Bladder cancer (BC) continues to be a prevalent malignancy within the urinary tract, characterized by high rates of recurrence, metastatic progression, and resistance to therapy, highlighting the importance of developing...Bladder cancer (BC) continues to be a prevalent malignancy within the urinary tract, characterized by high rates of recurrence, metastatic progression, and resistance to therapy, highlighting the importance of developing treatments that target regulated cell death pathways. Ferroptosis is a regulated form of cell death that depends on iron and is caused by excessive lipid peroxidation, whereas autophagy is a conserved catabolic process that can either buffer cellular stress or contribute to cell demise depending on context. Emerging evidence indicates that ferroptosis and autophagy intersect through shared metabolic and signaling nodes, including iron handling, glutathione and lipid metabolism, and stress-response pathways. In this narrative review, we summarize bladder-cancer-specific studies linking ferroptosis and autophagy, integrate mechanistic insights with evidence from patient cohorts and public datasets, and discuss translational opportunities and limitations for targeting this crosstalk in BC.
Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer mortality in the U.S., where more than 80% of the cases are diagnosed with metastatic PDAC (mPDAC). In this study, Maeda et al. utilized a CRISPR...Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer mortality in the U.S., where more than 80% of the cases are diagnosed with metastatic PDAC (mPDAC). In this study, Maeda et al. utilized a CRISPR screen in human patient-derived xenografts from primary and lung metastatic tumors and identified the transcription factor KLF5 as an upstream modulator regulating the mPDAC phenotype. Using a combination of biochemical and molecular experiments together with single-cell genome-wide assays, the authors discovered that KLF5 induces epigenetic modifiers including NCAPD2 and MTHFD1, which in turn regulate the expression of a distinct gene profiles controlling the biology of mPDAC. Altogether, the authors defined a cascade of events acting as a domino effect triggered by KLF5, modifying the epigenetic landscape in mPDAC to support metastatic growth.
BACKGROUND: EZH2 is a histone methyltransferase and a key component of polycomb repressive complex 2 (PRC2). It plays a critical role in genome remodeling, gene regulation and acts through PRC2-dependent and independent...BACKGROUND: EZH2 is a histone methyltransferase and a key component of polycomb repressive complex 2 (PRC2). It plays a critical role in genome remodeling, gene regulation and acts through PRC2-dependent and independent mechanisms, which comprise methylation of histone and non-histone substrates, and transcriptional activation through different transcriptional complexes. EZH2 is involved in many cancers, but its role in hepatoblastoma is poorly understood. METHODS: Potential correlation between EZH2 mRNA expression and clinical parameters was analyzed by computational and histological approaches using seven published transcriptomic datasets and tissue samples from patients with hepatoblastoma. EZH2 molecular function was deciphered using molecular approaches, gain- and loss-of-function genetic tools, proteomics, immunohistochemistry, pharmacological drugs, 2D cell- and spheroid-based assays, and four different animal models. RESULTS: Our data show that EZH2 mRNA expression correlated with poor prognostic markers such as tumor proliferation, and patients’ death and shorter survival. EZH2 protein potentiated hepatoblastoma cell proliferation, migration, survival and cisplatin resistance through its histone methyltransferase activity by repressing DUSP5, and transcriptionally inducing DUSP9 and HMGCR. In vivo EZH2 sustained tumor cell proliferation, and tumor development and angiogenesis. The EZH2 inhibitor GSK126 synergized with HMG-CoA reductase inhibitor statins to eradicate hepatoblastoma cells in vitro and block tumor development in mice. This combination was also very effective on various hepatoblastoma and non-hepatoblastoma tumor cell lines. CONCLUSION: Collectively, our data showed that the protein EZH2 promotes hepatoblastoma development, partly through its histone methyltransferase activity, by differentially modulating the expression of DUSP5, DUSP9 and HMGCR genes and by supporting the MAPK/ERK pathway in hepatoblastoma cells already displaying high Wnt signal activity. EZH2 inhibitors triggered lipid synthesis in hepatoblastoma cells and synergized with cholesterol-lowering statins to block hepatoblastoma development in vitro and in vivo. Therefore, we demonstrate the key role of EZH2 in proliferative hepatoblastoma and the therapeutic benefit of combining EZH2 inhibitor and statin to treat patients with cancer.
Drug development for digestive tumors depends on various preclinical models to evaluate their efficacy and safety. Traditional models, such as 2D cell lines and animal models, fail to recapitulate the complex pathology i...Drug development for digestive tumors depends on various preclinical models to evaluate their efficacy and safety. Traditional models, such as 2D cell lines and animal models, fail to recapitulate the complex pathology in the human body. Recently, novel models, such as 3D organoids, tumor spheroids, and organ-on-a-chip systems, have undergone rapid growth. These models can recapitulate tissue architecture and the microenvironment in a more faithful way, enhancing the translational relevance of in vitro experiments to clinical outcomes. Moreover, patient-derived xenografts and genetically engineered models retain the genetic heterogeneity and immune contexture of original tumors, which play critical roles in assessing drug efficacy and resistance mechanisms. This review aims to explore the strengths and limitations of diverse models in drug discovery for digestive tumors. In addition, we delineate their utility in target discovery or validation, lead compound screening, and preclinical mechanistic profiling. Current studies indicate that drug failure rates can be minimized by the integration of 2D high-throughput screening, 3D organoid/tumor spheroid screening, and in vivo animal validation. Multimodal synergy and personalized models can lead to the development of more efficient and precise approaches for treating digestive tumors.
BACKGROUND: Disruption of the Men1 locus in epithelial and endocrine tissues fails to generate the full spectrum of gastroenteropancreatic neuroendocrine tumors (GEP-NETs), raising the possibility of a potential stromal...BACKGROUND: Disruption of the Men1 locus in epithelial and endocrine tissues fails to generate the full spectrum of gastroenteropancreatic neuroendocrine tumors (GEP-NETs), raising the possibility of a potential stromal source for these cancers. Neural crest-derived glial cells were previously implicated in neuroendocrine tumors arising in the pituitary and pancreas, yet these studies lacked a clear mechanism for these events. Here, we investigated the hypothesis that Men1-driven Hedgehog (HH) signaling redirects the glial cell fate to give rise to neuroendocrine tumors in the gastrointestinal tract. METHODS: Hyperactivation of the HH signaling pathway in human GEP-NETs was evaluated using immunofluorescent staining and clinicogenomic databases. Men1 was deleted in the glial lineage by expressing Cre recombinase downstream of the human GFAP and Sox10 promoters. Overexpression of HH signaling proteins in mouse GEP-NETs was confirmed by immunofluorescent staining and immunoblot analysis. We generated human and mouse GEP-NET tumoroids and exposed them to agonists and inhibitors of HH signaling. HH activation of Men1-deficient glial cells was blocked by deleting the gene encoding primary ciliary protein KIF3A required for transducing SHH signaling. RESULTS: We demonstrated that human GEP-NETs overexpress HH signaling pathway components, including SHH and its cognate receptor PTCH1. We showed that patient-derived GEP-NET tumoroids proliferate in response to SHH pathway agonists. In contrast, pharmacologic inhibition of GLI1/2, but not inhibition of SMO alone, attenuated tumoroid growth. Genetic deletion of Men1 in GFAP+ and SOX10+ glial cells caused the development of pancreatic and intestinal NETs that overexpress HH proteins. Further use of tdTomato+ mice demonstrated the involvement of GFAP+ and SOX10+ glial cells in these tumors. Tumoroid cultures of mouse pancreatic, duodenal, and jejunal NETs recapitulated the drug response shown by patient-derived tumoroids. Lastly, Men1-deficient enteric glial cultures showed a glial-to-neuroendocrine transition that was alleviated upon HH inhibition, and these events were reproduced in genetic mice harboring GFAP+ cells with impaired primary cilia. CONCLUSIONS: Our study implicates the HH signaling pathway in GEP-NET development and underscores a glial cell of origin for these tumors.
Chronic inflammation within the tumor microenvironment (TME) is a critical driver of immune evasion, resistance to therapy, and progression of cancer, while epidemiological and immunological evidence indicates that aller...Chronic inflammation within the tumor microenvironment (TME) is a critical driver of immune evasion, resistance to therapy, and progression of cancer, while epidemiological and immunological evidence indicates that allergic inflammation is also associated with the risk of several cancer types. Key pro-inflammatory cytokines: IL-6, IL-1β, TNF-α, and TGF-β activate key signaling pathways such as STAT3, NF-κB, and HIF-1α which create a self-amplifying cycle fostering angiogenesis, epithelial–mesenchymal transition, and immunosuppression. The accumulation of regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages additionally promotes an immunologically “cold” TME limiting the efficacy of immune checkpoint blockade, chemotherapy, and radiotherapy. Recent advances have elucidated on how inflammatory signaling dynamically changes cellular and metabolic states fostering resistance. Targeting these inflammatory signaling axes has demonstrated promising therapeutic efficacy: IL-6R and IL-1β neutralization, JAK/STAT3 and NF-κB inhibition, TGF-β blockade, and CXCR2 targeted strategies all have demonstrated the ability to restore anti-tumor immunity. Rationally designed combination therapies utilizing cytokine inhibition in combination with checkpoint blockades or anti-angiogenic agents are beginning to convert refractory tumors to responsive tumors. Herein we review mechanistic insights linking chronic inflammation to immunosuppression and treatment failure across multiple cancer types and discuss the translational promise of inflammation-targeted treatments. Targeting the TME through multi-variate inhibition of inflammatory pathways may be able to allow durable therapeutic responses to be achieved in tumors previously resistant to conventional and immune-based therapies.
Histone H3.3K27M mutations are identified in diffuse midline glioma (DMG), resulting in a global reduction in H3K27me3. Analyzing the histone recognition mechanism at H3K27 position can enhance the understanding of this...Histone H3.3K27M mutations are identified in diffuse midline glioma (DMG), resulting in a global reduction in H3K27me3. Analyzing the histone recognition mechanism at H3K27 position can enhance the understanding of this highly lethal mutation. Here we identify a novel histone reader CBFA2T2, which recognizes non-mutated or un-modified histone H3K27. Biochemical assays confirm this binding specificity, indicating that it is mediated by NHR2 domain of CBFA2T2. CBFA2T2 represses the transcription of metabolic genes involved in carbon metabolism, glycolysis/gluconeogenesis and the TCA cycle pathways through its binding to H3K27, thereby regulating metabolite levels. These alter the alpha-ketoglutarate/Succinate ratio and indirectly impacts H3K27me3 level, through affecting the H3K27me3 demethylases. Our results uncover a novel mechanism by which CBFA2T2 transcriptionally regulates metabolism and tumor growth in H3.3K27M cells. These findings suggest that CBFA2T2 and its targeted genes may serve as potential therapeutic targets for the treatment of H3.3K27M cancer.
Cancer research has achieved remarkable breakthroughs over the past decades with the aid of patient-derived xenograft (PDX) models. However, the limitations of conventional PDX models in hindering clinical translation ha...Cancer research has achieved remarkable breakthroughs over the past decades with the aid of patient-derived xenograft (PDX) models. However, the limitations of conventional PDX models in hindering clinical translation have become increasingly apparent. In 2025, the National Institutes of Health (NIH) announced a funding shift away from exclusive reliance on animal models without justified integration of novel alternative methods (NAMs), human-relevant modeling approaches. Nevertheless, PDX models cannot be fully replaced currently due to the lingering immaturity and uncertainties of NAMs technologies, indicating that a complete non-animal research paradigm will require sustained methodological development. Therefore, developing an innovative, optimized PDX model to navigate this transitional phase remains the holy grail of preclinical cancer research. Herein, we propose PDX 2.0, a novel conceptual framework that advances conventional PDX models via the systematic integration of NAMs and complementary technologies, thereby enabling more efficient and precise cancer research. This review first delineates the core determinants, major applications, and critical limitations of traditional PDX models, then defines the conceptual architecture and distinctive characteristics of PDX 2.0. We further highlight emerging applications of this framework in high-throughput drug screening, biomarker discovery, and adaptive therapeutic evaluation, positioning PDX 2.0 as a critical evolution of PDX-based research to better support clinically actionable precision oncology.
Cervical cancer remains a major global health burden largely driven by persistent infection with high-risk human papillomavirus. Although immune-based therapies have transformed outcomes in several solid tumors, their be...Cervical cancer remains a major global health burden largely driven by persistent infection with high-risk human papillomavirus. Although immune-based therapies have transformed outcomes in several solid tumors, their benefit in cervical cancer has been modest, highlighting the need to understand and therapeutically exploit the tumor immune microenvironment. This review synthesizes current mechanistic and clinical evidence on viral-driven immunology, immune heterogeneity, and the bidirectional effects of radiotherapy on systemic and intratumoral immunity. We examine how radiation dose, fractionation, treatment volumes and temporal sequencing influence antigen release, innate sensing, T cell priming and trafficking, as well as detrimental consequences including lymphocyte depletion, checkpoint induction, expansion of suppressive myeloid and regulatory populations and stromal remodeling. Building on these insights, we discuss synergistic strategies to reprogram the tumor immune microenvironment, including combinations of radiotherapy with immune checkpoint inhibition, spatially informed field design that preserves anti-tumor immunity while limiting collateral lymphodepletion and adaptive response-guided treatment. We also highlight candidate biomarkers such as viral antigens, interferon pathway activation, T-cell clonality and spatial immune architecture that may enable patient selection, real-time treatment adaptation, and early detection of resistance. Converging preclinical and clinical data support a biomarker informed integration of radiotherapy and immunotherapy to overcome therapeutic resistance and to advance precision immuno-oncology in cervical cancer.
The progression of endometrial cancer (EC) involves substantial metabolic reprogramming, frequently driven by mutations in tumor suppressors and oncogenes. In this study, we identify a previously unrecognized pathway thr...The progression of endometrial cancer (EC) involves substantial metabolic reprogramming, frequently driven by mutations in tumor suppressors and oncogenes. In this study, we identify a previously unrecognized pathway through which FBXW7 mutations rewire glucose metabolism in EC cells. Specifically, we demonstrate that loss-of-function mutations in FBXW7 disrupt the SCF E3 ubiquitin ligase complex, resulting in the stabilization of the transcription factor ETV6 by preventing its ubiquitin-mediated degradation. Accumulated ETV6 subsequently enhances the transcriptional activation of glucose transporter 1 (GLUT1), elevating its expression and localization to the plasma membrane. This increased GLUT1 expression significantly enhances glucose uptake, fueling both aerobic glycolysis and oxidative phosphorylation, which collectively accelerate EC cell proliferation and tumor growth. Importantly, targeting GLUT1 pharmacologically partially reverses the proliferative advantage conferred by ETV6 overexpression, highlighting a promising therapeutic vulnerability. Our findings establish the FBXW7-ETV6-GLUT1 regulatory axis as a critical driver of metabolic adaptation and tumor progression, offering potential strategies for targeted therapy in FBXW7-mutant EC.
Nanomedicine's merging with artificial intelligence (AI) is fundamentally changing cancer theranostics through precise creation of multifunctional nanoparticles which can simultaneously diagnose and treat diseases. Tradi...Nanomedicine's merging with artificial intelligence (AI) is fundamentally changing cancer theranostics through precise creation of multifunctional nanoparticles which can simultaneously diagnose and treat diseases. Traditional cancer treatments today face issues with imprecise delivery and general body toxicity as well as late-stage disease recognition which theranostic nanoplatforms address through precision drug transport and live imaging functions. In this analysis, we examine the existing state and forthcoming developments of AI applications in cancer theranostics through nanoparticles. Our study first examines the three primary classes of theranostic nanomaterials that show clinical significance: liposomes, gold nanoparticles, iron oxide nanoparticles, and quantum dots. AI is being applied to nanoparticle development through machine learning, deep learning, reinforcement learning, and generative models that support physicochemical predictions, synthesis optimization, biodistribution modeling, and inverse design. We analyze clinical applications of AI solutions which support patient identification, response predictions, and implementation of virtual patient models for individualized cancer treatment. The paper evaluates major difficulties which are nanotoxicity, AI explainability, data limitations, and regulatory concerns while addressing ethical dilemmas. Rather than a broad overview of nanomedicine, we center on AI methods that directly improve theranostic decisions and support this with worked exemplars reporting datasets, baselines, metrics, and clinical tie-ins. This Task–Data–Method–Metric lens replaces generic background and grounds claims in reproducible evidence.
Maeda M, Sherman K, Zhou W
… +13 more, Cheng J, Nihongaki Y, Idrizi A, Tryggvadottir R, Camacho O, Shang X, Min J, Koldobskiy MA, Maitra A, Levchenko A, Slusher BS, Ji H, Feinberg AP
One of the major conundrums of cancer research and treatment is that the metastases that lead to death in most patients do not appear to involve additional driver mutations. Previously, we reported widespread loss of het...One of the major conundrums of cancer research and treatment is that the metastases that lead to death in most patients do not appear to involve additional driver mutations. Previously, we reported widespread loss of heterochromatin with activation of pro-metastatic genes in the subset of cells of primary pancreatic tumors that gave rise to liver and lung metastases. Here we hypothesized that this change in chromatin could create unique vulnerabilities in distant metastases. Using a CRISPR screen of human patient-derived xenografts from metastases and primary tumors, we identified KLF5 as essential for metastatic cell proliferation but not primary tumor growth. Further, we found that KLF5 induced epigenetic modifier genes, including NCAPD2 and MTHFD1, which themselves facilitated expression of specific genes driving migration and epithelial-mesenchymal transition, including TGFBR2, VIM, EMP1, and ITGB1. Inhibition of expression of these modifier genes restored heterochromatin in the specific regions that distinguish the primary and metastatic tumors. We backed up this causal chain of evidence with rigorous additional knockdown experiments with the modifier genes, and single cell RNA and chromatin experiments, and we also replicated the main findings in a second set of paired primary and distant metastasis xenograft lines. Finally, KLF5 expression was strongly associated with patient survival and human PDAC cell plasticity in a dataset of 70 PDAC patients and KLF5 expression was increased in the majority of lung, liver and peritoneal metastases compared to the matched primary tumor, confirming its importance in PDAC metastasis and mortality. In summary, we have identified a cascade of epigenetic modulators, modifiers and mediators that maintains the widespread heterochromatin loss supporting metastatic cell proliferation in human pancreatic cancer (see Graphical Abstract).
Synthetic lethality (SL) is a therapeutic approach that selectively target cancer cells via the disruption of two interdependent molecular targets, which together become essential in the cancer context to ensure cancer c...Synthetic lethality (SL) is a therapeutic approach that selectively target cancer cells via the disruption of two interdependent molecular targets, which together become essential in the cancer context to ensure cancer cell survival. Among anticancer SL strategies, poly ADP-ribose polymerase (PARP) inhibitors have revolutionized the treatment of homologous recombination repair deficient breast and ovarian cancers by targeting the remaining DNA repair mechanisms. However, resistance emergence is nearly universal providing the rationale to expand beyond classical DNA repair targets. Severe DNA lesions like double-strand breaks or extended single-strand stretches trigger the complex DNA damage response signaling cascade (DDR), which provides many SL targets in addition to direct DNA repair mechanisms. Epithelial ovarian cancer is the deadliest gynecologic malignancy, in part because of late detection and treatment resistance, which provides a rich environment to explore the concept of combining multiple targets to produce SL synergies that kill cancer cells. In this context we discuss the interplay among varied components of the DDR including DNA damage signalers, cell cycle regulation, metabolism, epigenetics, and subsequent cell fate decisions like apoptosis or senescence. Based on this knowledge we further explore innovative SL approaches that may elicit or restore drug sensitivity in resistant tumors. Overall, we provide the rationale for multidimensional strategies linking classic DNA repair mechanisms to various molecular vulnerabilities sometimes apparently unrelated or downstream from DNA damage to improve cancer treatment outcomes via more effective and durable therapeutic responses, offering additional options for the personalized treatment of this highly heterogeneous disease.
BACKGROUND: The success of novel antibody-drug conjugates, such as trastuzumab deruxtecan (T-DXd) and disitamab vedotin (RC48), has been pivotal in rendering “HER-2-low” gastric cancer (GC) a therapeutically targetable e...BACKGROUND: The success of novel antibody-drug conjugates, such as trastuzumab deruxtecan (T-DXd) and disitamab vedotin (RC48), has been pivotal in rendering “HER-2-low” gastric cancer (GC) a therapeutically targetable entity, expanding the population benefiting from anti-HER2 therapy by 2-3-fold. This advancement underscores the imperative to redefine and subclassify HER-2 status in GC. In this study, we innovatively proposed a four-tiered HER-2 classification standard for GC and, for the first time, conducted comparative analyses at the spatial single-cell multi-omics level across these four subgroups. METHODS: HER-2 status was recategorized into absent (immunohistochemistry (IHC) 0+, HER2_N), low (IHC 1+, HER2_L), moderate (IHC 2+/fluorescence in situ hybridization (FISH)-, HER2_M), and high (IHC 2+/FISH + or IHC 3+, HER2_H) groups. Primary tumor samples from 427 GC patients were collected and analyzed using Xenium5K in situ single-cell spatial transcriptomics (n = 153) and multiplex immunofluorescence (n = 427) detection base on tissue microassays. RESULTS: The proportion of samples that classified as HER2_N, HER2_L, HER2_M, and HER2_H was 43.13%, 22.88%, 11.11%, and 22.88%, respectively. Spatial HER-2 heterogeneous expression existed in 74.42% of HER-2 expressing GC and in 40.0% of HER2_H cases, which correlated with an unfavorable response to combined HER-2-targeted and immunotherapy and poor prognosis. In HER2_H group, lower infiltrates of exhausted T cells and regulatory T cells (Treg), higher cytotoxic activity of T cells, and enriched T cell-B cell niches were discovered, presenting a favorable tumor microenvironment that may benefit from immunotherapy. In HER2_M population, significantly higher CTLA4 + Treg infiltration, and their strengthened interactions with other cells via the CD80/CD86-CTLA4 axis were highlighted. HER2_L group exhibited increased infiltrates of SOX2-OT + mesenchymal cells and TGF-β-driven stromal-tumor cellular interactions. Moreover, HER2_N group presented a higher prevalence of diffuse and mixed histology, enriched endothelial cell-fibroblast-myeloid-derived suppressor cell niches, and augmented angiogenic activity. CONCLUSION: Differences in clinicopathologic, molecular, and immunological underpinnings were underscored across GC with differential HER-2 expression status, providing a rationale for a novel quaternary HER-2 classification system and the development of stratified therapeutic strategies.
Ovarian cancer (OC) is the predominant gynecological cancer and is associated with severe morbidity and high mortality worldwide. Therefore, clarifying the molecular mechanisms underlying OC progression and exploring nov...Ovarian cancer (OC) is the predominant gynecological cancer and is associated with severe morbidity and high mortality worldwide. Therefore, clarifying the molecular mechanisms underlying OC progression and exploring novel therapeutic targets are important. Here, using human OC samples, different OC cell lines, and xenograft nude mouse models in combination with multiple sequencings, we report that hnRPD, an RNA binding protein that modulates RNA stability, is highly expressed in OC tissues, and contributes to OC cell malignancy in human OC cells cultured in vitro and in OC cell-derived xenograft nude mouse models in vivo. Mechanistically, ectopically expressed GPR137 binds to hnRPD and enhances hnRPD protein stability, which reciprocally transactivates GPR137 through the transcription factor FLI1. On the other hand, elevated hnRPD upregulates RAB8A expression by interacting with RAB8A mRNA and promoting its stability, leading to activation of downstream cell signaling and thereby enhanced OC cell malignant behaviors including cell proliferation, cell invasion, cell migration, and colony formation ability as well as OC xenograft growth in nude mice. Moreover, cisplatin in combination with silencing of hnRPD expression, significantly induces apoptosis in cisplatin-resistant OC cells through regulation of OC cell metabolism. Therefore, our data provide evidence that hnRPD could represent an innovative prognostic indicator for OC and may be an attractive therapeutic target for improving clinical outcomes in OC treatment.
Phenotypic plasticity and drug tolerance are now recognized as major causes of tumor aggressiveness and therapy resistance. Melanoma represents a paradigmatic example of how solid tumors exploit non-genetic adaptive prog...Phenotypic plasticity and drug tolerance are now recognized as major causes of tumor aggressiveness and therapy resistance. Melanoma represents a paradigmatic example of how solid tumors exploit non-genetic adaptive programs, including the transition between proliferative and dormant states and the emergence of drug-tolerant persister cells, that sustain intratumoral heterogeneity and survive targeted and immune-based therapies. Increasing evidence shows that miRNAs are critical elements controlling these processes both directly, via shaping gene expression programs that enable cell plasticity, and indirectly, through vesicle-mediated communication that spreads resistant traits and remodels the tumor microenvironment. The combined impact on cell-intrinsic and cell-extrinsic pathways position miRNAs as promising biomarkers and therapeutic targets across malignancies. Even though early therapeutic efforts faced challenges in delivery and stability, recent advances in chemically modified antisense oligonucleotides, particularly locked nucleic acids (LNAs), have renewed interest in targeting oncogenic miRNAs in metastatic disease. This review combines current knowledge on phenotypic plasticity, drug-tolerant states and microenvironmental remodeling, with miRNA regulation, highlighting how insights gained from melanoma can shape the development of clinically relevant LNA-based therapeutics.
Microplastics are pervasive global environmental pollutants. While their potential health impacts are acknowledged, their link to cancer remains unclear. The colorectum is the primary microplastics absorption site and fu...Microplastics are pervasive global environmental pollutants. While their potential health impacts are acknowledged, their link to cancer remains unclear. The colorectum is the primary microplastics absorption site and further exploration of the effects of microplastics on colorectal cancer progression and immunotherapy efficacy are warranted. In this study, microplastics were isolated from colorectal cancer tumour tissues and blood, and their properties were examined. microplastics worsened colorectal cancer severity and promoted immunotherapy resistance in animal models. Moreover, microplastics uptake inhibited the JAK-STAT pathway; downregulated IFN-γ, CXCL9, CXCL11, B2m, and H2-K1 expression; decreased CD8+ and CD4+ T-cell infiltration; and increased tumour resistance to immunotherapy. Microplastics also triggered gut microbiota dysbiosis, significantly contributing to colorectal cancer immunotherapy resistance. Microplastics play an important role in colorectal cancer immunotherapy resistance by altering the tumour immune microenvironment and represent a novel target in colorectal cancer immunotherapy, especially amid increasing microplastics pollution.