Xu Y, Huang S, Chen J
… +7 more, Tang Z, Fu Y, Chen Z, Lin Z, Hu J, Zhang W, He S
Cancer Lett
· 2026 Jul · PMID 41936856
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Peritoneal metastasis is the most common form of metastasis in ovarian cancer (OC), resulting in a poor prognosis. Abnormal modification of proteins by glycosyltransferases is closely related to immunosuppression and tum...Peritoneal metastasis is the most common form of metastasis in ovarian cancer (OC), resulting in a poor prognosis. Abnormal modification of proteins by glycosyltransferases is closely related to immunosuppression and tumor metastasis. However, there were few reports on glycosyltransferase related biomarkers of peritoneal metastasis in OC. This study investigates the role of glycosyltransferase GLT8D2 in promoting peritoneal metastasis and tumor immune evasion through PD-L1 N-glycosylation in OC. Using single-cell RNA sequencing and clinical samples, we found that GLT8D2 is significantly upregulated in metastatic OC tissues and negatively correlated with immune pathways. Mechanistically, GLT8D2 interacts with PD-L1, mediates its N-glycosylation at the Asn192 site, thereby enhancing PD-L1 stability. The N-glycosylation of PD-L1 facilitated tumor cell migration and invasion, accompanied by decreased CD8 T cell infiltration and upregulated expression of T cell exhaustion markers including LAG3 and PD-1. Furthermore, GLT8D2 knockdown synergized with anti-PD-L1 therapy to reduce tumor metastasis in vivo. Hypoxia-inducible factor HIF-1α was identified as a direct transcriptional activator of GLT8D2. Our findings highlight GLT8D2 as a key regulator of metastasis and immune evasion in OC, offering a potential strategy to improve prognosis.
Sabit H, Yadav AK, Salimy S
… +10 more, Sakr A, Abdel-Ghany S, Soliman Wadan A, Alqosaibi AI, Rashwan R, AlGosaibi YS, Alnamshan MM, Almulhim J, Alaqeel NK, Arneth B
Cancer Lett
· 2026 Jul · PMID 41936855
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Breast cancer's (BC) diverse nature and global impact demand tailored clinical strategies. Conventional screening methods often fall short in early detection and individualized risk assessment. By merging multi-omics tec...Breast cancer's (BC) diverse nature and global impact demand tailored clinical strategies. Conventional screening methods often fall short in early detection and individualized risk assessment. By merging multi-omics technologies such as genomics, transcriptomics, proteomics, and metabolomics with artificial intelligence (AI), clinicians gain powerful tools to navigate this complexity. AI's ability to analyze vast, intricate multi-omics datasets enables precise risk stratification, early diagnosis, and the development of customized treatment plans. Applications range from refining mammographic analysis and forecasting therapy outcomes to uncovering novel biomarkers. However, barriers such as data standardization, model applicability across diverse patient groups, and AI interpretability limit clinical integration. This review provides clinicians with a comprehensive guide to current advances in multi-omics profiling, including genomics, transcriptomics, proteomics, and metabolomics, as well as their integration through AI-driven models to decode tumor heterogeneity and predict treatment response. We discuss cutting-edge computational frameworks, challenges in data integration, and clinical applications that enhance prognostic accuracy and facilitate precision oncology approaches. By embracing the convergence of multidimensional molecular data and AI, clinicians can deliver individualized BC care that optimizes therapeutic outcomes and advances the post-genomic era of oncology.
Zhou Y, Zang R, Li Z
… +7 more, Zhang Z, Wang J, Zhou X, Xie F, Chen G, Xue Q, He J
Cancer Lett
· 2026 Jun · PMID 41935777
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Lung adenocarcinoma (LUAD) presents a paradoxical association between SHOX2 DNA hypermethylation-a well-validated diagnostic biomarker-and its transcriptional overexpression, challenging conventional methylation-cancer b...Lung adenocarcinoma (LUAD) presents a paradoxical association between SHOX2 DNA hypermethylation-a well-validated diagnostic biomarker-and its transcriptional overexpression, challenging conventional methylation-cancer biology paradigms. Through validation in our clinical cohort (n = 142) and functional experiments, we demonstrate that SHOX2 overexpression is linked to oncogenic activation, correlates with advanced TNM stage (P = 0.0161), poor tumor differentiation (P = 0.0418), and reduced overall survival (HR = 1.583, 95% CI:1.027-2.442), establishing its role as an independent prognostic factor (multivariate Cox HR = 1.704, P = 0.021). Mechanistically, systematic literature/patent analyses revealed that commercially utilized SHOX2 hypermethylation biomarkers (e.g. Epi proLung BL, LungMe® kits) target CpG sites within the first intron-a gene body region whose methylation enhances oncogenic transcription-rather than promoter regions. Integrative TCGA-LUAD methylation profiling and demethylation experiments (5-aza-dC treatment in H1650/SK-LU-1/H1975/A549/H1299/H322/HCC827/H358 cells) further establish a dual regulatory mechanism: promoter hypomethylation (cg25694447/cg26129769 sites, P < 0.0001) and gene body hypermethylation (cg09220088/cg04521004 sites, P < 0.0001) cooperatively drive SHOX2 overexpression. This spatial resolution explains the high specificity of SHOX2 methylation-based diagnostics despite tumor overexpression, resolving longstanding contradictions. Our findings redefine epigenetic regulation in LUAD, demonstrating that regional methylation patterns-not global promoter status-orchestrate oncogene activation. We propose a novel framework for spatially resolved methylomics, advocating 1) dual-target assays monitoring both promoter and gene body methylation to improve diagnostic precision, and 2) therapeutic exploitation of SHOX2's intronic methylome as a druggable epigenetic switch.
Turkstani H, Alfaifi A, Jeyaraman P
… +2 more, Anbinselvam A, Akintoye SO
Cancer Lett
· 2026 Jun · PMID 41934779
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Ameloblastoma is a benign odontogenic tumor with an aggressive growth phenotype orchestrated by a complex and heterogeneous tumor microenvironment. This review addresses how tumor cells, cancer-associated fibroblasts, me...Ameloblastoma is a benign odontogenic tumor with an aggressive growth phenotype orchestrated by a complex and heterogeneous tumor microenvironment. This review addresses how tumor cells, cancer-associated fibroblasts, mesenchymal stem cells, endothelial cells, and immune cells interact with non-cellular elements especially the extracellular matrix and hypoxic niches to drive invasive growth and recurrence. Several genetic changes associated with ameloblastoma activate mitogen-activated protein kinase (MAPK), Hedgehog (HH), Wnt/β-catenin, and less commonly PI3K/AKT signaling pathways. These pathways increase matrix-degrading enzymes such as matrix metalloproteinases and heparanase and reorganize collagen to create paths for local spread of ameloblastoma cells. Hypoxic niches in ameloblastoma stabilize hypoxia-inducible factor (HIF-1)α and activate vascular endothelial growth factor (VEGF) thereby linking low oxygen tension to new blood vessel growth within the microenvironment. Crosstalk between ameloblastoma epithelium and stroma through interleukin-6, transforming growth factor (TGF)-β, and connective tissue growth factor (CTGF) activates a positive feedback loops that stiffen the extracellular matrix and promote collective invasion. Within the encompassing jaw bone, a higher receptor activator of nuclear factor kappa-Β ligand/osteoprotegerin (RANKL/OPG) ratio and parathyroid hormone-related protein (PTHrP) level stimulate osteoclastogenesis, which accounts for the characteristic osteolysis displayed by ameloblastoma. Additionally, PD-L1 expression in ameloblastoma weakens T-cell activity in spite of the high population of M1 macrophages at the tumor leading edge. Collectively, coordinated interplay of these molecular processes define the invasive and aggressive growth phenotypes of ameloblastoma. Opportunities abound for development of targeted therapies for management of ameloblastoma. Potential candidates are inhibitors of BRAF/MEK and smoothened (SMO) gene/HH pathways, interruption of the TGF-β-Cancer-associated fibroblast axis, anti-angiogenic strategies, immune checkpoint blockade, and RANKL-directed therapy.
Tang JJ, Chen C, Guan ZY
… +7 more, Zhu ZH, Pan YF, Fu ZY, Zhu JW, Cao D, Wang HY, Yu LX
Cancer Lett
· 2026 Aug · PMID 41933572
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Liver metastasis (LM) is a major cause of cancer-related mortality, driven largely by dynamic interactions between disseminated tumor cells (DTCs) and the liver microenvironment (LME). Liver fibrosis, a pathological cond...Liver metastasis (LM) is a major cause of cancer-related mortality, driven largely by dynamic interactions between disseminated tumor cells (DTCs) and the liver microenvironment (LME). Liver fibrosis, a pathological condition characterized by the disruption of the LME and imposing a significant global health burden, is primarily orchestrated by activated hepatic stellate cells (aHSCs). However, the precise mechanisms through which liver fibrosis facilitates LM are poorly understood. Here, we demonstrated that liver fibrosis potently enhanced LM by promoting the early hepatic colonization of tumor cells in an aHSC-dependent manner. Mechanistically, we identified prostaglandin E (PGE), secreted by aHSCs, as a key mediator that disrupted natural killer (NK) cell immune surveillance. Either the depletion of aHSCs or pharmacological inhibition of the PGE-synthesizing enzyme Cyclooxygenase-2 (COX-2) with Celecoxib (CLX) restored NK cell function and suppressed LM. Notably, CLX treatment synergized with anti-NKG2A-based immunotherapy, significantly boosting its efficacy against LM in the fibrotic liver. Our findings unveil a critical "aHSC-PGE-NK cell" axis in liver fibrosis-induced immunosuppression and provide a compelling therapeutic strategy for the clinical management of LM.
Li B, Wei P, Xie B
… +5 more, Zhong X, Wang X, Lou X, Zhang T, Dong C
Cancer Lett
· 2026 Jun · PMID 41921857
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Immunotherapies, especially immune checkpoint blockade, has achieved considerable success in multiple cancers; however, patients with "cold tumors", in particular pancreatic cancer, rarely respond, largely due to insuffi...Immunotherapies, especially immune checkpoint blockade, has achieved considerable success in multiple cancers; however, patients with "cold tumors", in particular pancreatic cancer, rarely respond, largely due to insufficient T cell activation and infiltration within the tumor microenvironment (TME). To understand the mechanisms whereby tumor cells regulate T cell activation, we conducted an in vivo CRISPR-Cas9 screen, and identified the CDK1/Cyclin B1 complex as a previously unrecognized tumor-intrinsic driver of immune evasion in pancreatic cancer. Genetic ablation or pharmacological inhibition of the CDK1/Cyclin B1 complex induced a T cell-inflamed TME, which synergized with PD-1 blockade to suppress tumor growth. Mechanistically, loss of Ccnb1 reduced phosphorylation of the retinoblastoma protein (Rb) at S249/T252 residues, and restored NF-κB activity, which elevated the production of granulocyte-macrophage colony-stimulating factor (GM-CSF), and promoted the recruitment and activation of conventional type 1 dendritic cells. Collectively, these findings uncover the CDK1/Cyclin B1 complex involved in tumor immune evasion and provide a compelling rationale for combining CDK1/Cyclin B1 inhibition with PD-1 blockade in the treatment of pancreatic cancer.
Hinz TK, Le AT, Doan T
… +9 more, Ast A, Jaramillo S, Avila JT, Skhisov D, Haines S, Navarro AC, Patil T, Nemenoff RA, Heasley LE
Cancer Lett
· 2026 Jun · PMID 41921856
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Oncogenic RET gene rearrangements drive a subset of lung adenocarcinomas (LUAD) and the tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib are approved therapeutics. However, acquired resistance remains a hu...Oncogenic RET gene rearrangements drive a subset of lung adenocarcinomas (LUAD) and the tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib are approved therapeutics. However, acquired resistance remains a hurdle to durable management. Two RET+ lung cancer cell lines (TR.1, TR.2) were established from a Trim24-Ret mouse model and lung tumors resulting from their orthotopic transplantation initially responded to selpercatinib followed by prompt progression within ∼3 weeks of initiating TKI treatment. Cell lines derived from the selpercatinib-resistant TR.1 and TR.2 tumors exhibited in vitro sensitivity to MET and ERBB-targeted TKIs, indicating acquired bypass signaling through these receptor tyrosine kinases (RTKs). The TKI-resistant cell lines showed no evidence for MET gene amplification, but exhibited transcriptional induction of genes that function within MET and ERBB2:ERBB4 interaction networks including ligands (HGF, NRG1), adaptors (GAB1) and co-receptors (NRP1). Exogenous HGF, but not NRG1 reversed in vitro growth inhibition by selpercatinib in TR.1 and TR.2 cells. Mice bearing orthotopic TR.1 or TR.2 lung tumors progressing on selpercatinib underwent significant re-shrinkage upon co-treatment with the MET inhibitor, crizotinib, although similar to the clinical experience, progression again occurred. By contrast, upfront treatment with selpercatinib and crizotinib in orthotopic tumors yielded complete elimination of 7 of 9 TR.1 tumors and both deepened and prolonged the duration of response in TR.2 tumors. The findings provide new insight into mechanisms of acquired resistance through bypass signaling and highlight the therapeutic benefit of simultaneous upfront blockade of driver oncogenes and dominant resistance mechanisms in LUAD.
Zhang Z, Yang X, Zheng R
… +8 more, Zang Y, Chen Q, Hu B, Liu M, Liu Y, Huang J, Liang T, Zhang Q
Cancer Lett
· 2026 Jun · PMID 41921855
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Emerging evidence highlights the perioperative period, particularly the immediate postoperative window of days to weeks, as a critical phase influencing long-term cancer outcomes. Here, we found that hepatocellular carci...Emerging evidence highlights the perioperative period, particularly the immediate postoperative window of days to weeks, as a critical phase influencing long-term cancer outcomes. Here, we found that hepatocellular carcinoma (HCC) cells cultured with postoperative serum exhibited enhanced anoikis resistance, invasion, migration, and increased potential for lung metastasis compared to those cultured with preoperative serum. This pro-metastatic effect was attributed to serum-derived exosomes. We therefore performed high-throughput miRNA sequencing to profile miRNAs in exosomes derived from the preoperative and postoperative serum of HCC patients. Sequencing analysis revealed a significant upregulation of exosomal miR-1246 in the majority of postoperative HCC patients. Mechanistically, exosomal miR-1246 directly targeted BMP9 mRNA, suppressing its protein expression. This led to inactivation of the downstream metastasis-inhibitory pathway mediated by SMAD7, ultimately accelerating HCC metastasis. Functional rescue experiments confirmed that either inhibiting miR-1246 or exogenously restoring BMP9 effectively reversed this pro-metastatic phenotype both in vitro and in vivo. In conclusion, our study elucidates a molecular mechanism by which postoperative exosomal miR-1246 promotes HCC metastasis via targeting the BMP9-SMAD7 signaling axis, thereby identifying a potential therapeutic target for inhibiting postoperative metastatic risk.
Jiang Y, Cheng S, Zhang CY
… +8 more, Jin X, Li L, Shin HE, Alrefai A, Luo A, Xu Y, Kim IY, Mu P
Cancer Lett
· 2026 Jun · PMID 41912135
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Cancer remains a leading cause of death worldwide, with lineage plasticity emerging as a hallmark that drives therapy resistance and tumor progression by enabling cancer cells to alter identity and evade targeted therapi...Cancer remains a leading cause of death worldwide, with lineage plasticity emerging as a hallmark that drives therapy resistance and tumor progression by enabling cancer cells to alter identity and evade targeted therapies. Although genomic and transcriptomic aberrations correlate with lineage plasticity, the absence of scalable cross-cancer markers to rapidly identify plastic subtypes has limited predictive utility. Homeobox (HOX) genes encode transcription factors that define tissue identity through distinct expression patterns, or HOX codes, within specific lineages. By analyzing multi-omics data encompassing 39 HOX genes across more than 80,000 RNA-seq samples across 23 cancer types spanning 114 cancer subtypes, we found that HOX code expression robustly stratifies lineage-constrained and lineage-plastic states at a cross-cancer level. This framework revealed previously unrecognized lineage-plastic subtypes in prostate cancer, lung cancer, and acute myeloid leukemia (AML), each displaying distinct HOX code divergence compared to non-plastic counterparts. Differential expression analysis across these representative malignancies identified RUNX1T1 as a consistent regulator associated with HOX-defined plastic states. We validated RUNX1T1 upregulation in bulk and single-cell RNA-seq from extensive preclinical and clinical cohorts and demonstrated that RUNX1T1 is functionally required for lineage-plastic programs in prostate cancer models. AI-based structural modeling and co-immunoprecipitation established the NCOR/HDAC3 complex as a critical binding partner of RUNX1T1. CUT&RUN profiling revealed that RUNX1T1 remodels chromatin by globally reducing active enhancer marks, thereby repressing lineage-defining differentiation programs and reshaping HOX positional identity. Selective pharmacologic inhibition of HDAC3 or targeted gene silencing via lipid nanoparticles suppressed the growth of lineage-plastic cancer cells, uncovering a therapeutically actionable vulnerability. Together, these findings establish RUNX1T1 as a cross-lineage regulator of HOX code-defined plasticity and identify the RUNX1T1-HDAC axis as a targetable mechanism underlying cancer lineage plasticity.
Cancer Lett
· 2026 Jun · PMID 41912134
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Metastasis is the primary cause of cancer mortality, a complex cascade driven by intertwined cellular adaptability and microenvironmental reprogramming. Although its mechanistic origins are multifactorial and context-dep...Metastasis is the primary cause of cancer mortality, a complex cascade driven by intertwined cellular adaptability and microenvironmental reprogramming. Although its mechanistic origins are multifactorial and context-dependent, metabolic plasticity, manifested by dynamic shifts in glycolysis, lipid oxidation, amino acid utilization, and mitochondrial bioenergetics, is increasingly recognized as a central orchestrator of metastatic progression. Emerging therapeutic strategies that target these metabolic adaptations, such as diet-exercise modulation, nanotechnology-enabled pathway inhibition, and metabolite neutralization, show promise for disrupting metastatic niches and enhancing immune surveillance. This review synthesizes the systemic and spatial roles of metabolism across the metastatic cascade to advocate a fundamental reconceptualization of metastasis as a metabolically programmable process. Future efforts should focus on mapping the dynamic heterogeneity of tumor metabolism to develop stage-specific, ecologically informed interventions against disseminated disease.
Chen H, Cai Q, Chen Y
… +10 more, Huang J, Shi P, Xie R, Yi S, Hou H, Wei H, He Y, Fu H, Song X, Yang D
Cancer Lett
· 2026 Jul · PMID 41912132
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Chemotherapy-associated metastasis is a major cause of failure of cancer treatment, especially neoadjuvant chemotherapy. Extracellular matrix (ECM) remodeling aways accompany with chemotherapy, but its role in chemothera...Chemotherapy-associated metastasis is a major cause of failure of cancer treatment, especially neoadjuvant chemotherapy. Extracellular matrix (ECM) remodeling aways accompany with chemotherapy, but its role in chemotherapy-associated metastasis is still unclear. Here, we reveal hyaluronidase-driven degradation of hyaluronic acid (HA) as a key mechanism underlying chemotherapy-associated lymphatic metastasis in gastric cancer. We found that chemotherapy-associated lymphatic metastasis of gastric cancer occurred during neoadjuvant chemotherapy in both patients and nude mice. The proportion of HA increased significantly in ECM during chemotherapy. We also found that cell migration inducing hyaluronidase 2 (CEMIP2) is the most highly expressed hyaluronidase to degrade HA into its effective type, low molecular weight HA (LMWHA), and promoted chemotherapy-associated lymphatic metastasis of gastric cancer. Mechanistically, CEMIP2-generated LMWHA activates CD44-ATF3 signaling to transcriptionally upregulate TGFβ receptor TGFBR1, driving metastasis. CEMIP2 is highly expressed in gastric epithelium naturally. To specifically target CEMIP2 and inhibit chemotherapy-associated lymphatic metastasis of gastric cancer, we developed bioengineered RGD-conjugated exosomes mimics (EMs) for targeted delivery of CEMIP2 siRNA. This strategy potently suppressed chemotherapy-associated lymphatic metastasis in vivo. Crucially, our results position CEMIP2 as a therapeutic target to inhibit chemotherapy-associated metastasis of gastric cancer.
Cancer Lett
· 2026 Jun · PMID 41905711
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The pathological features of invasion and metastasis in malignant tumors are intricately intertwined with the tumor microenvironment (TME). Recent investigations underscore that, alongside immune cells, blood vessels, an...The pathological features of invasion and metastasis in malignant tumors are intricately intertwined with the tumor microenvironment (TME). Recent investigations underscore that, alongside immune cells, blood vessels, and the lymphatic system, the nervous system emerges as a pivotal player within the TME. Tumors possess the remarkable ability to modify and even co-opt the architecture and functions of the nervous system, creating a dynamic interplay. Furthermore, aberrant neuronal activation has the potential to accelerate tumor progression. This review summarizes the emerging field of cancer neuroscience, encompassing both direct neuro-cancer cell communication and indirect interactions mediated through other TME components. It further outlines the commonly used experimental tools, cutting-edge technologies, and potential therapeutic targets identified along neuro-cancer interaction pathways. By elucidating the reciprocal interplay between the nervous system and tumors, this area of research offers new perspectives for understanding tumorigenesis and provides promising molecular targets and strategies for cancer therapy.
Liu H, Chen S, Cao M
… +6 more, Shu L, Ji M, Zhou J, Fan J, Wang P, Sun Y
Cancer Lett
· 2026 Jun · PMID 41905709
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Tertiary lymphoid structures (TLSs) have emerged as key regulators of anti-tumor immunity and biomarkers for immunotherapy response in liver cancer, including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcino...Tertiary lymphoid structures (TLSs) have emerged as key regulators of anti-tumor immunity and biomarkers for immunotherapy response in liver cancer, including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and combined hepatocellular-cholangiocarcinoma (cHCC-iCCA). Advances in single-cell and spatial multi-omics technologies have revealed unprecedented complexity in TLSs, challenging the traditional binary classification of TLSs as simply "good" or "bad". Their functional diversity appears to be shaped by spatiotemporal context, cellular composition, and maturation status. This review provides a comprehensive synthesis of TLSs in liver cancer, employing the Yin-Yang paradigm to navigate their functional dualism and prognostic contradictions through a detailed analysis of their identification, classification, and spatiotemporal interactions within the TME. Mechanistically, we elucidate how TLS functions are orchestrated by complex interactions between tumor cells, immune cell subsets, stromal components, and systemic factors. Within this framework, key metabolic drivers, notably ATP citrate lyase (ACLY), and signaling axes such as cGAS-STING/mTOR have emerged as pivotal regulators of TLS ontogeny. In addition, we evaluate current preclinical animal models and therapeutic strategies for clinical TLS induction. Furthermore, we have discussed the key unanswered questions in the field, including the three-dimensional architecture of TLSs and the mechanisms by which they establish durable immunological memory independent of the primary tumor. Clinically, TLSs exhibit great promise as prognostic and predictive biomarkers, particularly in the context of immune checkpoint blockade and locoregional therapies. Finally, we identify challenges in standardization, mechanistic understanding, and translational applications, providing directions for future research to harness TLSs for improving liver cancer outcomes.
Ganji SP, Behera SK, Reddy NR
… +5 more, Chowdary TVP, Nukala SSV, Alam A, Nagaraju GP, Srilatha M
Cancer Lett
· 2026 Jun · PMID 41905708
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Dietary and environmental factors significantly impact the development of colorectal cancer (CRC), especially when procarcinogens are metabolized by cytochrome P450 enzymes. Heterocyclic amines and other xenobiotics link...Dietary and environmental factors significantly impact the development of colorectal cancer (CRC), especially when procarcinogens are metabolized by cytochrome P450 enzymes. Heterocyclic amines and other xenobiotics linked to CRC are bioactivated by cytochrome P450 1A2. Quercetin is a naturally occurring dietary flavonoid that inhibits CYP1A2 activity, which has been identified as a potential target and shown to have chemopreventive and anticancer effects. However, little is understood about the molecular signals underlying the interaction between quercetin and CYP1A2. In this work, quantum theory, including DFT and NCI-RDG analysis, was used to investigate the binding mechanism and stability of quercetin within the active site of CYP1A2, followed by docking and MD (molecular dynamics) simulations. The theoretical analysis depicted the chemical reactivity and other properties of quercetin. The docking study results indicate that quercetin forms π-π interactions and hydrogen bonds with key residues of the catalytic site in the vicinity of the heme region of CYP1A2. High inhibitory activity is indicated by high binding affinity. After the MD simulation, quercetin-CYP1A2 complexes showed less variation in backbone and ligand structures, exhibited strong intermolecular interactions, and remained stable over the simulation timescale, representing a dynamically stable binding process. Blocking the catalytic site of CYP1A2 with quercetin, restricting access of the substrate to iron within the heme, was speculated to decrease the metabolic transformation of dietary procarcinogens and their association with colon cancer by the metabolic activation process of CYP1A2, as indicated by the results. Although the study indicated the valuable role of quercetin as a regulator of CYP1A2 metabolism, experimental evidence remains important to support the biological efficacy of quercetin in the prevention of CRC.
El Moukhtari SH, Rodríguez-Nogales C, Couvreur P
… +1 more, Blanco-Prieto MJ
Cancer Lett
· 2026 Jun · PMID 41903672
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Therapeutic regimens for pediatric malignancies such as neuroblastoma remain complex and are often associated with severe systemic toxicity. The development of more efficacious and less toxic therapeutic strategies is im...Therapeutic regimens for pediatric malignancies such as neuroblastoma remain complex and are often associated with severe systemic toxicity. The development of more efficacious and less toxic therapeutic strategies is imperative to enhance both overall survival and the quality of life for high-risk patients. Cancer nanomedicine has emerged as a transformative platform in oncology, enabling precision therapies and targeted delivery of chemotherapeutic agents. In this study, we designed solid lipid nanoparticles encapsulating the topoisomerase II inhibitor etoposide, aiming to reformulate this agent for oral administration in the treatment of aggressive neuroblastoma. Nanoencapsulation significantly improved the pharmacokinetic and biodistribution profiles of the drug, enhancing its bioavailability and tumor accumulation. To simulate a metronomic dosing regimen, MYCN-amplified SK-N-BE(2) tumor-bearing mice received up to ten oral administrations over a 30-day period. The nanoformulation demonstrated superior antitumor efficacy and a markedly reduced toxicity profile compared to both oral and intravenous commercial formulations. These findings support the potential of nanomedicine-based strategies as safer and more effective alternatives to conventional chemotherapy in neuroblastoma.
Wu Z, Wang Y, Yu B
… +17 more, Yu R, Chen M, Chen Z, Shan J, Ding Z, Li J, Jin X, Chen Y, Wang L, Zhu H, Zhu W, Pan Q, Zhang T, Zhang Y, Lv L, Wang L, Zhao Y
Cancer Lett
· 2026 Jun · PMID 41903671
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Tyrosine kinase inhibitor (TKI) resistance limits therapy for hepatocellular carcinoma (HCC). Integrating RNA-seq and public cohort data, we found consistent downregulation of the bile salt export pump (BSEP/ABCB11) in T...Tyrosine kinase inhibitor (TKI) resistance limits therapy for hepatocellular carcinoma (HCC). Integrating RNA-seq and public cohort data, we found consistent downregulation of the bile salt export pump (BSEP/ABCB11) in TKI-resistant HCC associated with poorer prognosis and reduced clinical response. Functional in vitro and xenograft studies, using BSEP overexpression/knockdown and TKI-resistant cell lines plus targeted metabolomics, showed BSEP expression deficiency leads to intracellular accumulation of primary conjugated bile acids (BAs)-especially glycocholic acid (GCA)-which activates EGFR signaling and drives resistance; restoring BSEP enhances BA efflux and resensitizes cells and tumors to TKIs. Mechanistic assays revealed that ursodeoxycholic acid (UDCA) upregulated BSEP and reversed resistance via an FXR-independent mechanism: UDCA directly binds cortactin (CTTN), reduces its PRMT1-dependent mono-methylation, and promotes CTTN degradation via chaperone-mediated autophagy (CMA), thereby enabling YY1 nuclear translocation and transcriptional activation of BSEP. Clinical specimen analyses corroborated an inverse BSEP-CTTN relationship and UDCA modulation. These findings identify impaired BSEP-mediated BA efflux and GCA accumulation as metabolic features of TKI resistance and support targeting the CTTN/YY1/BSEP axis, including UDCA, to overcome resistance.
Georges-Calderón N, Fuentes C, Hidalgo Y
… +9 more, Grunenwald F, Corrales-Bermúdez J, Figueroa-Valdés AI, Ramírez-Pereira M, Arriagada G, Bustos FJ, Ahumada-Marchant C, López M, Alcayaga-Miranda F
Cancer Lett
· 2026 Jun · PMID 41903670
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Recent evidence establishes that melanoma cells actively uptake mitochondria from stromal cells; however, the mitochondrial release in a physiological context remains unstudied. Here, we show that melanoma cells release...Recent evidence establishes that melanoma cells actively uptake mitochondria from stromal cells; however, the mitochondrial release in a physiological context remains unstudied. Here, we show that melanoma cells release dysfunctional mitochondria into the extracellular space through a predominantly non-vesicular route. Using melanocyte Melan-a and melanoma B16-F1 and B16-F10 cell lines, we observed increased extracellular mitochondrial release in malignant cells. Electron microscopy revealed these mitochondria lacked cristae and were primarily free organelles. Membrane potential analysis confirmed their dysfunctional state. Mitophagy analysis using mtKeima showed that, under oxidative stress, melanoma cells failed to activate canonical mitophagy and instead upregulated mitochondrial release as an alternative MQC mechanism. Western blot analysis revealed a fission-biased mitochondrial network in melanoma cells, with elevated phospho-DRP1/DRP1 ratio, and a tendency to reduce MFN1 and OPA1. Together with PINK1/ATG7 downregulation and BNIP3/NIX upregulation, suggest a secretory mitophagy phenotype. Tumor-derived mitochondria were detected in both the tumor microenvironment and plasma of melanoma-bearing mice, with extracellular mitochondria levels correlating with tumor burden. Plasma from melanoma patients exhibited elevated levels of TOMM20 mitochondria compared to healthy donors. Transcriptomic analysis of The Cancer Genome Atlas melanoma cohort revealed that high expression of MQC-related genes DRP1 and BNIP3L was associated with worse prognosis. Collectively, our findings uncover a tumor-intrinsic, non-canonical MQC pathway that releases dysfunctional mitochondria. This mechanism establishes a new paradigm of tumor-host systemic communication, wherein circulating tumor-derived mitochondria might actively influence disease progression. These findings open avenues for developing non-invasive biomarkers and therapeutic strategies targeting mitochondrial release.
Wu P, Ge J, Hou X
… +15 more, Qu H, Ouyang J, Wang D, Tong T, Meng Y, Yan Q, Shi L, Gong Z, Chen P, Xiang B, Zhou M, Tan M, Zhang W, Zeng Z, Xiong W
Cancer Lett
· 2026 Jun · PMID 41903669
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Cancer immunotherapy harnesses and amplifies the host's anti-tumor immune responses to eradicate malignant cells. Tumor neoantigens serve as ideal targets due to high specificity and immunogenicity. Circular RNA (circRNA...Cancer immunotherapy harnesses and amplifies the host's anti-tumor immune responses to eradicate malignant cells. Tumor neoantigens serve as ideal targets due to high specificity and immunogenicity. Circular RNA (circRNA), with a stable covalently closed structure, can be engineered as a novel vector for neoantigen expression. Here, we developed a circRNA-based vaccine encoding multiple melanoma neoantigens (circRNA). circRNA significantly suppressed tumor growth in both prophylactic and therapeutic murine models and induced robust anti-tumor immunity. Mechanistically, using single-cell RNA sequencing, we elucidated the antitumor mechanisms and alterations in the tumor and immune microenvironment following vaccination. circRNA immunization nearly eliminated the Ccl6Mel subcluster-highly active in chemokine signaling, leukocyte recruitment, and antigen presentation pathways. While residual Cdk1Mel and Cdhr4Mel subclusters exhibited downregulation of immune-response-related pathways. Furthermore, circRNA vaccination reshaped myeloid cell composition, markedly increasing infiltration of monocytes/macrophages (Monocyte/MФ) with antitumor phenotypes, including classical inflammatory monocytes (Mono-Vcan), Macro-C1qc, and activated M1-like macrophages (Macro-Ifng). Chemokine signaling was enriched in Ccl6Mel and Monocyte/MФ clusters. Moreover, circRNA enhanced T cell-mediated antitumor responses, elevating T cell receptor (TCR) clonotype diversity and expansion of TCR clonotypes especially in CD4 effector (CD4 Eff) and CD8 cytotoxic (CD8 Cyto) T cells. Notably, Tigit was identified as the most highly expressed checkpoint receptor in CD8 exhausted T cells (CD8 Tex), and combining circRNA with anti-TIGIT/PD1 blockade produced synergistic antitumor effects. Collectively, this study systematically elucidates the therapeutic potential and immune mechanisms of the neoantigen circRNA vaccine in melanoma, providing a mechanistic framework for developing personalized RNA vaccines and rational combination immunotherapies.