factor receptor (EGFR) signaling has emerged as a key regulator of tumor progression and drug resistance, ultimately governing cancer survival. Therefore, this review focused on the molecular mechanisms of aberrant EGFR signaling to promote chemoresistance in ovarian cancer through multiple interlinking pathways, including the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of the rapamycin (mTOR), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling cascades. These pathways act in concert to confer resistance, including proliferation, antiapoptotic effects, cancer stem cell maintenance, and facilitating epithelial-mesenchymal transition (EMT), which function together to decrease sensitivity towards platinum-based and taxane chemotherapies. Furthermore, we incorporate novel evidence regarding EGFR cross-talk with extracellular matrix (ECM) and metabolic reprogramming, especially their relevance to immune evasion mechanisms, hypoxia, and extracellular vesicles (EVs)-mediated signaling. In addition, we elaborated on the limitation of the current EGFR targeting therapy, which will be beneficial for further designing new combinatorial treatment approaches by using EGFR inhibitors with immunotherapy, nanocarriers, and microbiota modulators. Overall, this review highlights the updated role of EGFR signaling as a key regulator of chemoresistance in ovarian cancer, providing insights for developing targeted therapies to overcome drug resistance and improve patient survival. Full article

Gemcitabine-based chemotherapy has long served as a standard treatment for urothelial carcinoma (UC), particularly in perioperative and metastatic settings. However, therapeutic efficacy is frequently limited by intrinsic or acquired resistance. Gemcitabine functions as a prodrug whose activity depends on coordinated processes involving cellular uptake, intracellular activation, metabolic inactivation, and nucleotide metabolism. Increasing evidence suggests that resistance in UC is mediated by multiple interconnected mechanisms beyond alterations in gemcitabine transport, activation, and inactivation alone. Key molecular determinants include human equilibrative nucleoside transporter 1 (hENT1), deoxycytidine kinase (dCK), cytidine deaminase (CDA), and ribonucleotide reductase regulatory subunit M1 (RRM1), which is involved in nucleotide pool maintenance and DNA synthesis. In addition, replication stress responses, apoptosis evasion pathways, and tumor microenvironment-associated factors also contribute to gemcitabine resistance. Stress-adaptive pathways involving Y-box binding protein 1 (YB-1), hypoxia-inducible factor-1 alpha (HIF-1α), and autophagy-related mechanisms may further promote survival under chemotherapy-induced stress conditions. In addition, extracellular mucin-associated mechanisms may alter intratumoral drug accessibility and contribute to resistance. In this review, we summarize UC-specific evidence regarding gemcitabine resistance and discuss how these pathways collectively shape an integrated resistant phenotype. Full article

Resistance to 5-fluorouracil (5-FU) remains a major limitation in colorectal cancer therapy, prompting the development of combination strategies aimed at improving its efficacy. Bakuchiol (BAK), a natural compound with reported antioxidant and pro-oxidant properties, may modulate redox balance and enhance chemotherapy response. This study compared the effects of 5-FU and BAK, applied as monotherapies and in combination, in DLD-1 and HT-29 colorectal cancer cells. Cytotoxicity assays showed that co-treatment significantly reduced the IC₅₀ of 5-FU, particularly in DLD-1 cells, and revealed an enhanced anticancer effect of the combination treatment compared with either monotherapy. Flow cytometric analyses demonstrated enhanced apoptosis via extrinsic and intrinsic pathways, including increased caspase 8 activity, loss of mitochondrial membrane potential (ΔΨ_m), activation of caspase 9, and subsequent activation of caspases 3/7. These effects were associated with a pronounced redox imbalance, reflected by increased intracellular reactive oxygen species (ROS) levels, suggesting a central role of oxidative stress in mediating cytotoxicity. Antioxidant pre-treatment attenuated ROS accumulation and reduced apoptosis, confirming a causal relationship. Additionally, autophagy was induced selectively in DLD-1 cells, indicating cell-line-specific differences in redox adaptation. Taken together, BAK enhances 5-FU efficacy through ROS-dependent activation of mitochondrial and caspase-dependent pathways, with stronger effects observed in DLD-1 cells. Full article

Ovarian cancer is a major cause of gynecological cancer mortality, frequently associated with platinum-resistant recurrences. Given the limited efficacy of conventional chemotherapy in this setting, alternative targeted therapeutics are needed. Mirvetuximab soravtansine (MIRV) is an antibody–drug conjugate designed to deliver the cytotoxic maytansinoid DM4 to folate receptor alpha (FRα)-overexpressing cells. This systematic review of PubMed, ClinicalKey, and SpringerLink databases (2019–2026) evaluates five publications across three clinical trials (one phase II, two phase III) encompassing 925 patients with platinum-resistant disease. Notably, the phase III MIRASOL trial demonstrated improved survival outcomes with MIRV over standard chemotherapy, extending median overall survival (16.46 vs. 12.75 months; HR 0.67) and progression-free survival (5.62 vs. 3.98 months; HR 0.65), with an objective response rate (ORR) of 42.3% versus 15.9%. Furthermore, the single-arm phase II SORAYA trial reported an ORR of 32.4% in pretreated patients, including those with prior PARP inhibitor and bevacizumab exposure. Although the preceding FORWARD I trial missed its primary endpoint in the unselected population, its high-FRα subgroup analysis revealed a clinical benefit that influenced subsequent biomarker-driven enrollment strategies. From a safety perspective, MIRV exhibited lower rates of severe neutropenia and anemia than chemotherapy, with toxicities primarily consisting of manageable, reversible ocular events. Ultimately, MIRV serves as a therapeutic option for platinum-resistant, FRα-positive ovarian cancer, offering survival advantages; however, rigorous biomarker-based screening remains necessary to optimize therapeutic outcomes. Full article

Ovarian cancer, particularly high-grade serous ovarian cancer (HGSOC), remains one of the most lethal gynecological malignancies due to late diagnosis and the development of chemoresistance. The tumor microenvironment (TME) plays an important role in disease progression, with chemokines influencing cell recruitment, angiogenesis, metastasis, and immune modification. This review synthesizes current evidence on key chemokine axes in ovarian cancer, highlighting their dual roles as prognostic biomarkers and therapeutic targets. The most important axes include CXCL12/CXCR4 (which drives tumor proliferation, angiogenesis and chemoresistance via epithelial–mesenchymal transition), CCL2/CCR2 (promoting immunosuppressive tumor-associated macrophages and resistance), and CCL5/CCR5 (enhancing pro-oncogenic signaling and Treg/MDSC infiltration). Pro-angiogenic ELR+CXC chemokines like CXCL8 induce vascularization and inflammation. On the contrary, effector chemokines (CXCL9/10/11/13) correlate with “hot” immune subtypes and improved survival in several studies. High expression of immunosuppressive chemokines predicts poorer prognosis and therapy resistance, while immune-attracting profiles associate with better outcomes and chemotherapy responsiveness. Therapeutically, inhibitors like plerixafor (CXCR4), PF-04136309 (CCR2), and maraviroc (CCR5) show preclinical promise, synergizing with chemotherapy, anti-VEGF, and checkpoint inhibitors. Chemokines also represent actionable molecular targets to overcome ovarian cancer’s “cold” immune phenotype. Future research should validate multi-chemokine signatures for patient stratification and advanced clinical trials toward personalized therapies. Full article

Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation and is mechanistically distinct from apoptosis, necrosis and pyroptosis. Increasing evidence indicates that ferroptosis plays a critical role in cancer biology, including lymphoproliferative disorders, where chronic redox imbalance, dysregulated iron metabolism, and metabolic rewiring create a permissive environment for ferroptotic vulnerability. In these malignancies, altered iron handling, elevated reactive oxygen species, and a strong reliance on antioxidant systems such as glutathione and glutathione peroxidase 4 tightly control ferroptotic sensitivity. Dysregulation of key components, including SLC7A11, lipid metabolism pathways, and intracellular iron homeostasis, further shapes the susceptibility of malignant lymphoid cells to ferroptosis. Importantly, emerging preclinical studies suggest that therapeutic targeting of ferroptosis may overcome resistance to conventional chemotherapy, targeted agents, and immunotherapy, offering novel opportunities particularly in relapsed or refractory disease. This review provides a comprehensive overview of the molecular mechanisms governing ferroptosis in lymphoproliferative disorders, highlights the interplay between ferroptosis and major cellular and metabolic pathways, and discusses current and emerging strategies to pharmacologically induce ferroptosis, with an emphasis on biomarker-driven clinical translation. Full article

For decades, peritoneal metastases (PM) have been regarded as a terminal manifestation of advanced malignancies and managed primarily with palliative intent because of limited sensitivity to systemic therapies. Accumulating clinical, molecular, and immunological evidence now supports the view that PM is not merely an anatomic pattern of spread but a distinct metastatic niche with characteristic biological, microenvironmental, and therapeutic features. This review summarizes the major routes of PM development—transcoelomic, lymphatic, and hematologic dissemination—and emphasizes how these pathways converge through shared biological programs. Core mechanisms include epithelial–mesenchymal transition (EMT), adhesion signaling, extracellular matrix remodeling, and tumor–immune cell interactions. A central focus is the peritoneal tumor microenvironment: mesothelial-to-mesenchymal transition, cancer-associated fibroblast activity, adipocyte-derived metabolic support, macrophage polarization, and regulatory T-cell enrichment collectively shape an immunotolerant and treatment-resistant niche on the peritoneal surface. In addition, evidence from pre-metastatic niche biology suggests that primary tumor-derived exosomes and epitranscriptomic regulation can prime the peritoneal environment before overt implantation. These features provide a biological rationale for locoregional strategies such as cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, as well as emerging intraperitoneal modalities and microenvironment-targeted approaches. Finally, organoid platforms, liquid biopsy-based minimal residual disease monitoring, and theranostic technologies may enable more personalized, biology-driven management of PM. Full article

Chemotherapy has been used in cancer treatment for decades; however, standard chemotherapy treatments still have significant weaknesses, including collateral damage to healthy tissue, rapid development of drug resistance, and dose-limiting toxicity that limits therapeutic value. There is now an alternative approach using polymer materials that are responsive to biological stimuli that will allow for improved treatment of cancer while avoiding the limitations. Responsive polymer materials are designed to be inert during circulation until they reach their site of action; then, they will respond to specific triggers. These smart carriers respond to stimuli present in the tumor microenvironment (e.g., low pH, high glutathione levels, and increased proteolytic activity) or external stimuli applied at the bedside (e.g., localized heat, light, ultrasound, and applied magnetic fields). In both cases, there is a consistent pattern where the drug is released exactly where/when it is needed, with minimal drug release occurring outside that location and timeframe. Therefore, it is theorized that the use of polymeric-based delivery systems with stimuli-regulated drug release will significantly increase the concentration of drug delivered intratumorally, decrease the drug toxicity, and provide a potential mechanism to overcome the development of multidrug resistance from a variety of cancer treatments. To date, various types of responsive polymers have been developed and could be combined to give rise to a wide variety of different vehicle systems (e.g., micelles, nanogels, hydrogels, and hybrid delivery systems), with many of these carriers designed to respond to multiple stimuli simultaneously. Nonetheless, significant challenges remain in the clinical application of these materials due to tumor heterogeneity, immune system interactions, reproducibility issues, polymer chemistry advances, surface chemistry, and other interaction mechanisms. As a result of all of these evolving regulatory systems, as well as some of the emerging areas of polymer chemistry and surface engineering, theranostic integration will allow for new routes to provide therapy for patients with cancer. Additionally, because of these scientific advances, there will also be more opportunities to provide targeted, controllable, and on-demand treatments to patients using stimuli-responsive polymers. Full article

The primary goal in the treatment of pediatric malignancies is to maintain effective cancer control while minimizing toxicities and late effects. Radiotherapy is a component of standard therapy against many pediatric cancers, but tumor cell DNA damage repair mechanisms and the hypoxic tumor microenvironment may limit the effectiveness of this modality. Additionally, irradiated cancer cells often acquire resistance to radiotherapy that permits cancer cell survival or stimulates tumor regrowth after treatment, further limiting the efficacy of radiotherapy. Various preclinical studies have investigated the potential of combining chemotherapy or immunotherapy with radiotherapy, with the goal of inducing a more lethal amount of DNA damage and prohibiting cells from acquiring radiotherapy resistance. This review provides an overview of the current strategies to enhance cancer cell response to radiotherapy, providing a framework to improve outcomes for children with solid tumors. Full article

Background: Metal-based anticancer drugs, particularly platinum and gold complexes, play a central role in chemotherapy but are often limited by systemic toxicity, resistance, and suboptimal selectivity. Peptide conjugation has emerged as a versatile strategy to modulate the pharmacokinetic and biological properties of metal complexes, enabling targeted delivery, improved uptake, and controlled activation. This review aims to critically analyze platinum- and gold-peptide bioconjugates in cancer therapy, focusing on directly reactive metal complexes and redox-activated prodrug systems. Methods: Relevant literature from the past two decades was surveyed across major scientific databases, focusing on the design, conjugation strategies, biological activity, and mechanisms of action of Pt- and Au-peptide bioconjugates. Results: Reviewed studies reveal distinct behavior for platinum- and gold-based systems. Pt(II)-peptide conjugates primarily retain DNA-reactive interaction, with peptides mainly enhancing cellular uptake, selective targeting and solubility, although improved cytotoxicity is not consistently achieved. In contrast, Pt(IV)-peptide conjugates function as prodrugs, where axial peptide functionalization allows greater structural versatility and sometimes improved selectivity, with therapeutic efficacy strongly depending on intracellular reduction kinetics. Au(I)-peptide conjugates act as directly reactive species targeting thiol- and selenol-containing proteins, whereas Au(III) bioconjugates often behave as redox-activated prodrugs, with peptide conjugation influencing stability and cellular fate. Conclusions: Overall, peptide conjugation represents a powerful but non-trivial approach for optimizing metal-based anticancer agents. The success of metal-peptide bioconjugates critically depends on balancing peptide-mediated delivery with the intrinsic reactivity and activation pathways of the metal center. A function-guided design of bioconjugates is essential to achieve genuine selectivity and therapeutic benefit. Full article

Background: The treatment of rectal cancer frequently involves a multimodal approach, including neoadjuvant therapy prior to surgery in patients with locally advanced disease. However, the response to such treatment is variable. Robust biomarkers to predict neoadjuvant therapy response represent an unmet clinical need; they could help to stratify patients for organ preservation strategies or treatment intensification. The tumour–stroma ratio (TSR) is an established prognostic marker that has recently gained attention for its potential predictive value when assessed in pre-treatment biopsies. Objective: This narrative review critically evaluates the existing evidence regarding TSR as a predictive biomarker for neoadjuvant therapy response in rectal cancer. Results: Emerging evidence from retrospective studies of large cohorts suggests that stroma-high tumours often demonstrate resistance to standard neoadjuvant chemoradiotherapy, resulting in lower major pathological response rates. Conversely, some smaller studies report no significant association between biopsy TSR and treatment efficacy. This conflicting evidence could be attributable to methodological heterogeneity, including inconsistent definitions, varying measurement techniques (manual versus automated), and mixed patient cohorts. The predictive value of TSR appears to be neoadjuvant regimen-specific, with stroma-high phenotypes interacting differently with treatments like short-course radiotherapy or intensified chemotherapy. Conclusions: TSR is a simple, biologically plausible, and readily assessable promising biomarker with apparently predictive as well as prognostic potential. It is likely to represent a regimen-specific predictor rather than a universal marker of resistance to neoadjuvant therapy in rectal cancer. Future clinical translation will require standardised, AI-driven quantification and robust prospective clinical validation. Full article