Cancer letters最新文献

To elucidate the mechanisms underlying therapy-induced resistance, we investigated the temporal dynamics of the polyploid giant cancer cell (PGCC) life cycle following treatment with the microtubule-destabilizing agent vincristine (VCR). Longitudinal live-cell fluorescence imaging revealed that VCR-induced mitotic suppression activated a distinct PGCC life cycle characterized by nuclear amplification and progressive cellular reprogramming. At the cellular level, PGCCs entered a senescence-like state accompanied by an enhanced senescence-associated secretory phenotype (SASP), increased epithelial-mesenchymal transition (EMT), acquisition of early embryonic-like features, and multilineage differentiation potential into ectoderm, mesoderm, and endoderm. PGCC-derived progeny exhibited dose- and time-dependent changes in proliferative behavior, aggressive phenotypes in vitro, along with time-dependent tumorigenic potential in vivo. Remarkably, at the tissue level, PGCCs also underwent spatial nuclear reorganization and self-organization into morphologically defined glandular epithelial structures exhibiting varying degrees of tissue maturation, reminiscent of early embryonic development. Silencing IL1β, IL6, or IL8, or pharmacologically inhibiting their receptors, suppressed PGCC formation, budding, EMT, and embryonic-like reprogramming associated with tissue morphogenesis. Furthermore, NAMPT emerged as a key regulator of embryonic-like stemness, glandular morphogenesis, and structural expansion. Together, these findings reveal that therapeutic stress activates a PGCC life cycle capable of generating two divergent outcomes: resistant tumor regeneration through clonal selection of undifferentiated tumor cells and organized tissue differentiation through spatial nuclear reprogramming. Our study establishes a conceptual framework linking therapy-induced polyploidization, developmental plasticity, and resistance generation at both cellular and tissue levels.

Neoadjuvant immunotherapy has improved clinical outcomes in resectable non-small cell lung cancer (NSCLC); however, a substantial proportion of patients fail to achieve durable responses, and the mechanisms underlying therapeutic resistance remain incompletely understood. Here, we identified protein phosphatase 1 regulatory inhibitor subunit 1B (PPP1R1B) as a metabolic driver of immunotherapy resistance in NSCLC through RNA sequencing of tumors with differential responses to neoadjuvant anti-PD-1 therapy. PPP1R1B was significantly upregulated in non-responders and correlated with poor prognosis in NSCLC patients. Mechanistically, PPP1R1B directly interacted with IRF3 through the Arg29 residue and promoted dephosphorylation of IRF3 at Ser396, thereby suppressing IRF3 activation and downstream interferon-β (IFN-β) signaling. PPP1R1B-mediated inhibition of IFN-β signaling reduced CD8⁺ T-cell infiltration and impaired antitumor immunity, ultimately conferring resistance to anti-PD-1 therapy in vivo. Blockade of IFN-β signaling abrogated the antitumor effects induced by PPP1R1B depletion, supporting an immune-dependent mechanism. Notably, tumors resistant to neoadjuvant immunotherapy exhibited impaired oxidative phosphorylation and excessive lactate accumulation. Lactate induced PPP1R1B expression through NF-κB-dependent transcriptional activation, linking metabolic reprogramming to innate immune suppression. Collectively, our findings identify a lactate/NF-κB/PPP1R1B/IRF3 signaling axis that drives immune evasion and resistance to neoadjuvant immunotherapy in NSCLC, and nominate PPP1R1B as a potential biomarker and therapeutic target for overcoming anti-PD-1 resistance.

Mucin-16 (MUC16) is overexpressed in >60% of pancreatic ductal adenocarcinoma (PDAC) cases and correlates with poor outcomes, yet its role in regulating tumor-immune interactions remains incompletely defined. Using KPC and KPC-MUC16 knockout (KPC-MUC16^KO) genetically engineered and orthotopic mouse models, we show that loss of MUC16 markedly reduces tumor burden and reprograms the tumor microenvironment (TME) toward a less immunosuppressive state. MUC16 deficiency significantly decreased CD206⁺ and Ym1/2⁺ M2-like macrophages, increased the M1/M2 ratio, and improved survival. Cytokine profiling identified CCL2 and Serpin-E1 as MUC16- dependent secreted factors that promote macrophage recruitment and polarization; neutralization of these cytokines reduced macrophage migration in vitro. Bone marrow-derived macrophages (BMDM) exposed to MUC16-expressing tumor cells or conditioned media adopted a CD206⁺Arg1⁺ M2-like phenotype, whereas MUC16^KO tumor signals favored inflammatory CD86⁺iNOS ⁺ M1-like polarization. Macrophage depletion using clodronate liposomes significantly impaired tumor growth in MUC16-competent tumors but had minimal effect in KPC-MUC16^KO tumors, indicating dependence on macrophage-mediated immunosuppression in the former group. Spatial transcriptomics revealed a globally distinct TME in MUC16^KO tumors, including enhanced antigen-presentation programs, increased complement activation, and fibroblast states skewed toward pro-inflammatory signaling. These findings establish MUC16 as a key orchestrator of macrophage-driven immunosuppression in PDAC and support therapeutic strategies combining MUC16-targeted interventions with TME-reprogramming approaches.

Pancreatic ductal adenocarcinoma (PDAC) responds poorly to immune checkpoint blockade (ICB), largely because of its immunosuppressive and T-cell-excluded tumor microenvironment. While inducing immunogenic cell death (ICD) offers a promising strategy to enhance tumor immunogenicity, redox-targeted ICD inducers with defined molecular targets remain limited in PDAC. Here, a functional screen of natural compounds identified erianin as a potent ICD inducer in PDAC. Erianin triggered canonical ICD hallmarks, including cell-surface calreticulin exposure, extracellular release of HMGB1 and ATP, thereby promoting dendritic-cell maturation, antigen cross-presentation and CD8⁺ T-cell activation. Target-engagement assays together with genetic perturbation supported glutathione reductase (GSR) as a functionally important erianin target. Erianin decreased the GSH/GSSG ratio, accompanied by increased oxidative stress and preferential activation of the PERK-eIF2α-ATF4-CHOP branch of the endoplasmic reticulum (ER) stress response. Mutational and rescue experiments identified ARG-233 as an important residue required for GSR-dependent protection against erianin-induced redox stress and ICD. In syngeneic PDAC models, erianin-treated tumor cells elicited protective antitumor immunity in a tumor-challenge setting, while a therapeutic regimen combining erianin with anti-PD-1 antibody suppressed tumor growth and was associated with increased dendritic-cell activation and enhanced cytotoxic CD8⁺ T-cell infiltration. These findings define a GSR-associated redox-immune axis that links glutathione metabolism to immunogenic ER stress and provide a rationale for combining erianin with PD-1 blockade in immunologically cold PDAC.

In proliferative glioblastoma, a subset of tumor cells survives early temozolomide (TMZ) exposure and drives eventual-resistance, yet the underlying mechanism remains unclear. We found that MYC target activation was associated with attenuated TMZ survival benefit in CGGA cohorts. In patient-derived MYC-high glioma cells, TMZ increased apoptosis but left a larger residual viable population due to enhanced proliferation; we defined these surviving cells as pioneer resistant (P-R) cells, which exhibited reduced TMZ sensitivity and a competitive survival advantage. Mechanistically, P-R cells adopted a senescence-like state via two coordinated arms of chromatin remodeling. On one hand, H3K27ac-dependent super-enhancers were gained at senescence-associated secretory genes; the CBP/p300 inhibitor A485 reverted the senescence-like state and restored TMZ cytotoxicity; On another hand, chromatin closed, reducing MYC occupancy at cell-cycle genes despite unchanged MYC protein, and suppressed nascent transcription and m⁶A modification, accompanied by cell-cycle arrest in some P-R cells. Furthermore, time-course analysis revealed that chromatin closure at cell-cycle genes is likely a temporally ordered epigenetic remodeling process, initiated by DNA damage-associated G2/M arrest mediated by WEE1 activation, followed by γH2AX-mediated recruitment of SUV39H1, which deposits H3K9me3 at MYC-bound loci to close chromatin. Functionally, early, but not delayed, inhibition of WEE1 with the novel brain-penetrant inhibitor TSL2304 blocked senescence-like epigenetic reprogramming, synergized with TMZ in vitro, and significantly prolonged survival in an orthotopic glioblastoma model. Together, these findings reveal a temporally ordered epigenetic remodeling in MYC-high glioblastoma that promotes survival after early TMZ exposure, and identify early WEE1 inhibition as a strategy to synergize with TMZ.

Radiotherapy (RT) combined with PD-1/PD-L1 blockade can induce systemic antitumor responses, but robust control of distant lesions remains uncommon. We identified a quadruple regimen combining immunogenic hypofractionated RT (hRT; 8 Gy × 3) to the primary tumor, low-dose RT (LDRT; 3 Gy × 3) to the secondary tumor, anti-PD-1 (αPD-1), and fenofibrate (FFB), a clinically approved PPARα agonist, that enhanced antitumor efficacy in two bilateral tumor models. Only this regimen substantially improved secondary-tumor control, eradicating LDRT-treated secondary tumors in all mice in the immunologically cold C51 model and inducing prolonged control in the aggressive, αPD-1-poorly responsive B16-CD133 model. This effect required CD8⁺ T cells. Tumor-specific CD8⁺ TILs showed enhanced effector function, reduced exhaustion, increased mitochondrial fitness, and a shift toward mitochondrial fatty acid oxidation (FAO), with scRNA-seq supporting PPARα/FAO-associated remodeling, including upregulation of Cpt1a, encoding the FAO enzyme CPT1A, in effector-associated, proliferative, and clonally expanded subsets. Both antitumor efficacy and T-cell metabolic remodeling were reversed by the CPT1 inhibitor etomoxir. By contrast, LDRT impaired tumor-cell mitochondrial fitness, while FFB shifted tumor cells from FAO toward glycolytic reliance and induced only slight apoptosis. Consistently, in vivo data argued against direct LDRT-mediated tumor-cell debulking. The quadruple regimen increased vascular MECA-79 expression, while LDRT enhanced endothelial ICAM-1/VCAM-1 and tumor-cell CXCL9/CXCL10 expression in secondary tumors, consistent with local conditioning favoring T-cell recruitment. These findings highlight FFB as a clinically tractable metabolic modulator and link FFB-enhanced hRT/LDRT/αPD-1-induced systemic antitumor efficacy to metabolic reprogramming of tumor-specific CD8⁺ TILs and conditioning of the LDRT-treated tumor microenvironment.

Advanced-stage cholangiocarcinoma (CCA) frequently develops resistance to chemotherapy, highlighting an urgent unmet need for novel therapeutic strategies. Here, we analyzed 16 pairs of CCA and adjacent non-tumor tissues, and demonstrated that dysregulation of the cell cycle machinery is a hallmark of CCA, closely associated with chemoresistance and poor prognosis. Targeting aberrant cell cycle regulation therefore represents a promising approach to improve current treatment outcomes. We identify the CDC7 inhibitor XL413 as an effective agent capable of re-sensitizing gemcitabine-resistant tumors across multiple preclinical models of CCA. Mechanistic analyses, including transcriptomic profiling, reveal that combination therapy activates senescence-associated pathways, with therapeutic efficacy is mediated via a ROS-DNA damage-senescence cascade. Notably, synergistic induction of cellular senescence is observed in CCA cells upon co-treatment with a CDC7 inhibitor and gemcitabine. Collectively, these findings provide robust preclinical evidence supporting the combination of gemcitabine and CDC7 inhibitors as a viable therapeutic strategy to enhance the clinical management of CCA.

Tissue normalisation has emerged as an interesting therapeutic concept in oncology, aiming to correct the structural, metabolic, and immunological tissue abnormalities that enable tumour progression and treatment resistance. Rather than targeting cancer cells directly, this approach aims to re-establish homeostatic tissue architecture, immune surveillance, and metabolic balance. Interventions that target stromal components, such as cancer-associated fibroblasts (CAFs), immune cells, or stiffness of extracellular matrix (ECM), have been shown to shift tumour cells toward a less aggressive state, underscoring the plasticity of cancer cells and the importance of their interactions with the microenvironment. Extracellular vesicles (EVs) are increasingly recognised as both contributors to tissue dysfunction in tumours and promising tools for restoring tissue homeostasis. EVs circulate across most biofluids and can cross biological barriers to reach distant tissues. They naturally carry nucleic acids, including regulatory miRNAs, along with proteins, lipids, and metabolites that influence cell behaviour, making them attractive tools for tissue normalisation. Moreover, engineered EVs could be designed to deliver targeted "normalisation signals" and hold strong clinical potential as next-generation delivery systems. Here, we explore how EVs, whether native or engineered, can intervene in key tumour-driving processes, including senescence, fibrosis, inflammation, and immune evasion, to shift the microenvironment toward a normalised, less malignant state.

Tumor heterogeneity is a universal feature of cancer and may arise as early as precancer stages during lung adenocarcinoma evolution, yet the emergence of aggressive transcriptional programs remains incompletely understood. Here, we integrated spatial transcriptomics with single-cell RNA sequencing to characterize inter- and intratumoral heterogeneity across hyperplasia, adenoma, and invasive adenocarcinoma (IAC) in a genetically engineered mouse model (129S4/Sv Kras^LSL-G12D/+). Disease progression was accompanied by coordinated remodeling of epithelial, stromal, and immune compartments, along with dynamic changes in proliferation, immune response, and metabolic pathways. Notably, lesions of the same histological stage exhibited substantial transcriptional heterogeneity. By quantifying dedifferentiation states, we identified a subset of adenomas that had already diverged toward highly proliferative and metabolically active programs despite lacking invasive features. These lesions were further marked by early chromosome 6 amplification, whose corresponding human ortholog signature recapitulated aggressive proliferation-associated programs in early-stage human lung adenocarcinoma. Spatial analyses further revealed pronounced intratumoral heterogeneity within IAC, with tumor core regions showing increased proliferation and metabolism but reduced immune signaling compared to peripheral regions. In addition, immune checkpoint gene expression in T cells was transiently elevated at the hyperplasia stage, suggesting early immune modulation prior to overt malignancy. Together, these findings indicate that aggressive transcriptional divergence can emerge early during lung adenocarcinoma evolution and that spatial organization critically shapes tumor and immune programs before and after invasion.

Cancer-associated adipocytes (CAAs) are increasingly recognized as active and heterogeneous components of the tumor microenvironment. Initially defined as tumor-adjacent adipocytes characterized by lipid depletion, reduced expression of mature adipocyte markers, and inflammatory activation, CAAs are now understood to encompass a spectrum of context-dependent states. These states are shaped by anatomical location, preexisting adipocyte properties, tumor-derived signals, and therapeutic exposure. Through metabolic exchange, paracrine signaling, direct cell contact, extracellular-vesicle communication, and matrix remodeling, CAAs influence tumor-cell plasticity, metastatic colonization, immune dysfunction, stromal organization, and treatment response. In turn, signals from tumor, immune, and stromal cells continuously reshape adipocyte identity and function, placing CAAs within reciprocal multicellular networks. This review examines the evolving criteria used to identify CAAs, their lineage origins and plasticity, their spatial organization, and their interactions with tumor, immune, and stromal compartments. The contribution of CAAs to therapeutic adaptation is also discussed, together with potential intervention points involving CAA-derived outputs and the metabolic dependencies induced in recipient cells. Finally, major methodological challenges are considered. Adipocyte-resolved profiling, lineage tracing, spatial multiomics, lipid flux analysis, and physiologically relevant models will be needed to distinguish transient remodeling from stable state transitions and to identify context-specific therapeutic vulnerabilities.