Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous breast cancer subtype with limited therapeutic options. While the prevalence of overweight/obese (OW/OB) women continues to rise, the impact of obesity on molecular features of TNBC remains incompletely understood. We investigated clinicopathological and molecular data (including genomic, transcriptomic, proteomic and metabolomic profiling) using our largest original multi-omics database of TNBC (N = 465) for associations with patient body mass index (BMI). Multi-omics profiling revealed that OW/OB patients exhibited worse survival as well as elevated inflammation of tumor microenvironment, higher expression of immune checkpoints, and dysregulated lipid metabolism. Our in vivo experiments demonstrated that tumors in obese mice displayed faster growth rates, a higher proportion of PD-1+CD8+ T cells and enhanced responsiveness to anti-PD-1 treatment. In addition, we analyzed data from four independent clinical trials and discovered that OW/OB patients demonstrated higher pathological complete response rates and longer progression-free survival following anti-PD-1-based immunotherapy. In conclusion, our study systematically revealed that obesity is associated with coordinated immune-metabolic remodeling in TNBC, characterized by checkpoint enrichment and lipid dysregulation, which may help explain the enhanced anti-PD-1 responsiveness and should be taken into account in the field of precision medicine.
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with limited therapeutic options. Here, we identify long-chain acyl-CoA synthetase 5 (ACSL5) as a key oncogenic driver and prognostic biomarker in PDAC. Combined transcriptomic analysis of 51 PDAC samples and three public databases (GSE183795, GSE28735, GSE62452) reveals that ACSL5 is markedly upregulated in PDAC, and its overexpression is significantly associated with shorter patient survival and high diagnostic accuracy (AUC = 0.899), suggesting robust diagnostic potential. Functional assays demonstrate that ACSL5 promotes PDAC cell proliferation, migration, and tumor growth while inhibiting apoptosis. Mechanistically, ACSL5 activates the JAK1-STAT1 signaling pathway, leading to transcriptional upregulation of oligoadenylate synthetase-like protein (OASL). The ACSL5-OASL axis concurrently suppresses PINK1/Parkin-mediated mitophagy and enhances ferroptosis resistance by modulating GPX4, SLC7A11, and ACSL4 expression. Notably, the mitophagy activator CCCP effectively reverses ACSL5-driven tumor progression and restores ferroptosis sensitivity. Our findings establish ACSL5 as a promising diagnostic and therapeutic target and reveal that targeting mitophagy represents a potential strategy for ACSL5-high PDAC.
Osteosarcoma (OS) is an aggressive bone malignancy with poor outcomes in recurrent and metastatic disease. Although ferroptosis represents as a promising therapeutic strategy, its regulation in OS remains incompletely understood. Here, we identified STK25 as a regulator of ferroptosis susceptibility and tumor growth in OS. Transcriptomic analysis of paired parental and multidrug-resistant OS cell lines identified lower STK25 expression in the resistant derivatives. In a retrospective tissue microarray, low tumor STK25 expression was associated with a lower histological tumor necrosis rate after neoadjuvant chemotherapy and shorter survival. Mechanistically, METTL3 overexpression reduced STK25 reporter activity and accelerated STK25 mRNA decay in an m6A-site-dependent manner. STK25 depletion was accompanied by reduced Hippo pathway activity, increased YAP nuclear localization, and increased GPX4 expression, whereas STK25 restoration increased LATS1 and YAP phosphorylation, reduced GPX4 expression and sensitized OS cells to ferroptosis. GPX4 re-expression partially rescued cell viability and oxidative-stress phenotypes induced by STK25 overexpression, supporting GPX4 as a functional downstream effector. In xenografts, STK25 overexpression significantly suppressed tumor growth and increased ferroptosis-associated changes. These findings support an METTL3-STK25-YAP-GPX4 regulatory model that links epitranscriptomic control to ferroptosis susceptibility in OS and warrants further preclinical and prospective clinical validation.
Hepatobiliary cancers are highly heterogeneous malignant tumors, and the drug resistance frequently emerges at advanced stages. Patient-derived organoids (PDOs) are three-dimensional ex vivo cultures. They can reproduce essential biological aspects of primary tumors, and play a key role in personalized oncology. With advances in methodology and technology, PDOs are increasingly being used in hepatobiliary cancer research at both the fundamental and translational levels. This review summarizes recent advances in patient-derived organoids, including culture matrices, microenvironment reconstruction, and organoid-on-chips. We also discuss the applications of PDOs in hepatobiliary cancer modeling and organoid biobank construction. Hepatobiliary cancer organoids hold promise for drug development and may serve as complementary tools for preclinical prediction. Integrating in vitro drug testing, resistance mechanism identification and combination regimen screening, organoid-based workflows can provide platforms for treatment stratification and personalized treatment optimization in hepatobiliary cancers. The incorporation of artificial intelligence may further expand the capabilities of organoid-based platforms. Overall, hepatobiliary cancer organoids represent clinically promising models for overcoming therapeutic resistance and developing personalized treatment strategies. They are powerful tools for precision oncology and clinical translation.
Gastric cancer (GC) ranks as the fifth most common cancer worldwide, however, accurate and non-invasive diagnostic modalities for GC remain limited. Cell-free DNA (cfDNA) fragmentomics has emerged as a promising tool for cancer cell detection. Here we develop a gastric cancer detection model, named GaFraD model. The GaFraD model uses four cfDNA fragmentomics features, including fragment size ratio (FSR), copy number variation (CNV), 9-bp end motif (Motif), and fragment size at transcription start sites (TF). This model achieves an area under the receiver-operating characteristic curve (AUC) of 0.970 (95% CI: 0.944 - 0.990), a sensitivity of 95.0% and a specificity of 80.9%. By combining the GaFraD model and conventional protein biomarkers CA19-9 and PG-I/PG-II, the CONFIRM model was generated. The CONFIRM model attained an AUC of 0.986 (95% CI: 0.966 - 1.000), a sensitivity of 95.0% and a specificity of 95.6% in detecting GC. Moreover, the CONFIRM model achieved remarkable performance (AUC = 0.983, sensitivity 95.6%, specificity 94.2%) in distinguishing patients with early-stage GC from controls. Our work showed the high discriminatory power in distinguishing GC patients from controls, indicating the clinical potential of using cfDNA fragmentomics combined with protein biomarkers for non-invasive GC detection. The results of the study provide a new avenue for early, accurate, and non-invasive clinical diagnosis of GC.
KRASG12D-selective and pan-RAS inhibitors have shown promise in pancreatic ductal adenocarcinoma (PDAC), yet adaptive resistance is anticipated to limit durability of response. Exportin 1 (XPO1), a nuclear export protein frequently overexpressed in PDAC, represents a potential vulnerability in KRAS-mutant cancers. We evaluated whether pharmacologic inhibition of XPO1 enhances therapeutic efficacy and durability of KRAS pathway inhibition. KRASG12D inhibitor- and pan-RAS inhibitor-resistant PDAC cellular models were generated and assessed for sensitivity to the second-generation XPO1 inhibitor Eltanexor. Antiproliferative synergistic effects of Eltanexor combined with MRTX1133, Zoldonrasib (RMC9805), or Daraxonrasib (RMC6236) were evaluated in PDAC 2D cultures, 3D spheroids, patient-derived organoids, and tumor-fibroblast co-culture models. Eltanexor sensitized KRAS inhibitor-resistant PDAC cells and synergistically enhanced growth suppression across multiple KRASG12D-mutant models. Combination treatment reduced clonogenic survival, disrupted 3D spheroid integrity, and significantly inhibited viability of patient-derived organoids. The in vivo efficacy of the combination was tested in PDAC cell-derived xenograft/allograft and patient-derived xenograft models. Combining sub-therapeutic doses of Eltanexor with allele-specific inhibitors or pan-RASi resulted in significant tumor regression, prevention of metastatic spread and prolonged survival in vivo. Notably, Eltanexor maintenance therapy suppressed tumor regrowth following RAS inhibitor withdrawal and preserved responsiveness upon re-challenge. Mechanistically, molecular and phosphokinome profiling showed that the combination broadened suppression of MAPK- and mTOR-associated signaling and reduced activity of multiple oncogenic kinases. In conclusion, XPO1 inhibitor Eltanexor enhances the efficacy and durability of KRAS and pan-RAS inhibition in PDAC models. These findings provide a preclinical rationale for clinically evaluating Eltanexor in combination with RAS-targeted therapies to delay or overcome adaptive resistance in KRAS-mutant PDAC.
Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with a poor prognosis, highlighting the urgent need for novel diagnostic and therapeutic targets. In this study, through integrated proteomic profiling, we identify AP4M1 as a potential therapeutic vulnerability for HCC and characterize its upstream regulatory and downstream effector mechanisms. We show that AP4M1 is markedly upregulated in HCC, correlates with unfavorable prognosis, and is functionally involved in driving HCC progression. Mechanistically, the deubiquitinase USP15 stabilizes AP4M1 by removing K11- and K48-linked polyubiquitin chains at lysine 163 (K163). Additionally, MINK1-mediated phosphorylation of AP4M1 at threonine 69 (T69) is critical for its interaction with GPX4. Through upregulating GPX4, AP4M1 reduces intracellular lipid peroxidation, thereby suppressing ferroptosis and facilitating HCC tumorigenesis and progression. Importantly, combined treatment with the USP15 inhibitor USP15-IN-1 and the GPX4 inhibitor RSL3 exhibits potent anti-tumor efficacy in both in vitro and in vivo models, underscoring the therapeutic potential of targeting the AP4M1 axis in HCC. Collectively, this study delineates the USP15/AP4M1/MINK1/GPX4 axis as a previously unrecognized ferroptosis-suppressive pathway that promotes HCC progression, providing a critical theoretical basis for AP4M1-targeted therapeutic strategies in HCC.
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally, with many patients presenting with advanced disease that does not respond to standard treatments. While immune checkpoint inhibitors (ICIs) have improved outcomes, their effectiveness is limited in immunologically "cold" tumors, highlighting the urgent need to elucidate the complexity of the tumor immune microenvironment (TIME). Tertiary lymphoid structures (TLSs), ectopic and organized lymphoid aggregates that form at sites of chronic inflammation, have become key players in antitumor immunity. This review thoroughly covers the composition, multistage formation, and functional maturation of TLSs in HCC. We emphasize that the prognostic and predictive value of TLSs depends not only on their presence but also on their spatial localization, structural maturity, and specific immune cell composition. A high density of intratumoral TLSs (iTLSs), especially those with mature germinal centers containing B cells, T follicular helper (Tfh) cells, and dendritic cells (DCs), is strongly linked to better survival and lower recurrence rates. Additionally, TLSs serve as biomarkers for predicting favorable responses to ICIs in both neoadjuvant and adjuvant settings. We also explore how locoregional therapies and specific chemokine axes induce or modulate TLS formation. Finally, we discuss the emerging field of non-invasive TLS evaluation using radiomics and advanced imaging techniques, which promises to guide patient stratification for immunotherapy. TLSs therefore represent promising therapeutic targets with the potential to reprogram the immune milieu of HCC and enable more effective, personalized treatment approaches.
Neuroblastoma is a pediatric solid malignancy that primarily arises from poorly differentiated sympathoadrenal cells in the developing autonomic nervous system. The neuroblastoma genetic landscape is characterized by a paucity of somatic mutations and a far more common occurrence of chromosome copy number variations (CNVs). Two of the most common genetic abnormalities in neuroblastoma are the amplification of MYCN and the unbalanced gain of the long arm of chromosome 17 (17q+), both of which correlate with poor prognosis. Although mouse models exist for MYCN-driven neuroblastoma, no mouse models exist for 17q+. Thus, the mechanism by which 17q+ contributes to poor prognosis remains largely unknown. Here, we used a human pluripotent stem cell (PSC) model of neuroblastoma to show that 17q+ cooperates with MYCN amplification to accelerate tumorigenesis compared to MYCN amplification alone. We identified six genes on 17q that are upregulated in both our 17q+ PSC-derived tumors and 17q+ neuroblastoma patient tumors compared to WT 17q, correlate with poor prognosis in neuroblastoma patients, and are overexpressed at the protein level in our MYCN/17q+ tumors compared to MYCN alone. Of these six genes, knockdown of BIRC5, CDC6, IGF2BP1, or TK1 in MYCN/17q+ cells increases tumor latency in vivo and contributes to tumor progression through diverse mechanisms. Furthermore, knockdown of CDC6, IGF2BP1, and TK1 in neuroblastoma patient-derived xenografts with 17q+ slowed growth in vivo. Our findings provide new insights into potential candidate 17q drivers of neuroblastoma tumorigenesis and possible therapeutic vulnerabilities.
Tumor microenvironment (TME)-induced immunosuppression is a major driver of cancer treatment failure and resistance to immunotherapy. Myeloid-derived suppressor cells (MDSCs) are not only pivotal suppressors of effector immune responses but also central organizers of tumor-supportive metabolic, stromal, and cellular crosstalk. This review systematically summarizes the origin and phenotypic characteristics of MDSCs and the mechanisms governing their recruitment, expansion, and activation within the TME. This review integrates current knowledge of MDSC biology through two complementary frameworks. One framework highlights the bidirectional interactions between MDSCs and immune, tumor, stromal, endothelial, and adipocyte compartments. The other classifies therapeutic approaches according to their mechanisms and translational relevance, including combinations with immunotherapy. We further evaluate clinical translation, including lessons from unsuccessful or inconclusive trials, biomarker gaps, and rational combination strategies. Together, current evidence indicates that MDSCs represent context-dependent therapeutic nodes, while functional reprogramming, spatially resolved profiling, and patient stratification may improve immunotherapy outcomes.
Lineage plasticity has emerged as a central mechanism through which cancer cells adapt to therapeutic pressure, evade immune surveillance, and acquire aggressive phenotypes. Although recognized across tumor types, the regulatory principles governing how cancer cells reprogram cellular identity remain incompletely understood. In this review, we propose that lineage plasticity in cancer reflects the redeployment of regulatory frameworks established during normal development. Rather than representing a stochastic byproduct of genomic instability, cancer plasticity frequently unfolds within gene regulatory architectures that also govern cell fate specification, lineage commitment, and controlled state transitions during embryogenesis and tissue homeostasis. Developmental transcription factors, including members of the SOX family, FOXA1, ASCL1, NKX2-1, and epithelial-mesenchymal transition regulators, function as lineage gatekeepers during development but are repurposed in cancer to destabilize lineage commitment and enable phenotypic switching. Similarly, epigenetic regulators that guide developmental trajectories, including chromatin remodeling complexes, Polycomb group proteins, and DNA methylation machinery, are frequently dysregulated or redistributed in tumors, altering the repression of lineage-stabilizing and alternative lineage programs and thereby weakening epigenetic barriers to lineage transitions. Together, these observations support a model in which development and cancer operate as mirror regulatory systems: one establishing and stabilizing cellular identity, the other exploiting the same regulatory architecture to permit adaptive reprogramming under selective pressure. We further discuss how emerging single-cell and spatial multi-omics technologies, integrated with artificial intelligence-based modeling, enable mapping of cell state landscapes and transitional trajectories, transforming lineage plasticity from a descriptive phenomenon into a measurable and predictable property of tumor evolution.
Loss or lack tumor immunogenicity promotes immune escape and resistance to immunotherapy. Arginine methylation, a key protein post-translational modification, participates in tumor progression and therapy resistance. However, whether arginine methylation directly influences the tumor immunogenicity and thereby modulates antitumor immune responses remains poorly understood. Here, we report that protein arginine methyltransferase 3 (PRMT3) exhibited a significantly negative association with antitumor immune signatures and survival outcomes in multiple cancers. Tumor-intrinsic PRMT3 deletion markedly delays tumor growth by promoting CD8+ T cell infiltration and functional activation through the modulation of type I interferon (IFN) signaling. Mechanistically, PRMT3 catalyzes arginine asymmetric-dimethylation at the conserved Arg364 residue of cGAS, suppressing its capacity to activate the downstream STING signaling, which ultimately affects the tumor immunogenicity and overall antitumor immune responses. Combining PRMT3 deletion or pharmacological inhibition with anti-PD-1 antibody therapy achieved profoundly synergistic tumor control and elicited tumor-specific immunological memory. Collectively, our findings delineate a critical regulatory role of PRMT3 on tumor-intrinsic cGAS-mediated adaptive immunity, proposing immunogenicity-enhanced cancer treatment as a transformative strategy to achieve potentiated antitumor efficacy.
Leptomeningeal metastases are devastating complications of advanced HER2+ breast cancer, with limited therapeutic options. We developed a xenograft model of human HER2+ breast cancer cell line JIMT1-BR3-LM4 leptomeningeal colonization by four iterative cycles of intrathecal injection. The model reliably produced leptomeningeal lesions in brain and spinal cord and tumor cells in the CSF, as confirmed by endpoints of BLI, MRI, pathologic analysis and immunofluorescent staining. Upon RNA-seq, the LM model exhibited significant transcriptional changes as compared to the starting brain-tropic line. In a preclinical experiment, two doses of trastuzumab deruxtecan (T-DXd) were compared to human IgG, trastuzumab (T), nab-paclitaxel (nab-P) and T + nab-P for leptomeningeal metastasis. T-DXd demonstrated efficacy in terms of BLI imaging of the brain (P < 0.0001) and spine (P = 0.008), leptomeningeal lesion number and size in the brain (P = 0.06); efficacy was dose-dependent. T-DXd 10 mg/kg reduced leptomeningeal tumor Ki67 positivity (P = 0.0008) and increased apoptosis (P < 0.0001). In the brain, a comparison of leptomeningeal and parenchymal lesion number showed a reduction by T-DXd of 53% and 72%, respectively, compared to human IgG, with comparable effects on tumor proliferation and apoptosis. T-DXd also extended median survival to 38 days compared with 20 -24 days in control IgG or T + nab-P, with some mice surviving beyond 60 days (P = 0.003). These findings support ongoing clinical translation of T-DXd for HER2+ leptomeningeal metastasis and highlight the value of this model for future therapeutic development.
BACKGROUND:PBRM1 is an important subunit of the SWI/SNF complex, which broadly regulates gene transcription by chromatin remodeling. Genomic alterations of PBRM1 have been found in patients with pancreatic ductal adenocarcinoma (PDAC), but its molecular functions remain unclear. METHODS:Clinical relevance of PBRM1 was analyzed by using human PDAC samples and public genomic datasets. Mice with concomitant pancreas-specific Pbrm1 deletion in Kras-driven genetic PDAC models were generated. Single-cell transcriptomics were performed to determine tumor phenotype and microenvironment reprogramming. RESULTS:Reduction of PBRM1 expression was observed in human PDAC tissues and correlated with poor prognosis and metastasis. Pbrm1 loss promoted ductal metaplasia and delayed epithelial recovery in mice with caerulein-induced pancreatic injury. In PDAC model with either mutant Kras alone or in combination with Trp53 mutation, lack of Pbrm1 markedly accelerated tumor development and progression. Bulk transcriptomics and scRNA-seq identified reprogramming of both tumor compartment with mesenchymal phenotype acquisition and stroma compartment with inflammatory cancer-associated fibroblasts (iCAFs) transformation. Mechanistically, Pbrm1 deletion induced Zeb1 upregulation through epigenetic chromatin remodeling, thereby enhancing epithelial-mesenchymal and basal-like subtype transition. CONCLUSIONS:These findings indicated a tumor-suppressing role of PBRM1 in PDAC. PBRM1-deficient PDAC constitutes a specific subgroup of patients with aggressive phenotype and prognostic significance.
Cisplatin (CDDP) resistance represents a major determinant of poor prognosis in patients with oral squamous cell carcinoma (OSCC). While long non-coding RNAs (lncRNAs) are implicated in chemoresistance pathways, their mechanistic roles in OSCC treatment failure remain incompletely defined. This study identifies LINC00941 as a CDDP resistance-associated lncRNA, with elevated expression correlating significantly with adverse OSCC prognosis. Gain- and loss-of-function assays reveal that LINC00941 overexpression promotes both aerobic glycolysis and CDDP resistance in OSCC cells. Furthermore, elevated LINC00941 expression enhances pyruvate kinase activity, thereby fostering chemoresistance in vitro and in vivo. Mechanistic investigations reveal that LINC00941 physically interacts with pyruvate kinase M2 (PKM2), enhancing its protein stability by suppressing ubiquitin-mediated proteolysis. This stabilization amplifies glycolytic flux, ultimately inducing CDDP resistance in OSCC cells. Our findings elucidate a novel lncRNA-dependent pathway governing chemoresistance and propose targeting the LINC00941/PKM2/glycolysis axis as a translatable therapeutic strategy for overcoming CDDP resistance in OSCC.
Pancreatic ductal adenocarcinoma (PDAC) is often burdened by cachexia, a metabolic disorder characterized by extensive and severe adipose tissue wasting and muscle atrophy that shortens life expectancy. While adipose depletion frequently coincides with myopathy, the precise molecular mediators by which remodeled adipocytes drive muscle atrophy remain largely undefined. Here, we delineated a pathogenic ‘feed-forward’ axis wherein tumor-derived inflammatory stimuli (IL-6/TNF-α) drove adipocytes to secrete extracellular vesicles (EVs) enriched with miR-221-3p. Genetic tracing confirmed that these EVs circulated systemically and were actively taken up by skeletal muscle. At the molecular level, EV-delivered miR-221-3p repressed IRS1, leading to the collapse of the PI3K-AKT survival cascade. Consequently, this inhibition triggered severe metabolic dysregulation by coupling impaired GLUT4-dependent glucose transport with heightened ubiquitin-proteasome activity, ultimately culminating in muscle atrophy. Silencing miR-221-3p via AAV-sponges or antagomirs conferred significant protection against muscle wasting and functional decline in cachectic mice. Importantly, high levels of circulating EV-miR-221-3p not only marked the presence of cachexia but were also significantly associated with reduced overall survival in PDAC patients. Collectively, our findings uncover a pathogenic adipose-to-muscle axis mediated by EV-miR-221-3p, offering a novel therapeutic target and a promising non-invasive biomarker for PDAC-associated cachexia.
Mitochondria, central hubs of cellular metabolism, play a pivotal role in tumorigenesis and the regulation of cellular metabolic processes. Cancer cells frequently undergo metabolic reprogramming, characterized by enhanced glycolysis, dysregulated oxidative phosphorylation (OXPHOS), and rewired mitochondrial biogenesis to meet the high bioenergetic and biosynthetic demands of proliferation. In non-small cell lung cancer (NSCLC), these metabolic alterations are hallmark features, yet the upstream regulatory mechanisms governing mitochondrial function remain poorly defined. In this study, we report the novel finding that ubiquitin-specific protease 22 (USP22), a key regulator of protein ubiquitination and transcriptional activity, regulates mitochondrial protein expression and OXPHOS. We further demonstrate that USP22 directly binds to MYB-binding protein 1A (MYBBP1A), thereby modulating the expression of nuclear- and mitochondrial-encoded OXPHOS-related proteins, ultimately promoting mitochondrial biogenesis in cancer cells. To our knowledge, this work provides the first evidence linking USP22 to mitochondrial biogenesis in NSCLC. These findings offer valuable insights into the regulatory network governing mitochondrial metabolism in NSCLC and suggest new avenues for targeting metabolic vulnerabilities in molecular diagnosis and targeted therapies.
This guideline was developed under the auspices of the Pediatric Neurosurgery Group of the Neurosurgery Branch of the Chinese Medical Association, the Neuro-oncology Expert Committee of the Chinese Society of Clinical Oncology, and the Neuro-oncology Professional Committee of the China Anti-Cancer Association. Craniopharyngioma is the most common tumor in the sellar turcica region among children, with the majority being adamantinomatous craniopharyngioma (ACP) and a smaller proportion being papillary craniopharyngioma (PCP). Management of craniopharyngioma involves not only tumor control but also the treatment of tumor-related hypothalamic dysfunction and pituitary endocrine disorders. To standardize the diagnosis and management of pediatric craniopharyngioma, this guideline incorporates evidence from 398 literature references. It provides recommendations on diagnostic evaluation, surgical strategies, radiotherapy principles, prognostic assessment, follow-up and long-term management, and targeted therapy. This guideline is intended to serve as a reference for healthcare professionals engaged in pediatric neuro-oncology. Recommendations were developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, taking into account the quality of evidence, clinical applicability, and expert consensus. Key recommendations are supported by explanatory rationale. The guideline were reviewed and approved by 35 multidisciplinary experts and 6 external reviewers, followed by formal voting on each recommendation. For areas lacking high-quality evidences, future well-designed clinical trials are recommended to validate and update these recommendations.
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human malignancies, characterized by persistently poor survival rates and limited effective therapeutic options. Ferroptosis, an iron-dependent form of regulated cell death driven by uncontrolled lipid peroxidation, has recently emerged as a potentially targetable vulnerability in PDAC. In this Review, we synthesize current understanding of the core molecular mechanisms governing ferroptosis, including dysregulated iron metabolism, lipid peroxidation pathways, and failure of antioxidant defense systems. We further discuss the complex regulatory networks that shape ferroptosis sensitivity in PDAC, highlighting the contributions of endoplasmic reticulum stress, mitochondrial dysfunction, autophagy, and DNA damage-associated signaling pathways. Within the broader landscape of PDAC biology, ferroptosis exerts context-dependent and sometimes opposing effects, influencing both tumor initiation and the development of therapeutic resistance. Accordingly, PDAC cells engage diverse epigenetic, metabolic, and microenvironmental adaptations to evade ferroptotic cell death, thereby sustaining resistance to therapy. Finally, we review the rapidly expanding spectrum of ferroptosis-based therapeutic strategies, encompassing small-molecule inducers, natural products, and, in particular, advanced nanomedicine platforms designed to enhance intratumoral drug delivery, overcome stromal barriers, and enable coordinated induction of ferroptosis while remodeling the tumor microenvironment.
