Cancer pathogenesis and therapy最新文献

{"title":"Investigating hypoxia-inducible factor signaling in cancer: Mechanisms, clinical implications, targeted therapeutic strategies, and resistance","authors":"Abdul Halim Shaikat ,&nbsp;S.M. Asadul Karim Azad ,&nbsp;Md Azizur Rahman Tamim ,&nbsp;Mohammed Sailim Ullah ,&nbsp;Mohammad Nurul Amin ,&nbsp;Mofazzal K. Sabbir ,&nbsp;Md Towhidul Islam Tarun ,&nbsp;Md Saqline Mostaq ,&nbsp;Shohana Sabrin ,&nbsp;Md Zihad Mahmud ,&nbsp;Md Ashiq Mahmud","doi":"10.1016/j.cpt.2025.07.003","DOIUrl":"10.1016/j.cpt.2025.07.003","url":null,"abstract":"<div><div>Hypoxia, a hallmark of the tumor microenvironment (TME), drives cancer progression through immune modulation, angiogenesis promotion, metabolic reprogramming, and uncontrolled cell proliferation. This review explores the diverse functions of hypoxia-inducible factor (HIF) signaling in cancer development and progression, providing a comprehensive overview of the molecular pathways. HIFs, particularly HIF-1α and HIF-2α, regulate several genes related to cancer hallmarks such as invasion, metabolic reprogramming, angiogenesis, and therapy resistance, thus mediating a significant portion of the hypoxic response. Hydroxylation of proline and asparagine residues in HIF-α subunits, which occurs in an oxygen-dependent manner, serves as a key regulatory mechanism for both their stability and transcriptional function. Notably, this complex interaction is regulated by multiple signaling pathways, including the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK), phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/Akt/mTOR), and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways. In cancer, HIF signaling affects several aspects of tumor cell biology that contribute to the cancerous characteristics, including angiogenesis induction through the upregulation of vascular endothelial growth factor (VEGF) expression, metabolic reprogramming through the enhancement of the Warburg effect, facilitation of cancer invasion and metastasis by driving epithelial-to-mesenchymal transition (EMT) and matrix remodeling patterns, and mediation of therapeutic resistance partly due to the effects on drug efflux pumps and DNA damage repair. Direct and indirect HIF inhibitors—including small molecules, peptidomimetics, antibodies, and proteolysis-targeting chimeras (PROTACs)—are under preclinical and clinical evaluation for their therapeutic efficacy. Preclinical and early clinical trials have demonstrated significant synergistic effects in inhibiting tumor development when HIF inhibition is combined with traditional therapies (chemotherapy or radiation) or immunotherapies, emphasizing major clinical implications and the potential for improving patient outcomes. Although challenges exist, particularly regarding drug resistance, further research to improve therapeutic efficacy and prolong survival for patients is warranted.</div></div>","PeriodicalId":93920,"journal":{"name":"Cancer pathogenesis and therapy","volume":"4 3","pages":"Pages 174-191"},"PeriodicalIF":2.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146161694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting immune checkpoint therapy: The role of manganese in tumor immunotherapy","authors":"Xingyao Lyu ,&nbsp;Bixia Li ,&nbsp;Zhijie Lin","doi":"10.1016/j.cpt.2025.10.001","DOIUrl":"10.1016/j.cpt.2025.10.001","url":null,"abstract":"<div><div>Cancer immunotherapy has emerged as a promising complement to traditional treatments such as radiotherapy and chemotherapy. Although conventional therapies remain central to cancer management, the potential of immunotherapy is increasingly recognized. Immune checkpoint therapy, a key strategy in tumor immunotherapy, has demonstrated significant efficacy against solid tumors. However, its clinical application is hindered by its limited response rate, necessitating efforts to optimize its effectiveness. Recent studies have highlighted the pivotal role of the cyclic GMP-AMP synthase (cGAS) - stimulator of interferon gene (STING) pathway in immune checkpoint therapy. Manganese (Mn), an essential trace element, regulates the activity of CD8⁺ T and NK cells by modulating the cGAS-STING pathway. Furthermore, the combination of Mn with anti-programmed cell death protein 1 therapy has demonstrated promising anti-tumor effects. Mn also influences immunogenic cell death (ICD), further augmenting its potential as an adjunct to tumor immunotherapy. Despite a growing body of research on the role of Mn in modulating the cGAS-STING pathway and inducing ICD, comprehensive reviews that synthesize these findings and explore the potential of Mn in enhancing immune checkpoint therapy are still lacking. This review aimed to fill this gap by examining the immune mechanisms by which Mn enhances immune checkpoint therapy and its overall impact on tumor immunotherapy.</div></div>","PeriodicalId":93920,"journal":{"name":"Cancer pathogenesis and therapy","volume":"4 3","pages":"Pages 165-173"},"PeriodicalIF":2.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146161692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"C-X-C chemokine receptor type 4 (CXCR4) antagonism in precision oncology: Clinical applications and future directions","authors":"Aswini Rajendran,&nbsp;Veronica Elumalai,&nbsp;Saranya Balasubramaniyam,&nbsp;Karthikeyan Elumalai","doi":"10.1016/j.cpt.2025.08.003","DOIUrl":"10.1016/j.cpt.2025.08.003","url":null,"abstract":"<div><div>Physiologically, the C-X-C chemokine receptor type 4 (CXCR4) signalling pathway regulates key aspects of tumor behavior (growth, metastasis, and immune evasion) and modulates immune system function. Anticancer researchers have identified peptide-based CXCR4 antagonists as promising candidates due to their high targeting specificity and favorable safety profiles. This review provides an analytical examination of CXCR4 antagonistic peptides,the selective Mavorixafor (X4P-001), an advanced, selective CXCR4 inhibitor. When Mavorixafor binds to the same location as C-X-C motif chemokine ligand 12 (CXCL12), it disrupts the CXCR4 protein receptor, stopping signals that help cancer grow and spread, as well as the formation of new blood vessels. Mavorixafor blocks cancer cell progression and metastatic growth in different tumor models while enhancing chemotherapy, radiotherapy, and immune checkpoint inhibitor efficacy. Antagonistic peptides AMD3100 (Plerixafor), LY2510924, and POL6326, as well as their therapeutic potential. Mavorixafor is a promising option for cancer treatments that combine different therapies because it stays attached to its target for a long time and can be taken by mouth. Clinical studies have demonstrated that Mavorixafor produces promising outcomes when combined with chemotherapy or immune checkpoint inhibitors during the treatment of both hematological malignancies and solid tumors. Mavorixafor is promising for cancer treatment because it works well with other therapies, such as immune checkpoint inhibitors and chemotherapy, as well as targeted therapies and radiation therapy. Future research on Mavorixafor will focus on two main areas: personalized medicine development, new delivery systems and their broad medical applications extending beyond oncology. As a potential CXCR4 antagonist, Mavorixafor shows promise as a transformative tool in cancer care because it regulates the tumor microenvironment (TME) while increasing the degree of therapeutic benefits.</div></div>","PeriodicalId":93920,"journal":{"name":"Cancer pathogenesis and therapy","volume":"4 3","pages":"Pages 208-218"},"PeriodicalIF":2.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146192905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring marine-derived compounds as potential anti-cancer agents: Mechanisms and therapeutic implications","authors":"Nagaraju Bandaru ,&nbsp;Yash Pramod Patil ,&nbsp;Sumit Dilip Ekghara ,&nbsp;Kunal Sharad patil ,&nbsp;Mohan Gandhi Bonthu","doi":"10.1016/j.cpt.2025.08.004","DOIUrl":"10.1016/j.cpt.2025.08.004","url":null,"abstract":"<div><div>Marine-derived compounds have emerged as a promising frontier in cancer research due to their remarkable structural diversity and broad-spectrum bioactivities. The marine environment, encompassing diverse organisms (e.g., sponges, algae, tunicates, mollusks, and marine microbes), is a prolific source of novel bioactive molecules with potent anti-cancer properties. Key classes of these compounds include alkaloids, polysaccharides, peptides, terpenoids, and polyketides, which exert anti-tumor effects through diverse mechanisms, including the induction of apoptosis, inhibition of angiogenesis, modulation of immune responses, interference with cell cycle progression, and targeting of critical signaling pathways involved in tumorigenesis and metastasis. Notably, marine-derived drugs such as trabectedin, eribulin, and plitidepsin have received regulatory approval for the treatment of various malignancies, demonstrating the translational potential of these natural compounds. Ongoing clinical and preclinical investigations are exploring a wide range of marine metabolites for their cytotoxic, anti-proliferative, and chemosensitizing properties. Advances in marine biotechnology, including genome mining, synthetic biology, and fermentation technologies, have significantly facilitated the discovery, sustainable production, and structural optimization of marine natural products. However, challenges such as low yield, structural complexity, limited water solubility, and poor bioavailability hinder their broader clinical application. The integration of novel drug delivery systems, such as nanoparticles, liposomes, and conjugates, offers a viable solution to overcome these limitations and improve pharmacokinetic profiles. This review provides a comprehensive overview of the mechanisms of action, therapeutic applications, and clinical development of marine-derived anti-cancer compounds. It also emphasizes the need for deeper insights into their molecular targets and the potential for synergistic use with existing chemotherapeutic agents. Future directions should focus on exploring untapped marine biodiversity, developing eco-friendly harvesting strategies, and developing innovative delivery platforms to fully harness the therapeutic promise of the marine pharmacopeia in oncology.</div></div>","PeriodicalId":93920,"journal":{"name":"Cancer pathogenesis and therapy","volume":"4 3","pages":"Pages 192-207"},"PeriodicalIF":2.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146161743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Survival outcomes associated with surgery, radiotherapy, and chemotherapy in metastatic vulvar cancer","authors":"Md Faiazul Haque Lamem,&nbsp;Muaj Ibne Sahid","doi":"10.1016/j.cpt.2025.06.001","DOIUrl":"10.1016/j.cpt.2025.06.001","url":null,"abstract":"","PeriodicalId":93920,"journal":{"name":"Cancer pathogenesis and therapy","volume":"4 2","pages":"Pages 162-164"},"PeriodicalIF":2.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146183872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Right atrial intimal sarcoma with liver metastasis: A case report and literature review","authors":"Jiaen You ,&nbsp;Zebing Liu ,&nbsp;Kang He","doi":"10.1016/j.cpt.2025.11.001","DOIUrl":"10.1016/j.cpt.2025.11.001","url":null,"abstract":"<div><div>Primary cardiac tumors are rare and often present diagnostic challenges due to their non-specific symptoms and imaging characteristics. In this report, we present a case of right atrial intimal sarcoma (IS) with liver metastasis. A 49-year-old woman presented to the emergency department with acute dyspnea, cyanosis, nausea, vomiting, and upper abdominal pain. Echocardiography revealed a large pericardial effusion and a mass in the right atrium. Contrast-enhanced computed tomography (CT) and positron emission tomography/CT (PET/CT) confirmed the presence of multiple nodules in the right atrium and hepatic masses, suggesting metastatic disease. Laboratory tests indicated liver dysfunction, with elevated carbohydrate antigen 125 (CA125) and normal alpha-fetoprotein (AFP) levels. These clinical features initially suggested a diagnosis of hepatocellular carcinoma with isolated cardiac metastasis. However, the final pathological examination and gene sequencing results were unexpected, leading to the diagnosis of right atrial IS with liver metastasis. The patient was managed conservatively and remained alive for 8 months at the time of manuscript submission.</div></div>","PeriodicalId":93920,"journal":{"name":"Cancer pathogenesis and therapy","volume":"4 2","pages":"Pages 158-161"},"PeriodicalIF":2.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146078480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduced cytomegalovirus reactivation and viremia without increasing GVHD after URD-PBSCT: A prospective study using targeted ATG dosing strategy","authors":"Sheng Chen ,&nbsp;Lu Wang ,&nbsp;Songhua Luan ,&nbsp;Haitao Wang ,&nbsp;Jishan Du ,&nbsp;Dongxue Ge ,&nbsp;Fei Li ,&nbsp;Yongli Wu ,&nbsp;Zhenyang Gu ,&nbsp;Liping Dou ,&nbsp;Daihong Liu","doi":"10.1016/j.cpt.2025.04.001","DOIUrl":"10.1016/j.cpt.2025.04.001","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Anti-thymocyte globulin (ATG) is widely used in allogeneic hematopoietic stem cell transplantation (allo-HCT) to prevent severe graft-versus-host disease (GVHD) and graft failure. Insufficient ATG exposure may reduce its effectiveness in GVHD prophylaxis, while excessive exposure can elevate the risk of viral reactivation, non-relapse mortality (NRM), and disease relapse. Based on monitoring ATG (Thymoglobulin, Sanofi, Lyon, France) concentrations, we developed an ATG-targeted dosing strategy and conducted a prospective, single-arm study on patients undergoing unrelated donor peripheral blood stem cell transplantation (URD-PBSCT) to evaluate its efficacy and safety.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We enrolled 30 patients with malignant hematological diseases who underwent URD-PBSCT between January 2020 and June 2023. All patients received an ATG-targeted dosing strategy, involving a 4-day administration of ATG: 1.5 mg/kg on day −5, 2.5 mg/kg on day −4, with dose adjustments on day −3 and day −2 to achieve an optimal area under the concentration–time curve (AUC) for active ATG. Engraftment, viral infections, acute and chronic GVHD, relapse, and survival outcomes were statistically analyzed. A historical cohort of 38 patients who underwent URD-PBSCT between December 2014 and December 2020 was used for comparison. Patients in the historical cohort received a fixed total dose of 10 mg/kg ATG from day −5 to day −2.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;All patients in the targeted dosing cohort achieved successful neutrophil and platelet engraftment with 100% donor chimerism. The cumulative incidence of cytomegalovirus (CMV) reactivation and persistent CMV viremia at 180 days post-transplantation was 30.0% and 16.7%, respectively. The cumulative incidences of Epstein–Barr virus (EBV) reactivation and persistent EBV viremia at 180 days were 46.7% and 23.3%, respectively. The cumulative incidences of grades II–IV and III–IV acute GVHD at 100 days were 49.4% and 9.3%, respectively. The 1-year cumulative incidence of relapse (CIR) was 10.0%, the 1-year NRM was 10.0%, the 1-year disease-free survival (DFS) was 80.0%, and the 1-year overall survival (OS) was 86.7%. Compared with the historical cohort, the targeted dosing cohort showed significantly lower the cumulative incidences of CMV reactivation (30.0% &lt;em&gt;vs.&lt;/em&gt; 78.9%, &lt;em&gt;P&lt;/em&gt; &lt; 0.001) and persistent CMV viremia (16.7% &lt;em&gt;vs.&lt;/em&gt; 42.1%, &lt;em&gt;P&lt;/em&gt; = 0.026) on day 180. However, no significant differences were observed in EBV reactivation (46.7% &lt;em&gt;vs.&lt;/em&gt; 68.4%, &lt;em&gt;P&lt;/em&gt; = 0.170) or persistent EBV viremia (23.3% &lt;em&gt;vs.&lt;/em&gt; 44.7%, &lt;em&gt;P&lt;/em&gt; = 0.075) on day 180. Similarly, there were no statistically significant differences in the cumulative incidences of grade II–IV (49.4% &lt;em&gt;vs.&lt;/em&gt; 50.3%, &lt;em&gt;P&lt;/em&gt; = 0.700) or grade III–IV (9.3% &lt;em&gt;vs.&lt;/em&gt; 18.8%, &lt;em&gt;P&lt;/em&gt; = 0.390) acute GVHD on day 100, or 1-year chronic GVHD (10.0% &lt;em&gt;vs.&lt;/em&gt; 13.2%, &lt;em&gt;P&lt;/em&gt;","PeriodicalId":93920,"journal":{"name":"Cancer pathogenesis and therapy","volume":"4 2","pages":"Pages 145-152"},"PeriodicalIF":2.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145978048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pan-cancer gene signature analysis of macrophage polarization and compound prediction for reprogramming tumor-associated macrophages toward M1-like macrophages","authors":"Xiaojing Liu ,&nbsp;Cheng Liu ,&nbsp;Yuting Jin ,&nbsp;Jing Xu ,&nbsp;Chunyan Xu ,&nbsp;Wei Zhu","doi":"10.1016/j.cpt.2025.05.002","DOIUrl":"10.1016/j.cpt.2025.05.002","url":null,"abstract":"<div><h3>Background</h3><div>Resting tumor-associated macrophages (TAMs) are stimulated by the tumor microenvironment and can be primarily polarized into two subtypes: M1-and M2-like. M1-like TAMs promote inflammation and eradicate tumor cells, whereas M2-like TAMs suppress inflammation and facilitate tumor development. However, the mechanisms underlying phenotypic switching in these macrophages remain unclear. Therefore, we aimed to characterize the gene expression profiles of M1-like and M2-like TAMs in pan cancers.</div></div><div><h3>Methods</h3><div>Three computational methods were used to estimate the infiltration score of TAMs in 9239 tumor samples across 31 solid cancer types, based on RNA sequencing databases. Tumor samples were divided into high- and low-score groups based on the median M1/M2 ratio. Furthermore, gene enrichment, protein interactions, and transcription factors were analyzed. Multiple pharmaco–omics profiles were used to identify potential drugs. Finally, binding between the compounds and drug targets was validated using molecular docking.</div></div><div><h3>Results</h3><div>Of the top 100 dysregulated genes in each cancer type, 70 and 82 genes with upregulated and downregulated expression, respectively, were consistently differentially expressed. We identified candidate drugs targeting protein phosphatase 2A (PP2A), a core protein. These included efaproxiral, hesperidin, ezetimibe, calcitriol, and linopirdine.</div></div><div><h3>Conclusions</h3><div>This study provides a pan-cancer characterization of the TAM polarization-related gene profile. Network pharmacology and molecular docking analyses revealed five promising therapeutic agents for TAM reprogramming. Thus, our findings provide valuable insights into the enhancement of immune responses to inhibit tumor immune escape and metastasis.</div></div>","PeriodicalId":93920,"journal":{"name":"Cancer pathogenesis and therapy","volume":"4 2","pages":"Pages 136-144"},"PeriodicalIF":2.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145927297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Can probiotic-rich yogurt help prevent colorectal cancer in humans?","authors":"Biplab Adhikari","doi":"10.1016/j.cpt.2025.06.002","DOIUrl":"10.1016/j.cpt.2025.06.002","url":null,"abstract":"","PeriodicalId":93920,"journal":{"name":"Cancer pathogenesis and therapy","volume":"4 2","pages":"Pages 153-157"},"PeriodicalIF":2.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146023199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mevalonate pathway in pancreatic ductal adenocarcinoma: Mechanisms driving metabolic and cellular plasticity","authors":"Jenna N. Duttenhefner,&nbsp;Katie M. Reindl","doi":"10.1016/j.cpt.2025.06.004","DOIUrl":"10.1016/j.cpt.2025.06.004","url":null,"abstract":"<div><div>The mevalonate pathway plays a crucial role in the metabolic reprogramming of pancreatic ductal adenocarcinoma (PDAC), driving lipid biosynthesis, redox homeostasis, and oncogenic signaling, thereby sustaining tumor progression and therapeutic resistance. Its integration with Kirsten rat sarcoma viral oncogene homolog (<em>KRAS</em>)-driven signaling networks establishes it as a cornerstone of PDAC biology and a promising therapeutic target. The products of the pathway (sterols and isoprenoids) support key processes such as membrane biogenesis, protein prenylation, and immune evasion, facilitating tumor adaptation to the harsh microenvironment. Despite extensive research, therapeutic resistance and metabolic plasticity present considerable challenges in targeting this pathway. This review synthesizes current knowledge regarding the biochemical regulation of the mevalonate pathway in PDAC, its crosstalk with key oncogenic signaling networks, and emerging therapeutic strategies. In addition, we highlight critical knowledge gaps, including the complex regulatory crosstalk of the pathway with oncogenes, tumor suppressors, and nutrient-sensing pathways, and the mechanisms by which metabolic rewiring modulates tumor–immune interactions and therapy resistance. By integrating insights from pre-clinical and clinical studies, we highlighted promising novel combination therapies, including statins, bisphosphonates, and sterol regulatory element-binding protein (SREBP) inhibitors, as well as the potential for precision medicine approaches targeting mevalonate pathway vulnerabilities. Addressing these challenges may provide new avenues for improving therapeutic outcomes in PDAC.</div></div>","PeriodicalId":93920,"journal":{"name":"Cancer pathogenesis and therapy","volume":"4 2","pages":"Pages 110-123"},"PeriodicalIF":2.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145885693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}