Stem-like T cells are central to the efficacy of programmed cell death protein 1 (PD1) blockade, sustaining long-term immune responses by serving as a renewable reservoir for anti-tumor effector CD8+ T cells. However, th...Stem-like T cells are central to the efficacy of programmed cell death protein 1 (PD1) blockade, sustaining long-term immune responses by serving as a renewable reservoir for anti-tumor effector CD8+ T cells. However, the mechanisms governing their maintenance and regulation in cancer remain incompletely understood. Addressing this gap, Hor et al. combined high-dimensional 3D-imaging with immunological profiling to define the niche of stem-like T cells within tumor-draining lymph nodes in murine cancer models. Their study identifies a critical role for conventional type 1 dendritic cells (cDC1s) and the PD1 pathway in preserving high-affinity tumor-specific stem-like T cells. cDC1s deliver sustained T-cell receptor (TCR) stimulation together with PD-L1/2 co-inhibitory signals that support stemness, proliferation, and survival. Strikingly, disruption of PD1 signaling transiently enhances effector T cell expansion but promotes differentiation and apoptosis of stem-like T cells, ultimately depleting this essential pool. These findings reveal a potential long-term vulnerability of immune checkpoint blockade, particularly when tumors are not eradicated during the initial treatment response.
Over several decades, therapeutic advances have transformed oncology, yet for many tumour types, survival improvements have been incremental, with substantial treatment-related morbidity. A decisive pivot in oncology, fr...Over several decades, therapeutic advances have transformed oncology, yet for many tumour types, survival improvements have been incremental, with substantial treatment-related morbidity. A decisive pivot in oncology, from treating established malignancy to intercepting and preventing carcinogenesis, could deliver far greater population impact. Delivering this shift requires further mechanistic understanding of tumour initiation, validated biomarkers of premalignant progression and redesigned prevention trials in at-risk populations. Regulatory and commercial frameworks must evolve to enable scalable molecular prevention. Such trials must deliver tolerable side effect profiles and rely on biologically validated surrogate endpoints rather than traditional survival outcomes. Cancer interception should be established as a core pillar of oncological management, alongside early detection and the therapeutic management of established disease, together creating an opportunity to reduce global disease burden at a scale that decades of therapeutic progress in advanced cancer have yet to achieve.
Osteosarcoma is the most common malignant bone tumor, primarily affecting adolescents and young adults. Patients with metastases have a low survival rate, making the identification of prognostic markers crucial. The adap...Osteosarcoma is the most common malignant bone tumor, primarily affecting adolescents and young adults. Patients with metastases have a low survival rate, making the identification of prognostic markers crucial. The adaptor protein CIN85 is involved in various signaling pathways that regulate cell differentiation, adhesion, and motility. Its overexpression is associated with poor prognosis in multiple cancers. However, the role of CIN85 in osteosarcoma progression has not yet been explored. This study shows that CIN85 expression is higher in osteosarcoma than in normal bone tissue and further increased in metastatic lesions relative to primary tumors. CIN85 overexpression increases cell migration and Matrigel invasion, whereas silencing CIN85 suppresses these behaviors. Functional annotation and enrichment analyses of the CIN85-driven transcriptome suggest that CIN85 regulates migration, adhesion, and extracellular matrix organization in osteosarcoma. CIN85 affects MMP2 and COL3A1 gene expression and activates Akt/mTOR signaling. Knockdown of MMP2 and COL3A1 or pharmacological inhibion of Akt/mTOR signaling abrogates CIN85-induced motility. This study demonstrates that elevated CIN85 expression contributes to osteosarcoma migration and metastasis, highlighting its potential as a therapeutic target.
Metastasis remains the leading cause of cancer-related mortality. Even after major advances in early detection and systemic therapies, long-term disease recurrence frequently arises from the presence of dormant dissemina...Metastasis remains the leading cause of cancer-related mortality. Even after major advances in early detection and systemic therapies, long-term disease recurrence frequently arises from the presence of dormant disseminated tumor cells (DTCs) at distant sites. Dormant DTCs disseminate from the primary tumor and reside in secondary organs in a reversible quiescent state characterized by minimal proliferation, enabling resistance to therapies that target actively dividing cells. Despite their inactivity, dormant DTCs are far from inert. Dormant DTCs dynamically interact with the surrounding tumor microenvironment (TME), including stromal, vascular, and immune components, to establish niches that maintain quiescence while limiting immune detection. While the mechanisms by which proliferating cancer cells evade immune surveillance have been extensively studied, the processes governing immune regulation, immune-mediated dormancy, and immune evasion of dormant DTCs remain incompletely integrated across literature. In this review, we explore recent advances describing how microenvironmental cues and immune pressures converge on tumor cell-intrinsic programs to sustain dormancy, promote immune tolerance, and enable long-term survival of DTCs across different organs and cancer types. We further discuss conditions that disrupt this equilibrium and drive escape from dormancy, as well as emerging therapeutic strategies aimed at eliminating or controlling dormant DTCs by targeting dormancy-specific immune and microenvironmental interactions.
Irinotecan, a topoisomerase I (topoI) inhibitor, is widely used for colorectal cancer, but resistance remains a major clinical challenge. We previously showed that camptothecin induces ubiquitin-proteasome pathway (UPP)-...Irinotecan, a topoisomerase I (topoI) inhibitor, is widely used for colorectal cancer, but resistance remains a major clinical challenge. We previously showed that camptothecin induces ubiquitin-proteasome pathway (UPP)-mediated topoI degradation. In this study, we investigated whether inhibition of UPP could prevent topoI degradation and restore camptothecin sensitivity. SN-38, an active metabolite of irinotecan, induced topoI degradation in irinotecan-resistant colorectal cancer cell lines, which was suppressed by ixazomib. The combination significantly enhanced cytotoxicity, colony inhibition, and reduced IC values compared with SN-38 alone. Mechanistically, ixazomib prevented proteasome-mediated degradation of ubiquitinated topoI, restoring its stability. In vivo, the combination significantly suppressed tumor growth in a DLD-1 xenograft model compared with SN-38 alone. These findings indicate that UPP-dependent topoI degradation is a key mechanism underlying irinotecan resistance in colorectal cancer. Pharmacological inhibition of the proteasome effectively prevents topoI loss and restores irinotecan sensitivity, suggesting that proteasome inhibitors such as ixazomib may serve as promising therapeutic partners for camptothecin-based chemotherapy.
Long-lived and large-bodied organisms face an inherent challenge: The more cells they contain and the longer they live, the greater the cumulative risk of acquiring mutations that can drive cancer. Yet, paradoxically, ca...Long-lived and large-bodied organisms face an inherent challenge: The more cells they contain and the longer they live, the greater the cumulative risk of acquiring mutations that can drive cancer. Yet, paradoxically, cancer incidence does not always scale with size or lifespan-a phenomenon known as Peto's paradox. This observation implies that some species have evolved highly effective anticancer mechanisms that preserve cellular and tissue integrity over long lifespans. Whales, which combine extreme longevity with vast numbers of cells, exemplify this paradox. In this commentary, we discuss a recent study showing that a key contributor to bowhead whales' exceptional lifespan and cancer resistance is their superior genome maintenance capacity. We further discuss DNA repair as a determinant of longevity in other long-lived species and explore how these naturally occurring mechanisms could be harnessed to improve genome integrity, reduce cancer risk, and promote healthy aging in humans.
Cancer as the second leading cause of death in Europe poses an escalating challenge that needs urgent action. Translational cancer research should be the primary focus for addressing the increasing cancer burden in Europ...Cancer as the second leading cause of death in Europe poses an escalating challenge that needs urgent action. Translational cancer research should be the primary focus for addressing the increasing cancer burden in Europe and counteracting the present main strategy to convert cancer to a chronic disease. From a policy perspective, the translational cancer research continuum should be strengthened. The EU Mission on Cancer (MoC), alongside Europe's Beating Cancer Plan (EBCP), should be revisited to prioritize prevention, early detection, and improved treatment with a focus on increasing cure rates and enhancing patients' quality of life, especially for those with incurable disease. The MoC should be strengthened through long-term, sustainable funding of competitively selected Comprehensive Cancer Centers (CCCs) integrating cancer care, health care dependent prevention, research, and education across Europe to ensure stewardship by problem owners. This is critical to avoid the traditional, fragmented "short-term, project-based funding" structure of the European Commission's collaborative research, which relies on many small projects dispersed across varied institutional contexts. Articulation with frontier research in Europe, supported by the European Research Council (ERC), and with critical innovations, including those sponsored by the European Innovation Council (EIC), becomes paramount. The current goal to establish around 100 CCCs is highly commendable, with each CCC and related networks targeting between 3.5 and 4 million people, following adequate accreditation procedures. In addition, the political ownership of the MoC should ensure adequate coordination/integration with the EBCP, together with appropriate engagement and responsibility on the part of national and European authorities to address policy and implementation actions. In summary, our policy analysis recommends establishing a coherent cancer research continuum to drive therapeutic innovation and strengthen prevention.
The HCLS1-Binding Protein 3 (HS1BP3) interacts with the SH3 domain of cortactin (CTTN), a protein that contributes to a malignant phenotype in cancers. Here, we demonstrate that high expression of HS1BP3 is associated wi...The HCLS1-Binding Protein 3 (HS1BP3) interacts with the SH3 domain of cortactin (CTTN), a protein that contributes to a malignant phenotype in cancers. Here, we demonstrate that high expression of HS1BP3 is associated with reduced survival for gastric adenocarcinoma and triple negative breast carcinoma patients and that HS1BP3 is specifically upregulated in these cancers. We mapped the HS1BP3-cortactin interaction site to the third proline-rich region (PRR3.1) of HS1BP3 and show that this interaction is important for cancer cell proliferation, extracellular matrix degradation and secretion. HS1BP3 expression was found to correlate with expression of the invadopodia scaffold protein TKS5 and we show that the localisation of TKS5 inside multivesicular endosomes is increased in cells expressing an HS1BP3 PRR3.1 mutant. Overall, our results highlight the importance of the direct interaction between HS1BP3 and cortactin in cancer development by regulating cell proliferation, secretion and invasion, which may provide an explanation for the negative correlation between HS1BP3 levels and the survival of gastric adenocarcinoma and triple negative breast cancer patients.
T-cell acute lymphoblastic leukemia (T-ALL) originates from the malignant transformation of immature lymphoblasts committed to the T-cell lineage. Relapsed or refractory T-ALL patients show a dismal outcome with limited...T-cell acute lymphoblastic leukemia (T-ALL) originates from the malignant transformation of immature lymphoblasts committed to the T-cell lineage. Relapsed or refractory T-ALL patients show a dismal outcome with limited therapeutic options and cure rates below 10%. Accurate risk stratification is essential for optimizing first-line treatments and maximizing initial complete response rates. Minimal residual disease (MRD) assessment is the most relevant clinical parameter in T-ALL and a direct measure of treatment response, but it requires an initial treatment course that reduces the time for decision-making. Consequently, there is an urgent need to identify novel biomarkers that can predict the response to first-line treatments at diagnosis. By integrating clinical and transcriptomic data from diagnostic T-ALL samples, we found that high MRD patients show a specific transcriptional profile. Moreover, we identified a transcriptional signature characterized by the differential expression of HSH2D, LAT2, BCL2, MAST4, METRN, and PITPNM2 genes that is tightly associated with an increased MRD, which could improve the prediction of poor treatment response in T-ALL patients, especially during early treatment phases.
Breast cancer, the most frequently diagnosed cancer in women globally, is a heterogeneous disease with distinct subtypes requiring distinct therapeutic approaches. Regardless of molecular subtyping, breast cancer stem ce...Breast cancer, the most frequently diagnosed cancer in women globally, is a heterogeneous disease with distinct subtypes requiring distinct therapeutic approaches. Regardless of molecular subtyping, breast cancer stem cells significantly contribute to tumor heterogeneity, distant dissemination, and therapeutic resistance. The Hippo pathway is a key regulator of organogenesis and tissue development, and its deregulation is common in breast cancer and linked to cancer stem cell features across several cancer types. Dysfunctional pathway activity leads to the aberrant activation of Hippo downstream effectors, the Yes-associated protein (YAP) and its paralog transcriptional co-activator with PDZ-binding motif (TAZ), which promote epithelial-to-mesenchymal transition, growth factor-independent proliferation, and maintenance of the breast cancer stem cells' niche. This review summarizes the regulation of the Hippo pathway, emphasizing its significant role in coordinating stemness-related mechanisms in breast cancer. An overview of how the Hippo pathway fuels stemness in triple-negative breast cancer, the most aggressive BC subtype, is then provided. We also discuss how the activation of stem cell-like properties, driven by dysregulation of the Hippo pathway, contributes to the development of resistance to current therapies across the spectrum of breast cancer subtypes.
Early detection of cancer is essential for effective treatment. However, current prostate cancer screening methods lack sufficient sensitivity and specificity, leading to overdiagnosis and unnecessary treatment. There is...Early detection of cancer is essential for effective treatment. However, current prostate cancer screening methods lack sufficient sensitivity and specificity, leading to overdiagnosis and unnecessary treatment. There is also an unmet need to distinguish clinically significant from insignificant prostate cancer. To identify complementary biomarkers for improved screening and diagnosis, we performed transcriptional profiling of cancer-associated transcripts in circulating extracellular vesicles (EVs) isolated from peripheral blood of patients with suspected prostate cancer prior to biopsy and healthy donors. Expression data for 2549 mRNAs were obtained from 28 men. CAPN5 expression was significantly lower, whereas BIRC2, CASP3, CD63, FMO5, IRF6, PFDN1, PRDX6, PSMD2, RIT1, S100A2, THBS1, and XRCC2 were significantly elevated in EVs from patients with significant prostate cancer (n = 14) compared with cancer-free individuals and patients with insignificant disease (n = 14). Candidate biomarkers were subsequently evaluated by in silico validation using the The Cancer Genome Atlas (TCGA) prostate adenocarcinoma dataset and the GEO dataset GSE70768 containing benign and malignant prostate tissues. This analysis identified CASP3, XRCC2, and RIT1 transcripts in circulating EVs as promising biomarkers for the early detection of significant prostate cancer.
Cervical cancer is one of the leading causes of tumor-related deaths among women. Chemotherapy in cervical cancer is mainly based on cisplatin, but this drug has limited efficacy; therefore, alternative treatment options...Cervical cancer is one of the leading causes of tumor-related deaths among women. Chemotherapy in cervical cancer is mainly based on cisplatin, but this drug has limited efficacy; therefore, alternative treatment options are needed. Ferroptosis represents a novel form of cell death. In cervical epithelium, ferroptosis occurs in the early neoplastic stages of papillomavirus infection but shifts to evasion in carcinoma. Combination therapy has the potential to enhance cancer cell death and overcome resistance development. Herein we demonstrate that dimethyl fumarate (DMF), a Food and Drug Administration (FDA)-approved anti-inflammatory drug, induces ferroptosis in cervical cancer cells in a dose-dependent manner and inhibits growth in spheroid models. Cotreatment with DMF and cisplatin significantly decreases cell viability compared to either drug alone. Under DMF/cisplatin combination, cervical cancer cells underwent to glutathione depletion and p53 (re)activation, leading to cell death by both ferroptosis and apoptosis. We found a p53-mediated downregulation of the Solute Carrier Family 7 Member 11 (SLC7A11)/Cystine/Glutamate Transporter (xCT) expression and glutathione levels. Our results suggest that combined administration of DMF and cisplatin, by targeting the dependency of cervical cancer cells on glutathione and (re)activating p53, represents a promising anticancer therapeutic strategy.
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, with poor prognosis despite multimodal therapy. Chloride cotransporters NKCC1 and KCC2 are key regulators of intracellular chloride leve...Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, with poor prognosis despite multimodal therapy. Chloride cotransporters NKCC1 and KCC2 are key regulators of intracellular chloride levels and thereby determine whether GABA acts inhibitory or excitatory. In GBM, disrupted chloride homeostasis promotes proliferation, migration, and stem-like properties, but its clinical relevance is not fully understood. We analyzed NKCC1 and KCC2 expression in GBM samples, considering clinical parameters, such as age, gender, and MGMT promoter methylation. Statistical analyses included ROC-based cutoff determination, Kaplan-Meier survival analysis, and subgroup. Immunohistochemistry was performed to identify cell types expressing NKCC1. NKCC1 expression was significantly higher in older patients and emerged as a prognostic marker for recurrence-free survival, with lower levels correlating with delayed recurrence, although overall survival was unaffected. NKCC1 was expressed in stem-like, astrocytic, and neuronal progenitor cells, but not in mature neurons. These findings identify NKCC1 as a regulator of GBM progression and recurrence, linking chloride transporter imbalance to GABAergic signaling. Targeting NKCC1 and restoring chloride homeostasis may provide promising new treatment strategies.
Von Hippel-Lindau disease (vHL) predisposes to tumor development, mainly clear cell renal carcinoma and hemangioblastoma. The underlying cause is germline variants in the VHL gene, with tumorigenesis thought to require a...Von Hippel-Lindau disease (vHL) predisposes to tumor development, mainly clear cell renal carcinoma and hemangioblastoma. The underlying cause is germline variants in the VHL gene, with tumorigenesis thought to require additional somatic 'second-hit' events that most commonly include loss of 3p. However, the precise mechanisms of vHL-related tumor development remain incompletely understood. Genomic investigations of familial hemangioblastoma may help elucidate the early steps of tumorigenesis and contribute to improved disease prediction, biomarker discovery, and therapeutic strategies. We performed whole exome sequencing on 22 familial hemangioblastomas from 7 patients representing 5 unrelated families, and with 4 different causative VHL genotypes. The tumors exhibited low overall mutational burden but showed frequent loss of heterozygosity on chromosome 3 or 3p and single nucleotide variants in the VHL region. Variants were significantly enriched in genes associated with GABAergic and serotonergic neuronal cell types, as well as in pathways regulating cell cycle and neurogenesis. These findings suggest that, in addition to VHL loss, dysregulation of neuronal differentiation programs and cell cycle control may play important roles in hemangioblastoma tumorigenesis.
Treatment resistance has become a major challenge in cancer research, particularly for patients with advanced castration resistant prostate cancer (CRPC) where no curative therapies are available. Epigenetic alterations...Treatment resistance has become a major challenge in cancer research, particularly for patients with advanced castration resistant prostate cancer (CRPC) where no curative therapies are available. Epigenetic alterations play a significant role in cancer progression. In prostate cancer (PCa), where androgen receptor (AR) is the primary oncogenic driver, epigenetic coregulators, specifically lysine demethylases (KDMs), have previously been identified as factors that alter the transcriptome as cancer cells acquire resistance. KDM7A has been identified as a cancer-promoting factor in many cancers; however, its role in PCa remains largely unexplored. This study investigates the clinical relevance of KDM7A in comparison with the well-studied KDM1A in PCa. Using PCa cell line models, we confirm KDM7A as an AR coregulator. By exploiting commercially available pharmacological inhibitors, we demonstrate that in AR-positive CRPC cell lines, combinatory inhibition of KDM1A and KDM7A leads to a loss of AR and the AR-driven transcriptome, which in turn attenuates cancer-promoting cell phenotypes. These findings highlight the potential of combination-targeted therapies in tackling advanced prostate cancers.
Neutrophils are abundant innate immune cells with remarkable plasticity, capable of exerting both antitumour and protumour functions. Beyond their local roles in the tumour microenvironment, recent studies highlight tumo...Neutrophils are abundant innate immune cells with remarkable plasticity, capable of exerting both antitumour and protumour functions. Beyond their local roles in the tumour microenvironment, recent studies highlight tumour-induced granulopoiesis as a systemic process by which cancers rewire haematopoiesis to expand immature neutrophils with immunosuppressive and tumour-promoting activity. Sustained by tumour-derived cytokines, chemokines and alarmins, tumour-induced granulopoiesis activates developmental programmes such as STAT3-C/EBPβ and RORC1, driving persistent neutrophilia and systemic immune suppression. Here, we review neutrophil maturation and heterogeneity, their dual roles in tumour initiation and progression, and the emerging recognition of tumour-induced granulopoiesis as a critical axis of tumour-host interaction with clinical and therapeutic implications.
DNA double-strand breaks (DSBs) generated from collisions of DNA replication forks with cisplatin-induced interstrand crosslinks underpin cisplatin cytotoxicity. Yet, the impact of cell-cycle-dependent cisplatin-DNA addu...DNA double-strand breaks (DSBs) generated from collisions of DNA replication forks with cisplatin-induced interstrand crosslinks underpin cisplatin cytotoxicity. Yet, the impact of cell-cycle-dependent cisplatin-DNA adduct (CDA) formation on cell cycle progression and interactions with DNA replication remain incompletely characterized. Also, although cisplatin enhances tumor response to ionizing radiation (IR), the underpinning radiosensitizing mechanisms remain unresolved. Here, we close this void and analyze CDAs (GpG crosslinks) and DSB (γH2AX foci) induction and repair in a strictly cell-cycle-dependent manner. We report for the first time that CDAs form in a dose- and time-dependent manner in all cell cycle phases, whereas DSBs emerge only in S-phase. Repair of IR-induced DSBs remains largely unaffected by CDAs in G, S, and G phases, but is inhibited when S-phase-treated cells progressed to G. Radiosensitization occurs after prolonged cisplatin exposure, likely owing to G-phase accumulation and lesion evolution from S-phase, thus impairing repair of IR-induced DSBs. Cisplatin fails to radiosensitize quiescent (G) cells. In summary, CDA formation is similar across the cell cycle, but DSBs form only in S-phase. Whereas CDAs fail to interfere with repair of IR-induced DSBs, progression-dependent repair disruptions cause radiosensitization. Elucidation of the underpinning mechanisms may help to design improved cisplatin-radiation schedules for more efficacious therapies.
Genova E, Montrone M, Rangaswamy U
… +12 more, Diversi F, Schiavo I, Ferrarini D, Di Florio R, Longo I, Coscia M, Zamboni N, Demontis G, Veghini L, Corbo V, Sanges R, Heppenstall P
Neuronal innervation of the pancreas has historically been characterized using marker-based classification and physiological studies, but its transcriptomic landscape remains only partially explored. A detailed molecular...Neuronal innervation of the pancreas has historically been characterized using marker-based classification and physiological studies, but its transcriptomic landscape remains only partially explored. A detailed molecular profile of pancreatic sensory neurons could provide insights into their role in health and disease, particularly in pancreatic ductal adenocarcinoma (PDAC), where neural remodeling influences tumor progression and pain signaling. Wild-type and PDAC mice were injected with the retrotracer Fast Blue into pancreatic or cancerous tissue. Dorsal root ganglia were dissociated, and Fast Blue-positive sensory neurons were isolated, lysed, and analyzed using single-cell RNA sequencing. Data were validated using immunofluorescence, organoid cultures and qPCR. We performed transcriptomic profiling of sensory neurons innervating the pancreatic head and tail under normal and cancer conditions. Our analysis identified neurofilament-containing neurons as the predominant sensory subtype in both contexts, while non-peptidergic neurons were underrepresented in tumor-associated innervation. Differential gene expression analysis revealed a unique subset of genes upregulated in sensory neurons innervating pancreatic tumors, many linked to mitochondrial activity. Further validation also revealed the presence of transcripts transferred via extracellular vesicles (including the Pdx1-CreERT2 transgene from the KPC mouse model), suggesting a novel mechanism of tumor-neuron interaction. Our findings provide a detailed characterization of pancreatic and pancreatic ductal adenocarcinoma sensory innervation. We identified tumor-derived RNA within sensory neurons in the PDAC mouse model, suggesting an extracellular vesicle-mediated RNA transfer mechanism that may remodel sensory signaling and open new prospects for diagnostic and therapeutic innovation in PDAC. Impact statement Transcriptomic profiling of pancreatic sensory neurons reveals shifts in neuronal populations, tumor-specific mitochondrial gene upregulation, and potential extracellular vesicle-mediated transcript transfer. Circulating tumor transcripts in KPC mice provide a reference for pancreatic innervation, tumor-nerve interactions, and therapeutic targets.
Transforming growth factor-β (TGF-β) regulates epithelial homeostasis by inducing growth arrest and apoptosis during early carcinogenesis; however, these tumor-suppressive functions are frequently lost in advanced nonsma...Transforming growth factor-β (TGF-β) regulates epithelial homeostasis by inducing growth arrest and apoptosis during early carcinogenesis; however, these tumor-suppressive functions are frequently lost in advanced nonsmall cell lung cancer (NSCLC) despite intact signaling. We identify the transcription factor E2A as a critical mediator of resistance to TGF-β-induced apoptosis in mutant KRAS-driven NSCLC. TGF-β induces E2A expression in a SMAD3-dependent manner in NSCLC cells harboring mutant KRAS, but not in those with wild-type KRAS. Silencing E2A restores TGF-β-induced apoptosis in mutant KRAS cell lines without affecting epithelial-mesenchymal transition. E2A depletion promotes mitochondrial apoptosis through mitochondrial outer membrane permeabilization, caspase-3 activation, and regulation of BCL-2 family and inhibitor-of-apoptosis proteins. In contrast, wild-type KRAS NSCLC cells fail to upregulate E2A in response to TGF-β and remain resistant to apoptosis following E2A silencing. Knockdown of mutant KRAS abrogates the pro-apoptotic effects of E2A silencing, establishing KRAS dependency. E2A silencing enhances radiation-induced growth inhibition, likely through increased sensitivity to TGF-β signaling. E2A is overexpressed in lung adenocarcinoma and is significantly elevated in tumors harboring mutant KRAS. These findings identify E2A as a context-specific suppressor of TGF-β-mediated apoptosis and a potential therapeutic target in mutant KRAS NSCLC.