Lin LL, Bai JW, Song L
… +7 more, Lou KL, Gao YY, Chen HY, Lin SJ, Li CX, Zhang Y, Zhang GJ
Cancer Lett
· 2026 Jun · PMID 42276408
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The precise intraoperative delineation of tumor margins and the controlled intratumoral release of chemotherapeutic agents remain major challenges in breast cancer therapy. Tumor microenvironment (TME)-responsive nanopla...The precise intraoperative delineation of tumor margins and the controlled intratumoral release of chemotherapeutic agents remain major challenges in breast cancer therapy. Tumor microenvironment (TME)-responsive nanoplatforms provide a promising approach by utilizing the distinctive biochemical properties of tumors to achieve targeted imaging and treatment. Herein, we developed a glutathione (GSH)-activatable theranostic nanoprobe (DSM-cRGD) emitting fluorescence in the second near-infrared window (NIR-II). The probe is constructed from Nd-doped rare-earth nanoparticles coated with a manganese dioxide (MnO) shell and functionalized with cyclic RGD peptide. The MnO shell quenches NIR-II fluorescence during systemic circulation and undergoes GSH-responsive degradation within the TME. In addition, the nanoprobe shows favorable tumor-targeting ability via specific binding to integrin αβ thereby enabling real-time, high-contrast surgical navigation. Moreover, the newly developed therapeutic agent, DSM-cRGD@DOX, formed by loading doxorubicin (DOX) onto DSM-cRGD, enables the simultaneous release of DOX and Mn ions upon degradation of the MnO shell in the TME, thereby inducing synergistic chemodynamic and chemotherapeutic effects. This further induces immunogenic cell death, which activates anti-tumor immune responses and suppresses tumor recurrence and metastasis. Collectively, this DSM-cRGD-based platform represents an integrated nanoplatform that combines precise tumor imaging with stimuli-responsive drug delivery, offering an advanced strategy for the precision management of breast cancer.
Aristin Revilla S, Verheem A, Frederiks CL
… +8 more, Kim Y, Chalkiadakis T, Viergever BJ, Győrffy B, Mocholi E, Kranenburg O, Prekovic S, Coffer PJ
Cancer Lett
· 2026 Jun · PMID 42276407
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In colorectal cancer (CRC), tumor-infiltrating regulatory T (Treg) cells suppress anti-tumor immunity, promoting immune evasion and tumor progression. Effective therapies require selectively targeting tumor-infiltrating...In colorectal cancer (CRC), tumor-infiltrating regulatory T (Treg) cells suppress anti-tumor immunity, promoting immune evasion and tumor progression. Effective therapies require selectively targeting tumor-infiltrating Treg (TI-Treg) cells while preserving systemic Treg cells, necessitating insight into their adaptations within the tumor microenvironment. Here, CRC-organoids were implanted in the liver of Foxp3eGFP mice to investigate location-specific phenotypic differences in TI-Treg cells. In our cohort, tumor tissue exhibited an increased proportion of Treg cells and a decrease proportion of effector CD4 and CD8 T cells compared to matched healthy tissue. RNA sequencing of Treg cells isolated from the spleen, primary liver tumor transplant, or metastases identified gene expression profiles previously associated with CRC-related Treg cells in patients. Location-specific differences included elevated expression of WNT-pathway genes in peritoneal TI-Treg cells compared to liver counterparts. Higher expression of genes upregulated in liver TI-Treg cells correlated with poor CRC prognosis. Splenic Treg cells from tumor-bearing mice displayed distinct transcriptional profiles from both their healthy counterparts and TI-Treg cells, suggesting they represent a distinct CD4 population. Taken together, these findings highlight TI-Treg cells heterogeneity across different tumor sites and the distinct nature of splenic Treg cells in tumor-bearing hosts.
Moldenhauer MR, Mahadevan A, Hom C
… +17 more, Nguyen ATM, Rangel V, Hasson S, Hsu NH, Ubbaonu C, Nathan D, Chandan VS, Shen KV, Damozonio EM, Zhou GG, Chichili T, Le A, Masri S, Dayyani F, Qiao F, Valerin JB, Pannunzio NR
Cancer Lett
· 2026 Jun · PMID 42269807
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Lynch syndrome significantly increases the risk of developing colorectal cancer (CRC) due to an inherited defect in mismatch repair (MMR). Early detection relies on the identification of pathogenic mutations in patients...Lynch syndrome significantly increases the risk of developing colorectal cancer (CRC) due to an inherited defect in mismatch repair (MMR). Early detection relies on the identification of pathogenic mutations in patients with a family history of cancer, but few canonical Lynch mutations exist. Here, we describe four CRC patients found to carry an identical mutation in the MLH1 gene. Despite a strong family history of cancer, the MLH1 mutation was labeled discordantly regarding pathogenic potential. This highlights the need for improved diagnostics to screen for non-canonical Lynch variants. In addition to designing a novel digital PCR (dPCR) assay to rapidly detect MLH1 gene variants, we conducted in-depth analyses via molecular modeling, mutational signature analyses, and functional genetic assays to demonstrate that the MLH1 mutation results in a definitive MMR defect that increases cancer risk. This study emphasizes the need for improved diagnostic tools to identify pathogenic mutations in diverse populations.
Xue Q, Ye J, Chakraborty S
… +9 more, Sang X, Sun M, Zhang Y, Chen S, Lin W, Munasinghe J, Yang C, Wang H, Zhuang Z
Cancer Lett
· 2026 Jun · PMID 42263837
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We established a novel syngeneic glioblastoma stem cell (GSC) line from PDGFB-driven RCAS/tv-a glioblastomas and subsequently generated a Pten-deficient derivative, WYZ-1. In vitro, WYZ-1 cells exhibited robust self-rene...We established a novel syngeneic glioblastoma stem cell (GSC) line from PDGFB-driven RCAS/tv-a glioblastomas and subsequently generated a Pten-deficient derivative, WYZ-1. In vitro, WYZ-1 cells exhibited robust self-renewal, high expression of GSC markers (CD133, Nestin, SOX2), and multipotent differentiation into neuronal and astrocytic lineages. In vivo, intracranial implantation in immunocompetent mice produced highly infiltrative and vascularized tumors with marked proliferation, necrosis, and white matter invasion, closely recapitulating key histopathological features of human glioblastoma. Immunohistochemical analysis confirmed the retention of oncogenic, stem-like, and mesenchymal-associated markers. Importantly, WYZ-1 tumors displayed an immune-excluded ("cold") tumor microenvironment characterized by dense infiltration of immunosuppressive macrophages/microglial cells within the tumor core and restricted localization of exhausted T cells to the tumor margins. Consistent with these features, WYZ-1 tumors are resistant to temozolomide and anti-PD-1 monotherapy, with only a modest survival benefit observed following CTLA-4 blockade. Collectively, these findings establish WYZ-1 as a highly aggressive, stem-like, and immunocompetent glioblastoma model that mirrors the therapeutic resistance of human disease and provides a valuable platform for investigating tumor biology and evaluating novel immunotherapeutic strategies.
Hamid M, Siddig AMA, Suliman R
… +3 more, Saeed A, Mussa A, Al-Hatamleh MAI
Cancer Lett
· 2026 Jun · PMID 42263836
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Colorectal cancer stem-like cells (CRC-SCs) represent a tumor subpopulation with enhanced tumor-initiating capacity and have been implicated in metastasis, therapeutic resistance, and disease relapse. These cells not onl...Colorectal cancer stem-like cells (CRC-SCs) represent a tumor subpopulation with enhanced tumor-initiating capacity and have been implicated in metastasis, therapeutic resistance, and disease relapse. These cells not only possess intrinsic resistance mechanisms, such as quiescence, enhanced DNA repair, and ABC transporter overexpression, but also actively orchestrate a profoundly immunosuppressive tumor microenvironment (TME). Emerging evidence suggests that CRC-SCs may contribute to shaping an immunosuppressive TME through secretion of exosomes and cytokines that influence immune cells (e.g., regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages) and key stromal cell populations (e.g., cancer-associated fibroblasts). This review provides a comprehensive analysis of the evolving landscape of immunotherapies designed to target CRC-SCs. We evaluate immunotherapeutic strategies including immune checkpoint inhibitors, while also discussing the targeting of critical signaling pathways like Wnt, Notch, and Hh. Furthermore, we explore the growing role of artificial intelligence (AI)-based approaches in deciphering CRC-SC heterogeneity, identifying predictive biomarkers, and accelerating therapeutic target discovery. Despite these advancements, significant challenges remain, including tumor heterogeneity, the immunosuppressive TME, and on-target/off-tumor toxicity. We conclude by outlining future directions that emphasize combination therapies, novel delivery systems, and AI-driven precision medicine as crucial strategies to more effectively target CRC-SC populations and improve durable disease control.
Wang PX, Zhong YC, Zheng WJ
… +16 more, Xian JR, Song F, Xu J, Sun YF, Cheng JW, Feng HY, Jiang X, Xu Y, Zhang ZF, Zhou KQ, Guo W, Hu B, Gu LD, Zhou J, Fan J, Yang XR
Cancer Lett
· 2026 Jun · PMID 42250756
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Tumor-associated macrophages (TAMs) are key regulators of the metastatic immune microenvironment, yet the specific TAM subsets that drive immune suppression and tumor progression in colorectal cancer liver metastasis (CR...Tumor-associated macrophages (TAMs) are key regulators of the metastatic immune microenvironment, yet the specific TAM subsets that drive immune suppression and tumor progression in colorectal cancer liver metastasis (CRLM) remain poorly defined. Here, we integrated CyTOF, single-cell and spatial transcriptomics, bulk RNA sequencing, and lipidomics to identify a distinct population of lipid-laden, immunosuppressive TREM2 TAMs enriched in CRLM. These cells exhibited high expression of lipid metabolism-related genes, including APOE, LIPA, and GPNMB, and accumulated abundant intracellular lipid droplets. Spatial analyses revealed their preferential localization at the invasive margins and within intratumoral colonic lumen-like structures-regions characterized by the buildup of APOE protein, mucinous material, and apoptotic tumor debris. Transcriptional analyses suggest these macrophages follow a Kupffer cell-related differentiation trajectory and acquire an immunoregulatory phenotype via uptake of tumor-derived lipids. Functionally, TREM2 TAMs produced leukotrienes via the ALOX5/ALOX5AP pathway, which in turn sustained chronic inflammatory signaling. This inflammatory milieu potentiated neutrophil recruitment and fostered tumor cell stemness, thereby reinforcing an immunosuppressive metastatic niche and correlating with poor patient prognosis. In vivo murine depletion model and ex vivo organotypic tumor models confirmed that either selective ablation of TREM2 TAMs or pharmacological inhibition of leukotriene synthesis alleviated immunosuppression and potentiated the efficacy of anti-PD-1 therapy. Our study defines a conserved lipid-associated TREM2 TAM population as an essential contributor of immune evasion and microenvironment remodeling in liver metastasis, and suggest it as a potential therapeutic target in metastatic colorectal cancer.
Chen Y, Fang Y, Zhao G
… +4 more, Zhou Y, Yang DH, Han J, Zheng Y
Cancer Lett
· 2026 Jun · PMID 42250754
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Endometrial cancer is one of the most prevalent malignancies of the female reproductive system, and the global rising prevalence of obesity has further increased its incidence and poor clinical prognosis. Although obesit...Endometrial cancer is one of the most prevalent malignancies of the female reproductive system, and the global rising prevalence of obesity has further increased its incidence and poor clinical prognosis. Although obesity is recognized as a critical modifiable risk factor for endometrial cancer, it remains unclear whether and how obesity drives tumor initiation and progression by modulating the tumor microenvironment at single-cell resolution. Using a genetic mouse model with pten conditional knockout in the uterine endometrium, clinical samples from endometrial cancer patients, and single-cell RNA sequencing from 10 endometrial tumor samples, we delineated a comprehensive single-cell atlas of endometroid endometrial cancer altered by obesity. The results reveal a unique SOX9LGR5 epithelial subpopulation exhibiting cancer stem cell features, which establishes an intratumoral estrogen-signaling circuit. Tumor-associated macrophages and NK/T cells undergo profound metabolic reprogramming toward pro-tumor and immunosuppressive phenotypes. Fibroblasts exhibit remarkable phenotypic and metabolic rewiring within a lipid-rich microenvironment, facilitating extracellular matrix remodeling. Emerging endothelial subsets drive angiogenesis and vascular dysfunction, fostering intratumoral hypoxia and cancer cell metastasis. These components engage in extensive intercellular crosstalk centered on tumor-associated macrophages, forming a self-reinforcing network that drives immunosuppression, stemness maintenance, cell migration, and aberrant angiogenesis. Our findings highlight that obesity-induced tumor microenvironment remodeling and metabolic communication constitute key mechanisms underlying tumor aggressiveness of obesity-related endometrial cancer, providing novel mechanistic insights and potential therapeutic targets for clinical intervention.
Zhao L, Huang W, Li C
… +6 more, Wang Q, Han Y, Yang W, Zhu L, Lin Z, Piao J
Cancer Lett
· 2026 Jun · PMID 42250753
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The immunosuppressive tumor microenvironment, particularly M2-like tumor-associated macrophages (TAM), critically contributes to colorectal cancer (CRC) progression and resistance to immune checkpoint inhibitors. Here, w...The immunosuppressive tumor microenvironment, particularly M2-like tumor-associated macrophages (TAM), critically contributes to colorectal cancer (CRC) progression and resistance to immune checkpoint inhibitors. Here, we identify Bruceine D (BD), a natural compound, as a potent regulator of macrophage-associated immunometabolism in CRC. BD suppressed tumor progression and enhanced anti-programmed cell death protein 1 (anti-PD-1) immunotherapy efficacy in both MC38 and CT26 syngeneic mouse models without inducing significant systemic toxicity. Mechanistically, BD inhibited M2-like macrophage polarization in THP-1-derived macrophages, bone marrow-derived macrophages (BMDMs), and human monocyte-derived macrophages (MDMs), while attenuating the tumor-promoting effects mediated by macrophage-conditioned medium. Integrated transcriptomic, metabolic, and mechanistic analyses indicated that BD interacts with CCAAT/enhancer-binding protein beta (C/EBPβ) and suppresses stearoyl-CoA desaturase 1 (SCD1) transcription, thereby reducing the production of palmitoleic acid (C16:1). In turn, C16:1 maintained C/EBPβ protein stability, forming a positive feedback loop that sustained M2-associated macrophage phenotypes. Molecular docking, molecular dynamics simulation, cellular thermal shift assay, and surface plasmon resonance collectively supported the direct interaction between BD and C/EBPβ. Multiplex immunohistochemistry analysis of human CRC tissue microarrays further demonstrated positive correlations among C/EBPβ, SCD1, and the M2 marker CD206 in clinical specimens. Collectively, our findings support the C/EBPβ/SCD1/C16:1 axis as an important immunometabolic pathway involved in regulating M2-like macrophage phenotypes and suggest that BD represents a promising therapeutic strategy for improving anti-PD-1 immunotherapy in CRC.
Lin A, Chen Y, Liu J
… +7 more, Jiang A, Zhu W, Cheng Q, Zhang J, Yuan Q, Mao W, Luo P
Cancer Lett
· 2026 Jun · PMID 42248320
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Metabolic dysregulation of immune cells within the tumor microenvironment represents a fundamental mechanism underlying tumor immune evasion. Nanomedicine, representing the interdisciplinary integration of nanotechnology...Metabolic dysregulation of immune cells within the tumor microenvironment represents a fundamental mechanism underlying tumor immune evasion. Nanomedicine, representing the interdisciplinary integration of nanotechnology and medicine, holds transformative potential for cancer immunotherapy. This narrative review demonstrates that by reprogramming four key metabolic domains-glucose metabolism, lipid metabolism, mitochondrial function, and iron metabolism-nanomedicine can achieve precise, multi-target regulation of core immune cell functions, including those of T cells, dendritic cells, and tumor-associated macrophages. Consequently, nanotherapeutics significantly enhance antitumor immunity through multiple mechanisms: increasing antigen presentation efficiency and T-cell activation, remodeling the immunosuppressive tumor microenvironment, normalizing aberrant tumor vasculature, alleviating hypoxia, and augmenting tumor cell immunogenicity. Furthermore, synergistic combination strategies employing nanotherapeutics alongside immune checkpoint inhibitors significantly improve therapeutic efficacy by optimizing drug delivery efficiency and targeting specificity, while simultaneously overcoming resistance to immune checkpoint inhibitors and mitigating systemic adverse reactions. Despite the remarkable preclinical potential of these approaches, critical knowledge and technological gaps remain, including incomplete elucidation of molecular mechanisms, insufficient optimization of biosafety profiles, suboptimal tumor-targeted delivery efficiency, and a lack of systematic integration with adjuvant therapies. Future efforts focused on advancing in-depth mechanistic research, designing advanced biomaterials, exploring rational combination regimens, and developing personalized treatment protocols will ultimately establish nanomedicine as a pivotal breakthrough in precision oncology.
Xu T, Lu B, Song F
… +6 more, Jiang B, Gong S, Ma Y, Zhang Y, Huang P, Ge M
Cancer Lett
· 2026 Jun · PMID 42248319
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The aggressive and immunotherapy-resistant characteristics of anaplastic thyroid carcinoma (ATC) are driven by an immunosuppressive tumor microenvironment and intercellular crosstalk; however, its regulatory mechanisms r...The aggressive and immunotherapy-resistant characteristics of anaplastic thyroid carcinoma (ATC) are driven by an immunosuppressive tumor microenvironment and intercellular crosstalk; however, its regulatory mechanisms remain poorly understood. Here, we identified Glucose-6-Phosphate Isomerase (GPI) as a pivotal metabolic immune checkpoint that orchestrates myeloid cells-driven immunosuppression in ATC. We demonstrated that GPI enhances the hexosamine biosynthesis pathway to promote O-GlcNAcylation of thrombospondin-1 (THBS1) at serine-1068. This site-specific modification competes with ubiquitination to stabilize THBS1 and augment its secretion. Released THBS1 engages macrophages to trigger a CEBPB-dependent transcriptional program that drives the expression of the chemokine CCL2. Macrophage-derived CCL2 then acts on tumor-associated neutrophils, promoting their STAT3-dependent differentiation into polymorphonuclear myeloid-derived suppressor cells, which ultimately suppresses CD8 T cell function. Genetic deletion of either GPI or THBS1 robustly inhibited tumor growth and reversed immunosuppression in vivo. To intervene this axis, we repurposed the multi-kinase inhibitor Regorafenib as a novel GPI inhibitor. We confirmed that Regorafenib disrupts this entire axis and, in combination with anti-PD-1 therapy in ATC, overcomes immunosuppression to elicit potent anti-tumor immunity. Our studies revealed the GPI/O-GlcNAcylation/THBS1 signal as a master regulator of myeloid cell crosstalk and established a novel therapeutic strategy for targeting this metabolic checkpoint to potentiate ATC immunotherapy.
Lin PH, Cheng SH, Raj EN
… +5 more, Wen ZH, Sheu JJ, Chang R, Chiang AJ, Li CJ
Cancer Lett
· 2026 Sep · PMID 42241805
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The management of endometrial cancer (EC) has transitioned from a histopathological model to a framework based on molecular precision. This change is centered on the integration of immune checkpoint inhibitors, which has...The management of endometrial cancer (EC) has transitioned from a histopathological model to a framework based on molecular precision. This change is centered on the integration of immune checkpoint inhibitors, which has altered clinical standards for different genomic subsets. For patients with mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumors, PD-1 and PD-L1 blockade has moved from late-line therapy to a frontline standard. Results from the RUBY and NRG-GY018 trials show that combining dostarlimab or pembrolizumab with platinum-based chemotherapy improves survival in patients with untreated advanced disease. Mismatch repair proficient (pMMR) tumors, which make up the majority of cases, remain difficult to treat due to an immune-cold microenvironment. Overcoming this resistance requires combination strategies, such as using anti-angiogenic agents like lenvatinib with immune checkpoint inhibitors, as shown in the KEYNOTE-775 trial. Data from the DUO-E study also suggest that including DNA damage response inhibitors may improve results in pMMR populations. As molecular monitoring via liquid biopsy and the use of antibody-drug conjugates (ADCs) evolve, the personalization of immunotherapy continues to progress. This review examines current clinical evidence and the mechanisms of resistance to define the future of precision medicine in endometrial cancer.
Cancer Lett
· 2026 Jun · PMID 42229825
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Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and remains largely incurable because of diffuse invasion, cellular heterogeneity, therapy resistance, and recurrence. These traits depend not only...Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and remains largely incurable because of diffuse invasion, cellular heterogeneity, therapy resistance, and recurrence. These traits depend not only on tumor-intrinsic programs but also on dynamic interactions between glioma cells and the tumor microenvironment. Connexins are extensively remodeled in GBM and are best known for forming gap junction channels, whose broad inhibition risks disrupting essential homeostatic functions in the healthy brain. By contrast, connexin hemichannels (HCs) are regulated plasma membrane conduits that can open under inflammatory, hypoxic, oxidative, and metabolic stress. Here, we review evidence that connexin HCs may act as conditionally activated amplifiers of tumor-microenvironment signaling in GBM. We discuss connexin expression in normal brain and GBM, with emphasis on Cx43, Cx46, Cx26, and Cx30, and examine how HC opening may influence glutamate and ATP release, macrophage/microglia-associated inflammation, neuronal hyperexcitability, vascular remodeling, metabolic adaptation, and redox signaling. We distinguish direct evidence from GBM models from mechanistic inferences derived from related systems. Emerging studies indicate that HC-targeting interventions can reduce GBM invasiveness, alter extracellular ATP and glutamate accumulation, modulate tumor-associated pathology, and attenuate network hyperexcitability in preclinical models. We conclude that connexin HCs are promising but incompletely validated therapeutic targets at the GBM tumor-microenvironment interface and highlight the need for biomarkers of pathological HC activation in human tumors.
Krishna M, Garg P, Horne D
… +2 more, Salgia R, Singhal SS
Cancer Lett
· 2026 Sep · PMID 42229824
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Chronic inflammation has emerged as a central driver for the initiation, progression, and therapeutic resistance of prostate cancer (CaP). While androgen receptor (AR) signaling serves as the primary axis for prostate tu...Chronic inflammation has emerged as a central driver for the initiation, progression, and therapeutic resistance of prostate cancer (CaP). While androgen receptor (AR) signaling serves as the primary axis for prostate tumorigenesis, mounting evidence suggests that continuous activation of inflammatory signaling pathways, especially nuclear factor kappa B (NFκB) and interleukin-6 (IL6)/Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathways, profoundly reshape the transcriptional and epigenetic landscape of advanced disease. These signaling pathways largely converge with AR signaling to form a common axis and promote tumor survival, proliferation, angiogenesis, immune evasion, epithelial to mesenchymal transition (EMT), and metastasis. Furthermore, prolonged exposure to cytokines such as IL6 and tumor necrosis factor-α (TNFα) leads to constitutive activation of STAT3 and NFκB signaling pathways. This persistent inflammatory signaling increases AR transcriptional activity even under androgen-deprived conditions, thereby facilitating the development of castration-resistant prostate cancer (CRPC). Apart from transcriptional crosstalk, inflammatory signaling pathways interact with epigenetic remodeling mechanisms, including histone modifications, DNA methylation, and dysregulation of chromatin modifiers such as EZH2, LSD1, and BRD4. These epigenetic variations stabilize aberrant gene expression programs and promote therapeutic resistance in metastatic CRPC. The present review discusses the crosstalk between inflammatory signaling, AR reprogramming, and epigenetic remodeling, and illustrates emerging therapeutic strategies targeting NFκB and JAK/STAT3 signaling pathways. This review highlights the importance of the integrated inflammatory-AR-epigenetic axis in CRPC progression and emphasizes its potential for improved biomarker stratification and the development of effective combinatorial therapeutic strategies to overcome resistance and improve clinical outcomes in advanced CaP.
Roy A, Ghosh A, Bhoumick A
… +8 more, Paul S, Halder R, Mandal S, Das B, Basu A, Mukhopadhyay S, Das K, Sen P
Cancer Lett
· 2026 Sep · PMID 42219057
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Deregulation of coagulation proteases can lead to a spectrum of hemostatic abnormalities, ranging from subtle subclinical to life-threatening coagulopathies. Additionally, coagulation factors play critical roles in many...Deregulation of coagulation proteases can lead to a spectrum of hemostatic abnormalities, ranging from subtle subclinical to life-threatening coagulopathies. Additionally, coagulation factors play critical roles in many abnormalities beyond thrombosis, extending to hyperactive inflammatory responses and promoting tumorigenesis. Triple-negative breast cancers (TNBCs) are marked by a pro-thrombotic and highly inflammatory tumor microenvironment that fuels progression and therapeutic resistance, yet the molecular crosstalk linking coagulation signaling to inflammatory transcription remains incompletely understood. Here, we identify DNA topoisomerase I (Top1) as a critical downstream effector of thrombin-PAR1 driven inflammatory reprogramming in breast cancer cells. Thrombin enhances Top1 activity without altering its expression, amplifying NF-κB dependent cytokine production. Mechanistically, this response is governed by suppression of the tumor suppressor Par-4, which resides at the epicentre of this signaling axis and negatively regulates both Top1 and NF-κB. PAR1 activation enforces Par-4 loss through coordinated epigenetic silencing and phosphorylation-dependent cytoplasmic inactivation, thereby relieving transcriptional constraints and sustaining pro-tumorigenic inflammation. Importantly, targeting PAR1 markedly sensitizes TNBC tumors to the Top1 inhibitor irinotecan, highlighting a therapeutically actionable vulnerability. These findings reveal a previously unappreciated convergence of coagulation, epigenetic control, transcriptional activation and DNA topology control in breast cancer-suggesting the possibility of repurposing FDA-approved oral anticoagulants as an effective combinatorial therapy along with Top1 poisons in treating TNBCs.
Wang JD, Liao CJ, Lei XX
… +6 more, Peng ZZ, Lin ZL, Liu JJ, Liu Q, Zhang L, Long ZJ
Cancer Lett
· 2026 May · PMID 42217563
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Nucleophosmin 1-mutant (NPM1) acute myeloid leukemia (AML) represents a distinct molecular subtype, yet the mechanisms underlying NPM1 mutation-driven malignant transformation remain incompletely understood. Here, we fin...Nucleophosmin 1-mutant (NPM1) acute myeloid leukemia (AML) represents a distinct molecular subtype, yet the mechanisms underlying NPM1 mutation-driven malignant transformation remain incompletely understood. Here, we find prevalent copy number variations (CNVs) of N-methyladenosine (mA) key regulators in NPM1 wild-type (NPM1) AML patients, whereas such alterations are rarely detected in NPM1 subgroup. Moreover, a reduction in mA modification is observed in leukemic cells overexpressing NPM1 protein, concomitant with an increase in FTO expression. Co-immunoprecipitation shows that NPM1 protein mislocates in the cytoplasm and binds to FTO to block its ubiquitin-proteasome degradation through K422 specific site. Of note, creatine metabolism-related signaling and FTO-mediated macrophage M2 polarization signaling are enriched in NPM1 patients according to TCGA data analysis. Indeed, FTO promotes creatine anabolism in NPM1 leukemic cells by stabilizing the mRNA of GAMT, a key enzyme in the creatine synthesis pathway. Creatine facilitates macrophage M2 polarization, as evidenced by the upregulation of M2 polarization-related genes (CD206, CCL2, IL-10 and CXCL13). This effect is abrogated upon FTO knockdown in leukemic cells. Selinexor, an exportin 1 inhibitor to impede NPM1 export from nucleus, enhances FTO degradation and reduces macrophage M2 polarization. This work reveals that FTO-creatine signaling plays an oncogenic role in NPM1 AML, guiding more effective therapy strategies and clinical benefits for this distinctly leukemic entity.
Zhao Z, Zheng ZY, Lei JT
… +19 more, Baik MJ, Wu YH, Somes LK, Mosquera Paternina AF, Harb OA, Chang OA, Liu F, Holt MV, Wang J, Bado I, Wang H, Miles G, Gugala Z, Anurag M, Elkhanany A, Li Y, Hoyos V, Zhang XH, Chang EC
Cancer Lett
· 2026 Sep · PMID 42217562
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Estrogen receptor-positive (ER) breast cancer exhibits a marked propensity for skeletal metastasis; however, the molecular drivers of bone colonization remain incompletely defined. We investigated the tumor suppressor ne...Estrogen receptor-positive (ER) breast cancer exhibits a marked propensity for skeletal metastasis; however, the molecular drivers of bone colonization remain incompletely defined. We investigated the tumor suppressor neurofibromin (NF1), a dual repressor for RAS and ER signaling, whose inactivation promotes endocrine therapy (ET) resistance and is associated with inferior relapse-free survival. NF1 copy number loss was detected in 62% of ER patients who subsequently developed metastases and was associated with an increased likelihood of bone metastases at initial diagnosis. In mouse xenograft models, NF1-depleted ER breast cancer cells demonstrated enhanced dissemination to skeletal sites following surgical resection of primary tumors. Furthermore, after intra-iliac injection, NF1-depleted cells generated significantly greater tumor burden in bone. Transcriptomic profiling revealed enrichment of bone-related gene signatures in NF1-depleted ER breast cancer cells, which more potently induced osteoclast differentiation and bone loss in co-culture systems. In parallel, low NF1 expression correlated with repressed T cell functional states in primary breast tumors and bone metastases. Consistent with these clinical observations, NF1-depleted ER breast cancer cells more effectively inhibited proliferation, interferon-γ secretion, and cytotoxicity of human primary CD8 T cells. Collectively, these findings identify NF1 inactivation as a key driver of bone metastasis in a substantial subset of ER breast cancers. By amplifying the osteolytic "vicious cycle" and promoting immune evasion, NF1 loss remodels the microenvironment to favor tumor expansion. These results further suggest that NF1 loss functionally links therapy resistance with increased skeletal metastatic potential.
Aleman JD, Young CD, Ke Y
… +8 more, Nguyen KA, Lu I, Goon JB, Abello AE, Lind HT, Karam SD, Birkeland AC, Wang XJ
Cancer Lett
· 2026 May · PMID 42217561
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Distant metastasis often predicts poor survival for squamous cell carcinoma (SCC) patients. To identify potential targets for metastatic SCCs, we performed spatial profiling of SCC specimens from head and neck cancer pat...Distant metastasis often predicts poor survival for squamous cell carcinoma (SCC) patients. To identify potential targets for metastatic SCCs, we performed spatial profiling of SCC specimens from head and neck cancer patients to identify stage-associated markers. Laminin-binding integrins, normally restricted to basal keratinocytes, were enriched in Stage IV-A intratumoral regions vs Stage II/III SCCs, consistent with poor survival correlations of these integrins in TCGA. Due to the association of multiple laminin-binding integrins with poor prognosis, we assessed their collective impact on metastasis by knocking down integrin β1, a common partner of α-integrins, in mouse SCC cells derived from keratin 15 (K15) stem cells harboring a Kras mutation and Smad4 deletion (Smad4). SCC cell lines derived from primary tumors with or without spontaneous lung metastasis were established. Metastatic SCC cells had higher levels of laminin-binding integrins than non-metastatic SCC cells derived from this model. Knockdown of the integrin β1 gene (shITGB1) in metastatic SCC cells ablated lung metastases following implantation into immunocompetent but not immunocompromised hosts. RNA sequencing of control/shITGB1 murine SCC cells identified that integrin β1 was linked to pathways related to leukocyte recruitment. At the protein level, inflammatory cytokine arrays and immunostaining of metastatic murine tumors revealed that metastatic SCCs exhibited elevated myeloid chemotactic proteins, granulocyte infiltration, and low CD8 T cell presence. shITGB1 reversed these patterns. Conversely, CD8α depletion enabled shITGB1 SCC cells to reestablish lung metastasis in immunocompetent hosts. Our results reveal an unappreciated role of SCC cell-produced integrin β1 in driving immune suppression-associated metastasis.
Cañadas García A, Thombare K, Jahangiri L
… +10 more, Burman AR, Ducray SP, Burke GAA, Goodman A, Woodward ER, Cheesman E, Penn A, Mondal T, Turner SD, Pucci P
Cancer Lett
· 2026 May · PMID 42217560
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