Piccand C, Gauthier C, Klöckner P
… +9 more, Danielli SG, Vokuhl C, Haesler V, Schoeberlein A, Brüningk S, Furtwängler R, Rössler J, Timpanaro A, Bernasconi M
Cancer Lett
· 2026 Jun · PMID 42336095
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Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, remains difficult to treat in relapsed, metastatic, or refractory disease. Chimeric antigen receptor (CAR) T cell therapy has demonstrated promising...Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, remains difficult to treat in relapsed, metastatic, or refractory disease. Chimeric antigen receptor (CAR) T cell therapy has demonstrated promising results in hematological diseases, but its application to solid tumors including RMS is limited by antigen heterogeneity, on-target/off-tumor toxicity, and insufficient activity against moderate antigen density. We investigated L1 cell adhesion molecule (L1CAM) as a candidate CAR T cell target in RMS by profiling expression in cell lines, patient-derived xenografts, and healthy tissues. Using the CE7-derived single-chain variable fragment, we engineered and compared L1CAM-CAR constructs differing in hinge and costimulatory domains, including the clinically tested 4-1BB-based CE7-CAR configuration. Functional activity was assessed across fusion-positive and fusion-negative RMS models in vitro and in orthotopic mouse models, with B7-H3-CAR T cells included as a benchmark. L1CAM was expressed at variable but specific levels across RMS models, with more prominent expression in fusion-positive RMS and limited expression in healthy tissues. Among constructs, the CD28-based L1CAM.III-CAR showed the strongest cytotoxicity and IFN-γ release, including partial activity in a low-L1CAM model. In vivo, L1CAM.III-CAR T cells improved expansion, delayed tumor progression, and prolonged survival compared with the clinical-reference L1CAM.CT construct, although responses were incomplete and less pronounced than those achieved with B7-H3-CAR T cells. These findings support L1CAM as a rational target for L1CAM-positive RMS cases and demonstrate that CAR optimization can enhance activity against moderate-density antigens. The potent antitumor activity and favorable selectivity profile of L1CAM.III-CAR T cells support their development for pediatric sarcoma immunotherapy.
Loggia D, Peppino G, Vit C
… +4 more, Cherubin L, Arshad Z, Barutello G, Quaglino E
Cancer Lett
· 2026 Jun · PMID 42323004
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Teneurin-4 (TENM4) has been reported as deregulated in a range of cancer histotypes; however, its functional contribution to tumour biology remains incompletely defined. Elevated TENM4 expression has been described in se...Teneurin-4 (TENM4) has been reported as deregulated in a range of cancer histotypes; however, its functional contribution to tumour biology remains incompletely defined. Elevated TENM4 expression has been described in several malignancies, including breast, lung, colon, gastric, and pancreatic cancers, as well as in primary brain tumours, even if much of the available evidence remains correlative and predominantly based on in silico analyses. Emerging evidence, predominantly from triple negative breast cancer (TNBC) models, suggests a potential association between TENM4 expression and tumour cell plasticity, migratory behaviour, and stem-like properties, in part through focal adhesion kinase-associated signalling. Indeed, genetic silencing of TENM4 has been shown to reduce tumour spheroid formation and cell motility in murine and human in vitro TNBC models. In this review, we examine current knowledge of TENM4 expression patterns, structural characteristics, and reported molecular interactions in both physiological and pathological contexts. We review available interactome data, highlighting methodological constraints and variability between datasets, and discuss how proposed TENM4-associated networks may intersect with pathways regulating cytoskeletal dynamics, cell adhesion, and transcriptional programmes within the tumour microenvironment. We further outline key gaps in the field, including the need for more comprehensive in vivo validation and high-resolution interactomic approaches. The overview provided by this review highlights TENM4 as a relatively understudied molecule whose potential relevance in tumour cell plasticity and cancer progression requires further mechanistic and translational validation.
Zhao H, Tian H, Nuerbieke T
… +9 more, Ma K, Li W, Niu X, Li J, Ashby CR, Chen ZS, Zhou T, Li W, Li D
Cancer Lett
· 2026 Jun · PMID 42323003
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Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options and a poor prognosis. Immunotherapies, particularly immune checkpoint inhibitors (ICIs), have expanded the the...Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options and a poor prognosis. Immunotherapies, particularly immune checkpoint inhibitors (ICIs), have expanded the therapeutic options for TNBC. Despite the revolutionary breakthroughs in the treatment of TNBC, some patients still exhibit primary or acquired resistance to immunotherapy. A comprehensive understanding of the mechanisms of immunotherapy resistance is crucial for developing new strategies to overcome the resistance. In this review, we discuss the multifactorial resistance mechanisms to immunotherapy in TNBC, including tumor cell-intrinsic mechanisms (low tumor mutation burden, driver gene mutations, antigen presentation defect, and aberrant PD-L1 expression) and alterations in the tumor microenvironment (T cells, dendritic cells, cancer-associated fibroblasts, tumor-associated macrophages, mast cells, B cells, myeloid-derived suppressor cells, cytokines, hypoxia, metabolic reprogramming, neurological factors, ferroptosis, cuproptosis, and microbiome). Furthermore, we discuss strategies to overcome immunotherapy resistance (including combination of ICIs with other existing treatments and nanotechnology-assisted immunotherapy), and identify emerging biomarkers enabling the selection of patients who may benefit from immunotherapy. Therefore, our review provides insights into immunotherapy resistance mechanisms, developing novel therapeutic strategies, and guiding treatment plans.
Zoi I, Rajput M, Holguín-Horcajo A
… +13 more, Haidar M, Brusa D, Chu K, Xie J, Shields M, Ferreira SM, Stanger B, Attardi LD, Kopp J, Stemmler MP, Nicolle R, Rovira M, Jacquemin P
Cancer Lett
· 2026 Jun · PMID 42320878
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Dhawan K, Allevato MM, Lesperance J
… +8 more, Camargo MF, Cheng MM, Mortaja M, Zareh B, Hingorani DV, Adams SR, Gutkind JS, Advani SJ
Cancer Lett
· 2026 Jun · PMID 42320877
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Tumor resistance to radiotherapy continues to be a significant problem in improving cancer patient outcomes. To overcome radioresistance, drugs that sensitize cancer cells to ionizing radiation (IR) have been tested. In...Tumor resistance to radiotherapy continues to be a significant problem in improving cancer patient outcomes. To overcome radioresistance, drugs that sensitize cancer cells to ionizing radiation (IR) have been tested. In theory, radiosensitizers should increase irradiated tumor kill and improve patient outcomes. However, in practice, the clinical utility of such drugs is curtailed by radiosensitization of peri-tumoral normal tissues causing toxicities. To target radiosensitizer delivery to tumors, we developed an activatable cell penetrating peptide (ACPP) drug conjugate for spatially tumor-restricted delivery of the potent ataxia-telangiectasia mutated kinase inhibitor (ATMi) AZD0156. The ACPP scaffold cloaks a cell penetrating peptide-drug conjugate until it is unmasked within tumors through tumor-associated matrix metalloproteinase thus promoting preferential tumor uptake. Using clinically validated antibody-drug conjugate linker chemistry, we conjugated AZD0156 to ACPP (ACPP-AZD0156) and evaluated its immune stimulating and therapeutic activity with IR in immune-competent murine cancer models. Transcriptomic profiling revealed combining ACPP-AZD0156 with IR enhanced radiation-induced immune activation programs, including type I interferon signaling and leukocyte activation network. Importantly, ACPP-AZD0156 combined with IR stimulated intratumoral CD8 T cell infiltration and improved tumor control compared to non-targeted ATM inhibitor. Mechanistically, the therapeutic effect of ACPP-AZD0156 + IR was abrogated by CD8 T-cell depletion, establishing a role for adaptive immunity engagement by ACPP-AZD0156 radiosensitization. Finally, the combination of IR and ACPP-AZD0156 with PD-1 blockade resulted in durable tumor control and long-term survival. Taken together, these data provide a basis for tumor-targeted ATMi delivery as a precision oncology based immunogenic radiosensitization strategy.
Marsh SR, Beard C, Sheng Z
… +5 more, Bannon MS, Amin MR, Letteri RA, Athanasiadi I, Gourdie RG
Cancer Lett
· 2026 Jun · PMID 42320876
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Ionizing radiation is central to cancer therapy, where normal-tissue toxicity limits dose escalation, and is also a major hazard in accidental or mass-casualty exposures, where practical radiomitigators for radiosensitiv...Ionizing radiation is central to cancer therapy, where normal-tissue toxicity limits dose escalation, and is also a major hazard in accidental or mass-casualty exposures, where practical radiomitigators for radiosensitive organs are urgently needed. We investigated orally delivered milk extracellular vesicles (mEVs) loaded with the connexin43 carboxyl-terminal peptide αCT11 (XOlacta) in a murine 14 Gy total-body irradiation model and a syngeneic GL261 glioma radiotherapy model. A single oral XOlacta dose given 1 h after total-body irradiation conferred 42% 30-day survival despite an expected 100% lethality from a 14 Gy challenge, with marked preservation of ileal architecture and femoral bone marrow cellularity, and significant benefit was retained when dosing was delayed to 24 h. Biodistribution studies with fluorescently labeled mEVs showed radiation-enhanced uptake in brain, gut, and bone marrow, consistent with injury-licensed targeting of radiosensitive tissues. In glioma-bearing mice, XOlacta protected normal tissues without diminishing tumour radiosensitivity. These findings identify oral αCT11-loaded mEVs as a potent, non-parenteral radiomitigator that preserves normal-tissue integrity while maintaining tumour response in a therapeutic context, and support connexin-linked mEV-targeting as a promising strategy for both radiotherapy adjuncts and management of high-dose radiation exposures.
Muneer A, Showkatian E, Saad MB
… +28 more, Hong L, Li S, Salehjahromi M, Aminu M, Sujit SJ, Xu H, Waqas M, Zafar A, Shroff GS, Wu CC, Carter BW, Chang JY, Liao Z, Altan M, Vokes NI, Cascone T, Le X, Haymaker CL, Wistuba II, Chung C, Jaffray D, Gibbons DL, Vaporciyan A, Lee JJ, Lou Y, Heymach JV, Zhang J, Wu J
Cancer Lett
· 2026 Jun · PMID 42314966
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Immune checkpoint inhibitors (ICIs) benefit only a subset of patients with metastatic non-small cell lung cancer (NSCLC), but current selection relies on tissue PD-L1 immunohistochemistry (IHC), which is invasive and pro...Immune checkpoint inhibitors (ICIs) benefit only a subset of patients with metastatic non-small cell lung cancer (NSCLC), but current selection relies on tissue PD-L1 immunohistochemistry (IHC), which is invasive and prone to sampling bias. We developed and validated SCENT (Scalable Ensemble Transformer), a CT-based deep learning model for noninvasive prediction of PD-L1 status and immunotherapy outcomes. In this retrospective study, 972 stage IV NSCLC patients treated with ICIs at MD Anderson were analyzed; SCENT was developed and validated in 640 patients with paired CT and PD-L1 IHC, and clinical applicability was assessed in an additional 332 CT-only patients. Generalizability was evaluated in independent cohorts from Mayo Clinic (n = 72) and the phase III LONESTAR trial (n = 116), where paired baseline and 3-month CT enabled longitudinal assessment. SCENT classified PD-L1 status (50% or higher vs lower) in the MD Anderson cohort with AUC 0.84 (95% CI 0.785 to 0.887), specificity 83.9%, and sensitivity 85.3%, outperforming clinical and radiomics models; external validation achieved AUC 0.80 (Mayo) and 0.78 (LONESTAR). SCENT-derived PD-L1 stratified progression-free survival (HR 1.49, p < 0.001) and overall survival (HR 1.40, p = 0.009), comparable to IHC, and provided complementary prognostic value when combined with IHC, with concordant low-low patients showing the poorest survival (OS HR 1.45, p = 0.008). In LONESTAR, serial SCENT-inferred PD-L1 status showed a borderline association with 3-month progression without paired post-treatment tissue confirmation. SCENT is a generalizable CT-based virtual biopsy for baseline PD-L1 prediction and complementary tissue IHC stratification, with longitudinal use requiring prospective validation.
Zhou Y, Yu JH, Sui QQ
… +13 more, Liao LE, Lv RX, Liu Y, He S, Li YQ, Xu ZH, Jia ZX, Zheng MX, Mei WJ, Xiao BY, Luo CL, Bei JX, Ding PR
Cancer Lett
· 2026 Jun · PMID 42309220
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Immune checkpoint blockade (ICB) therapy has demonstrated promising efficacy in patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancer (CRC). However, a substantial pr...Immune checkpoint blockade (ICB) therapy has demonstrated promising efficacy in patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancer (CRC). However, a substantial proportion of these patients remain resistant to treatment. This study aims to investigate the mechanisms underlying ICB resistance in dMMR/MSI-H CRCs. We analyzed single-cell transcriptomic data from 34 CRC patients treated with ICB and integrated ten spatial transcriptomic datasets to compare the tumor microenvironment (TME) features between responders and non-responders. Our analysis identified a distinct subset of tumor-associated fibroblasts (CAFs), marked by elevated POSTN expression (POSTN CAFs), which was significantly enriched in non-responders. These cells encapsulate tumor cell aggregates and contribute to extensive extracellular matrix (ECM) remodeling, forming a dense, fortress-like stromal architecture at tumor periphery. Notably, cytotoxic T cells including CXCL13CD8 T cells were enriched in the ECM surrounding POSTN CAF regions but were largely excluded from the adjacent tumor core, suggesting that POSTN CAFs function as a physical and biochemical barrier to T cell infiltration. Differentiation trajectory analyses revealed that POSTN CAFs originate from precursor CAFs (PI16 CAFs and SFRP2 CAFs), potentially driven by malignant cell-derived cues. Specifically, we identified GDF15 as key tumor-cell ligands that may interact with precursor CAFs to promote POSTN CAF differentiation. Our findings uncover a stromal mechanism of ICB resistance in dMMR/MSI-H CRC mediated by POSTN CAFs and highlight novel therapeutic strategies to enhance immunotherapy efficacy.
Xue S, Xu H, Ma J
… +4 more, Wang Y, Lu W, Cui J, Wang L
Cancer Lett
· 2026 Jun · PMID 42303056
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Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive, with KRAS mutations, particularly KRAS G12D, present in the majority of cases. While development of KRAS G12D inhibitors is rapid, acquired resistance remains...Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive, with KRAS mutations, particularly KRAS G12D, present in the majority of cases. While development of KRAS G12D inhibitors is rapid, acquired resistance remains a major clinical challenge. Therefore, in this study, we aimed to evaluate the efficacy of novel KRAS G12D inhibitor HRS-4642, investigate its potential resistance mechanisms, and overcome resistance through combination therapy. The results demonstrated that although HRS-4642 showed potent and selective anti-tumor activity, acquired resistance has been observed in a clinical trial (NCT06520488). Through integrated analyses in vitro (HRS-4642-resistant cell lines), in vivo (HRS-4642-resistant patient-derived xenograft (PDX)), and in clinical samples (HRS-4642-resistant patients from NCT06520488), we identified reactivation of the unfolded protein response (UPR) via the MEK/ERK pathway as a key resistance mechanism. To overcome this, we performed a comprehensive drug combination screen and found that nimotuzumab synergized strongly with HRS-4642. This combination effectively enhanced efficacy and reversed resistance both in vitro and in vivo (cell-derived xenograft (CDX) and PDX). Mechanistically, while the addition of nimotuzumab was validated both in vitro and in vivo to sustain the suppression of the MEK/ERK/UPR axis, it concurrently exacerbated endoplasmic reticulum stress in vitro, thereby driving profound cellular damage. Our findings not only reveal a clinically relevant resistance mechanism to KRAS G12D inhibition but also provide a rational, effective combined strategy. Ultimately, the combination of HRS-4642 with nimotuzumab offers a promising therapeutic strategy for PDAC patients harboring KRAS G12D mutations, laying a foundation for advancing clinical research in overcoming resistance to KRAS G12D-targeted therapies.
Gobert AP, Hawkins CV, Asim M
… +15 more, Barry DP, Delgado AG, Tyree RN, Carson KS, Kahlon NPS, Ciampa MV, Rose KL, Patel P, Pusapati GV, Rohatgi R, Yu W, Zhao S, Coburn LA, Blanca Piazuelo M, Wilson KT
Cancer Lett
· 2026 Jun · PMID 42297232
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Hypusination of eukaryotic translation initiation factor 5 A (EIF5A) by the enzyme deoxyhypusine synthase (DHPS) is a mechanism of regulation of translation that plays a role in cell proliferation. Herein, we assessed th...Hypusination of eukaryotic translation initiation factor 5 A (EIF5A) by the enzyme deoxyhypusine synthase (DHPS) is a mechanism of regulation of translation that plays a role in cell proliferation. Herein, we assessed the role of hypusination in established colorectal cancer (CRC). Using molecular and biochemical approaches in established CRC cell lines and human colon organoids, we found that the tumor suppressor p53 is a critical regulator of expression of the gene EIF5A1 in the colon, thus supporting EIF5A synthesis and hypusination. Therefore, tissues and cells isolated from patients with CRC harboring TP53 mutation associated with loss of function of p53 exhibited a marked reduction of EIF5A and hypusine level. Further, TP53 mutant CRC cells remained unresponsive to a DHPS inhibitor. However, restoration of wild-type TP53 in these mutated cells supported hypusination-dependent translation of proteins involved in cell growth and rendered them susceptible to DHPS inhibition. Our studies show that loss of EIF5A is an unrecognized molecular feature of TP53 mutation in CRC cells and patients with WT TP53 CRC may benefit from drugs that can inhibit hypusination.
Cancer Lett
· 2026 Jun · PMID 42297231
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Cellular plasticity is a fundamental driver of tumor heterogeneity, cancer stemness, immune evasion, therapeutic resistance, and disease progression. In malignancies such as breast cancer and glioblastoma, tumor cells un...Cellular plasticity is a fundamental driver of tumor heterogeneity, cancer stemness, immune evasion, therapeutic resistance, and disease progression. In malignancies such as breast cancer and glioblastoma, tumor cells undergo reversible phenotypic transitions between proliferative, stem-like, invasive, and drug-tolerant states in response to intrinsic regulatory programs and extrinsic signals from the tumor microenvironment. These adaptive dynamics are governed by complex interactions among signaling pathways, transcriptional networks, chromatin remodeling, DNA methylation, histone modifications, non-coding RNAs, and immune-mediated microenvironmental cues. Such epigenetic instability enables stochastic and therapy-induced shifts between alternative cellular states, thereby contributing to tumor evolution, metastasis, resistance to targeted therapies, and variable responses to immunotherapy. Understanding the mechanisms that govern epigenetic plasticity remains a central challenge in cancer biology. Recent advances in CRISPR/dCas9-based epigenome editing have provided powerful experimental tools for investigating the functional consequences of locus-specific chromatin modifications without altering the underlying DNA sequence. Catalytically inactive Cas9 (dCas9) fused to epigenetic effector domains, including DNMT3A, TET1, KRAB, and p300, enables targeted modulation of gene expression programs implicated in cell-state transitions, lineage specification, and adaptive resistance. These technologies offer a versatile platform for interrogating causal relationships between chromatin states and cellular phenotypes and for modeling mechanisms of tumor adaptation. This review examines the molecular basis of epigenetic plasticity in cancer, evaluates current CRISPR-based epigenome editing strategies, and discusses their application in studying tumor heterogeneity, microenvironment-driven adaptation, immune escape, and therapy resistance. This study highlights emerging opportunities and persistent challenges associated with epigenome editing, including delivery barriers, durability of epigenetic modifications, context-dependent biological responses, and translational limitations. Collectively, these approaches provide valuable experimental frameworks for dissecting the regulatory logic of cancer cell plasticity while informing future therapeutic development.
Li H, Shi R, Gao Y
… +7 more, Cheng X, Wang Z, Gao Y, Shi Z, Guo M, You Y, Wang X
Cancer Lett
· 2026 Jun · PMID 42297230
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Meningioma is the most common central nervous system tumor and high-grade tumors frequently show progressive growth or recurrence, posing substantial therapeutic challenges. However, the lack of effective chemotherapy an...Meningioma is the most common central nervous system tumor and high-grade tumors frequently show progressive growth or recurrence, posing substantial therapeutic challenges. However, the lack of effective chemotherapy and targeted therapies contributes to poor prognoses in patients with high-grade disease. In this study, we evaluated KRT18 expression in meningiomas and examined its correlation with patient prognosis using RNA sequencing and immunofluorescence staining. The oncogenic role of KRT18 in high-grade meningioma was further investigated using IOMM-Lee and CH157-MN cells, xenograft mouse models, and paraffin-embedded meningioma tissue sections. Finally, small-molecule inhibitors targeting KRT18-related mechanisms were explored. Analysis of clinical specimens across different meningioma grades demonstrated that KRT18 overexpression is associated with more advanced clinical features and poorer prognosis. Functional studies showed that KRT18 promotes meningioma cell proliferation and facilitates cell cycle progression by activating the PI3K/AKT signaling pathway. Mechanistically, KRT18 interacted with LDHA, an upstream regulator of PI3K/AKT signaling, and enhanced LDHA stability via inhibition of ubiquitination, which drives oncogenic growth by activating glycolysis and the PI3K/AKT signaling pathway. These findings were corroborated in a xenograft model. Finally, Fluvastatin was identified as a novel inhibitor that specifically targets the interaction between KRT18 and LDHA, thereby inhibiting meningioma proliferation by suppressing glycolysis and PI3K/AKT signaling. Collectively, these findings indicate that KRT18 serves as a potential diagnostic, prognostic, aggressiveness-related, and potential grading biomarker. It also functions as an oncogene by activating glycolysis and the PI3K/AKT signaling pathway through interaction with LDHA. Additionally, Fluvastatin is identified as a candidate for drug repurposing in high-grade meningioma.
Li Y, Cai Z, Fang R
… +8 more, Chen W, Sun K, Shuai Y, Li Y, Guo W, Fan X, Chen L, Lei W
Cancer Lett
· 2026 Jun · PMID 42296563
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Tumor metabolic reprogramming is a hallmark of aggressive head and neck cancer (HNC), with enhanced glycolytic activity representing a major metabolic phenotype. However, how stromal signals in the tumor microenvironment...Tumor metabolic reprogramming is a hallmark of aggressive head and neck cancer (HNC), with enhanced glycolytic activity representing a major metabolic phenotype. However, how stromal signals in the tumor microenvironment (TME) sustain this process remains unclear. Here, we identify LINC02420 as a long noncoding RNA (lncRNA) enriched in cancer-associated fibroblast-derived extracellular vesicles (CAF-EVs). CAFs delivered LINC02420 to recipient HNC cells through EVs. LINC02420 increased lactate production and cell migration in HNC cells, and enhanced glucose-derived labeling of glycolytic intermediates and lactate. Reducing LINC02420 in donor CAFs attenuated the glycolysis-enhancing and pro-malignant effects of CAF-EVs. Mechanistically, CAF-EV-associated LINC02420 binds AEG-1, encoded by MTDH, and stabilizes AEG-1 protein. Stabilized AEG-1 enhances NF-κB signaling and p65 nuclear translocation. It also supports formation of an AEG-1-p65-p300 transcriptional complex at the HIF1A promoter, thereby increasing HIF1A transcription and glycolysis-related gene expression. In vivo, CAF-derived LINC02420 promoted HNC tumor growth. Clinically, LINC02420 was elevated in HNC tissues and plasma-derived EVs, and high tumor LINC02420 expression was associated with poorer overall survival. These findings identify a CAF-EV-associated lncRNA mechanism linking TME-derived stromal communication to HIF1A-dependent glycolytic regulation and support plasma EV-associated LINC02420 as a potential circulating biomarker for monitoring HNC progression.
Xiong W, Shi X, Pan S
… +16 more, Li H, Yang G, Wang C, Liu Y, Xu M, Chen B, Liu R, Lu N, Ling X, Zhao J, Zhang Y, Wang J, Liu L, Meng F, Sun X, Song R
Cancer Lett
· 2026 Jun · PMID 42288240
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Biomolecular condensates formed through liquid-liquid phase separation (LLPS) are emerging as key regulators of chromatin organization and gene expression. However, how phase separation is coupled to specific noncanonica...Biomolecular condensates formed through liquid-liquid phase separation (LLPS) are emerging as key regulators of chromatin organization and gene expression. However, how phase separation is coupled to specific noncanonical DNA structures to confer locus-selective transcriptional regulation remains poorly understood. G-quadruplex DNA (G4 DNA) is enriched at promoters, CpG islands, and other regulatory genomic regions, suggesting a potential role in guiding chromatin regulators to defined genomic loci. KDM2B is a CpG island-binding chromatin regulator involved in transcriptional repression, yet whether and how it senses G4 DNA to establish gene-specific regulatory programs in hepatocellular carcinoma (HCC) remains unclear. Here, we identify KDM2B as a G4 DNA-responsive phase-separating chromatin regulator. KDM2B undergoes LLPS through its intrinsically disordered regions and preferentially recognizes parallel G4 DNA structures. Mechanistically, G4 DNA promotes KDM2B condensate assembly and facilitates its chromatin targeting to G4-and CpG-rich regulatory loci. This process establishes a local repressive chromatin environment and restrains inflammatory transcriptional programs. Conversely, loss of KDM2B impairs G4-dependent condensate formation and weakens chromatin-associated transcriptional repression, leading to a proinflammatory secretory phenotype characterized by increased cytokines and chemokines, including IL-6 and CXCL8. This inflammatory remodeling promotes SPP1 macrophage accumulation, reshapes the tumor immune microenvironment, and accelerates HCC progression. Together, these findings reveal that KDM2B-G4 DNA phase-separated condensates function as an epigenetic regulatory platform that couples noncanonical genome architecture with locus-selective inflammatory gene repression, thereby restraining inflammation-associated HCC progression.
Bhattacharya S, Saha I, Mukherjee S
… +10 more, Rachamalla HK, Gaiani L, Albelal D, Angom RS, Wang E, Dutta S, Dutta N, Story MD, Mukhopadhyay D, Babiker HM
Cancer Lett
· 2026 Jun · PMID 42288239
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Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers, with a 5-year survival rate of 3.2% in metastatic cases. Cisplatin, a DNA-damaging agent, offers minimal benefit due to PDAC's altered DNA repair an...Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers, with a 5-year survival rate of 3.2% in metastatic cases. Cisplatin, a DNA-damaging agent, offers minimal benefit due to PDAC's altered DNA repair and protective stroma. Tumor Treating Fields (TTFields), low intensity alternating electric fields that disrupt mitosis, have shown promise in other solid tumors. We investigated whether TTFields enhance cisplatin efficacy in PDAC and explored the underlying biology. PDAC cell lines were treated with TTFields and cisplatin alone or in combination. Assays assessed viability, migration, and clonogenic survival. Orthotopic mouse models evaluated tumor volume. Mechanistic studies included KRAS signaling analysis and RNA sequencing. TTFields significantly reduced PDAC cell viability, migration, and clonogenic survival, with the strongest effects in combination with cisplatin. In vivo, combined therapy achieved ∼85% tumor volume reduction. Molecular profiling revealed suppression of KRAS-driven signaling, stromal activation, and survival pathways beyond single-agent effects. Transcriptomic analysis showed alteration of immunogenic tumor microenvironment, downregulation of inflammatory survival signaling, and upregulation of genes linked to cytoskeletal and mitochondrial remodeling, changes predicted to limit tumor spread and promote apoptosis. TTFields potentiate cisplatin's therapeutic impact in PDAC and reveal a novel biology where electrical and chemical stress converge to reprogram tumor survival. This well tolerated multimodal strategy offers a promising avenue for improving outcomes in PDAC, a cancer urgently needing more effective treatments.
Wang C, Dong X, Zhang G
… +13 more, Ren N, Chen X, Xie J, Shi X, Guo Z, Zheng Y, Luo Z, Zhu X, Cao W, Wang F, Tan F, Li N, He J
Cancer Lett
· 2026 Jun · PMID 42285215
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Metabolic biomarkers offer promising opportunities for lung cancer risk assessment and early detection. This study aimed to identify metabolites with both screening and early diagnostic value, and to develop and external...Metabolic biomarkers offer promising opportunities for lung cancer risk assessment and early detection. This study aimed to identify metabolites with both screening and early diagnostic value, and to develop and externally validate a metabolite-based risk prediction model for lung cancer. We employed a hospital-based case-control design combined with a population-based nested case-control study. In the first stage, 210 lung cancer patients and 210 matched healthy controls were included. In the second stage, we included 142 incident lung cancer cases with pre-diagnostic blood samples and 264 cancer-free participants from the Cancer Screening Program in Urban China. Multivariable logistic regression was used to construct risk models based on epidemiological risk factors alone, and in a combination of metabolites. Five overlapped differential metabolites were identified in both prevalent cases and pre-diagnostic samples: decanoylcarnitine, histidine, tryptophan, L-carnitine, and octanoylcarnitine. The area under the curve (AUC) of the five-metabolite-incorporated risk model was 0.878 (95% CI: 0.832, 0.925), outperforming models based solely on epidemiological risk factors. Model performance was consistently validated internally (AUC 0.858; 95% CI: 0.808, 0.907) and externally (AUC 0.770; 95% CI: 0.702, 0.837). Logistic regression demonstrated the strongest predictive ability compared with machine-learning approaches. Our findings provide insights that incorporating metabolomic profiles into risk assessment may significantly enhance the identification of high-risk individuals and facilitate precise screening and early detection.
Sun D, Han C, Li D
… +9 more, Li P, Tian X, Liang Z, Chen Y, Wang L, Li S, Sun L, Liang Y, Niu H
Cancer Lett
· 2026 Jun · PMID 42285214
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The malignant progression of bladder cancer is closely linked to the tumor microenvironment, yet the role of urine-derived stem cells (USCs) remains poorly understood. USCs were isolated from healthy individuals and blad...The malignant progression of bladder cancer is closely linked to the tumor microenvironment, yet the role of urine-derived stem cells (USCs) remains poorly understood. USCs were isolated from healthy individuals and bladder cancer patients, followed by multi-omic and functional characterization. The bladder cancer cell line T24 was used for in vitro co-culture and in vivo co-injection assays. Sustained exposure to tumor-derived factors (TNF-α, IL-6, and TGF-β) reprogrammed normal USCs (N-USCs) into tumor-associated USCs (T-USCs). This transition was marked by E-cadherin downregulation, vimentin upregulation, cell cycle arrest, and reduced adhesion, facilitating detachment and shedding of USCs into urine. Consequently, urine from tumor-bearing conditions showed increased USC counts and elevated CXCL2 levels. USC-derived CXCL2 activated the CXCR2 receptor on bladder cancer cells, triggering the ERK/β-catenin axis. This significantly upregulated stemness markers (CD44, ALDH1A1), promoting malignant progression. In a co-injection model, T-USCs and bladder cancer cells formed an organized stromal sheath that facilitated tumor invasion. In vivo, USCs drove tumor growth and microenvironment remodeling, effects suppressed by targeting the CXCL2/CXCR2/ERK axis. We propose a model in which hematogenous tumor factors induce urinary USC reprogramming, potentially establishing a CXCL2-enriched niche that fuels malignancy. These findings suggest a biologically plausible "tumor associated USCs-CXCL2-bladder cancer" circuit, providing insights into a putative blood-urine interactive regulatory axis and revealing a potential therapeutic target.
Yan P, Jiang W, Xue X
… +7 more, Hou T, Wang J, Huang D, Chen L, Inuzuka H, Dai X, Wei W
Cancer Lett
· 2026 Jun · PMID 42285213
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As a master serine/threonine kinase, LKB1 phosphorylates a network of downstream kinases that regulate energy homeostasis, polarity, and cellular stress adaptation. As such, LKB1 functions as a pivotal tumor suppressor i...As a master serine/threonine kinase, LKB1 phosphorylates a network of downstream kinases that regulate energy homeostasis, polarity, and cellular stress adaptation. As such, LKB1 functions as a pivotal tumor suppressor in non-small cell lung cancer (NSCLC). Mutations, deletions, or other disruptions of LKB1 biological functions occur in 20-30% of NSCLC. Loss of LKB1 kinase activity impairs energy and metabolic stress sensing through the downstream AMPK and related kinase networks, deregulates mTOR signaling, promotes metabolic reprogramming, enhances oxidative stress, and therapy resistance. Functionally, LKB1 deficiency contributes to disrupted cell polarity, enhanced invasion and metastasis, altered tumor microenvironment and therapeutic resistance to radiotherapy and immune checkpoint inhibitors in NSCLC. Hence, understanding these LKB1 downstream targets and signaling pathways provides critical insight into how LKB1 loss rewires the tumor phenotypes. This review summarizes the LKB1 protein structure and domains, its regulatory mechanisms, and the diverse cellular functions that underpin its tumor-suppressor role in NSCLCs, therefore paving the road for novel therapeutic interventions to better treat NSCLC patients.
Fu H, Gao W, Gao A
… +6 more, Deng K, Li D, Huang J, Wang X, Wang B, Wu M
Cancer Lett
· 2026 Jun · PMID 42276409
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Glioblastoma (GBM) frequently develops resistance to temozolomide (TMZ), a process critically mediated by pro-survival autophagy. While phosphatase signaling plays an essential role in regulating autophagic adaptation, t...Glioblastoma (GBM) frequently develops resistance to temozolomide (TMZ), a process critically mediated by pro-survival autophagy. While phosphatase signaling plays an essential role in regulating autophagic adaptation, the specific molecular drivers that functionally link phosphatase activity to TMZ resistance through autophagy remain poorly understood. We identified ELFN2 as a brain-enriched PP1 regulatory subunit that inhibits dephosphorylation activity, leading to phosphorylation of the splicing factor SRRM1. This triggers widespread alternative splicing, particularly a proautophagic mutually exclusive exon switch in TMBIM6, thereby promoting autophagy and TMZ resistance. Upstream, the transcription factor LRRC4 represses ELFN2, while the lncRNA LINC00470 sequesters LRRC4 in the cytoplasm to antagonize this repression. Preclinically, the HDAC inhibitor Vorinostat targets ELFN2, restores PP1 activity, and synergizes with TMZ to overcome resistance in vitro and in vivo. Our study reveals a novel PP1-centered phospho-splicing circuit governing pro-survival autophagy in GBM and provides a mechanistically grounded, immediately translatable combination therapy to combat TMZ resistance.