Cancer research最新文献

{"title":"PI3K Regulates Wild-type RAS Signaling to Confer Resistance to KRAS Inhibition.","authors":"Xiangyu Ge, Jaffarguriqbal Singh, Wenxue Li, Cassandra S Markham, Christian Felipe Ruiz, Edward C Stites, Moitrayee Bhattacharyya, Yansheng Liu, Mandar Deepak Muzumdar","doi":"10.1158/0008-5472.CAN-25-3625","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-25-3625","url":null,"abstract":"<p><p>Despite the availability of RAS inhibitors and the dependence of >90% of pancreatic ductal adenocarcinomas (PDAC) on oncogenic KRAS mutations, resistance to KRAS inhibition remains a serious obstacle. We showed here that PI3K plays a major role in this resistance through upstream activation of wild-type RAS signaling - beyond its known KRAS effector function. The combination of proximity labeling, CRISPR screening, live-cell imaging, and functional assays revealed that PI3K orchestrates phosphoinositide-mediated GAB1 recruitment to the plasma membrane, nucleating assembly of RAS signaling complexes that activate MAPK in an EGFR/SHP2/SOS1-dependent manner. Inhibiting PI3K enhanced sensitivity to mutant-specific KRAS inhibitors in PDAC cells, including in cells with clinically identified PIK3CA mutations. These findings refine RAS-PI3K signaling paradigms, reveal that PI3K-driven wild-type RAS activation drives resistance to KRAS inhibition, and illuminate avenues for augmenting KRAS-targeted therapies in PDAC.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Arginine Deprivation of ASS1-Deficient Cancers Drives Mistranslation and Shared Neoepitope Production.","authors":"Remco Nagel, Adva Kochavi, Karine Flem-Karlsen, Mrittika Adhikary, Yali Gal-On, Maria G Klaoudatou, Julien Champagne, Lorenzo Valcanover, Heyilimu Palashati, Morten M Nielsen, Xiaodong Feng, Pierre-Rene Körner, Lisanne Giebel, Weiwen Yang, Arno Velds, Liesbeth Hoekman, Onno B Bleijerveld, Olaf van Tellingen, Johanna Olweus, Reuven Agami","doi":"10.1158/0008-5472.CAN-25-4773","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-25-4773","url":null,"abstract":"<p><p>Arginine biosynthesis is frequently suppressed in cancer due to loss of ASS1 expression, rendering cancer cells reliant on extracellular arginine. This feature has driven the development of systemic arginine-depleting strategies, which are clinically safe but offer limited clinical benefit. Here, we demonstrated that under arginine scarcity, cancer cells with low ASS1 expression resort to aberrant mRNA translation, characterized by ribosomal frameshifts and amino acid misincorporations. While aberrant proteins originated from most arginine codons, the predominant effect was observed at AGA. This codon preference was caused by a selective decrease in tRNAArg(UCU) levels following arginine deprivation, linked to METTL1-mediated tRNA modification. Proteomics and immunopeptidomics analyses validated that arginine shortage induced aberrant protein production at the endogenous level. T cell receptor (TCR) T cells that specifically recognize these HLA-presented mistranslated peptides efficiently killed cancer cells after arginine deprivation. These results lay the foundation for improved cancer therapies by combining systemic arginine-depleting strategies with TCR-based targeting of non-classical neoantigens.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting DOT1L Reactivates HERV-K to Drive Cell Autonomous and Paracrine Senescence in Adenocarcinoma of the Esophagogastric Junction.","authors":"Huolun Feng, Fa Ling, Zhihui Xi, Renjie Li, Xi Lv, Jieqing Guo, Liping Su, Jianlong Zhou, Jiabin Zheng, Fan Xing, Yong Li","doi":"10.1158/0008-5472.CAN-25-2437","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-25-2437","url":null,"abstract":"<p><p>Emerging evidence implicates human endogenous retroviruses (HERVs) in cellular senescence and stemness suppression, suggesting that they may also play a role in tumor cell senescence. In this study, we identified the histone methyltransferase DOT1L as a key epigenetic repressor of HERV-K in adenocarcinoma of the esophagogastric junction (AEG). Comparison of expression of HERV and epigenetic regulators in AEG using two independent datasets revealed an inverse correlation between DOT1L and HERVs, and DOT1L was also overexpressed in AEG and correlated with poor clinical prognosis. Pharmacological inhibition of DOT1L in vitro and in vivo diminished H3K79 methylation, reactivated HERV-K expression, and triggered STING-dependent innate immune signaling, thereby inducing tumor cell senescence and conferring potent antitumor effects. By promoting the assembly and secretion of HERV-K-derived retrovirus-like particles (RVLPs), DOT1L inhibition propagated senescence to neighboring tumor cells via STING pathway activation. Together, this study not only establishes DOT1L as a druggable epigenetic target in AEG but also proposes a therapeutic strategy that leverages HERV-K and RVLPs to drive tumor cell senescence and intercellular senescence transmission for antitumor therapy.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CellFuse enables Multi-modal Integration of Single-cell and Spatial Proteomics Data for Systems-level Analysis in Cancer.","authors":"Abhishek Koladiya, Zinaida Good, Sricharan Reddy Varra, Pablo Domizi, Sean C Bendall, Kara L Davis","doi":"10.1158/0008-5472.CAN-25-3699","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-25-3699","url":null,"abstract":"<p><p>Analysis of tumors using single-cell and spatial modalities is critical to advance our understanding of cancer. The growth of technologies that enable these studies provides an increasing number of single cell datasets. Integrating such data across studies will increase the impact of individual studies and speed cancer research. Most existing integration approaches are tailored to transcriptomic data and assume large sets of shared features, an assumption that fails for lower-dimensional proteomic measurements. Here, we developed CellFuse, a deep learning-based integration framework that unifies antibody-based proteomic datasets including high-dimensional cytometry, CITE-seq, and spatial proteomics data. Leveraging supervised contrastive learning, CellFuse learned a shared embedding space that enabled accurate cross-modality cell type prediction and robust label transfer across tumor samples and experimental conditions. Applied to datasets spanning peripheral blood, bone marrow, and lymphoma, CellFuse consistently outperformed existing approaches in recovering clinically relevant populations, including rare malignant and immune subsets. In solid tumors, it reconstructed spatially resolved microenvironments, capturing interactions between malignant, stromal, and immune cells that correlated with treatment response. By enabling scalable, modality-agnostic integration, CellFuse provides a powerful tool to uncover prognostic cell states and delineate the architecture of the tumor-immune ecosystem with translational relevance, driving cancer discoveries.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer-Associated Fibroblasts Promote Epithelial-Mesenchymal Transition and Classical to Basal Subtype Shift in Pancreatic Cancer.","authors":"Kylie Belanger, Samantha Guinn, Brayan Perez, Yeonju Cho, Joseph A Tandurella, Mili Ramani, Jae W Lee, Daniel J Zabransky, Emma Kartalia, Jignasha Patel, Haley Zlomke, Norman G Nicolson, Nicole E Gross, Sarah M Shin, Benjamin C Barrett, Samantha Sun, Nicholas Sun, Ethan Firth, Alexei G Hernandez, Erin M Coyne, Courtney D Cannon, Eunji Moon, Soren Charmsaz, Ludmila Danilova, James M Leatherman, Melissa R Lyman, Jacob T Mitchell, Lei Zheng, Michael G Goggins, Kelly J Lafaro, Jin He, Christopher R Shubert, William R Burns, Elana J Fertig, Luciane T Kagohara, Elizabeth M Jaffee, Richard A Burkhart, Won Jin Ho, Jacquelyn W Zimmerman","doi":"10.1158/0008-5472.CAN-25-0331","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-25-0331","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) carries an extremely poor prognosis, in part resulting from cellular heterogeneity that supports overall tumorigenicity. Cancer-associated fibroblasts (CAF) are key determinants of PDAC biology and response to systemic therapy, and multiple CAF subtypes have been defined. However, defining the effects of patient-specific CAF heterogeneity and plasticity on tumor cell behavior is required to better characterize the role of CAFs in PDAC. Here, we used multi-omic analyses to characterize the tumor microenvironment (TME) in tumors from patients undergoing curative-intent surgery for PDAC. In these same patients, matched tumor organoid and CAF lines were established to functionally validate the impact of CAFs on the tumor cells. CAFs promoted epithelial-mesenchymal transition (EMT) and a switch in tumor cell classification from classical to basal subtype. Furthermore, CAF-specific interleukin 8 (IL-8) functioned as a modulator of tumor cell subtype. Finally, neighborhood relationships between tumor cells and T cell subsets were defined, demonstrating a distinct spatial coordination among CAF and tumor cell subtypes. Overall, this study provides data supporting CAF signaling as a regulator of the cellular and behavioral heterogeneity in the PDAC TME. These findings can be used to explore rational approaches to improve therapies for this difficult-to-treat disease.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Farnesyl Transferase Inhibitor Darlifarnib (KO-2806) Resensitizes Relapsing Tumors to RAS Inhibition.","authors":"Hetika Vora Patel, Alison Elizabeth Smith, Stacia Chan, Jovylyn Gatchalian Gasendo, Ayuna Jombik, John Edward Greer, Tejas Samantaray, Linda Kessler, Amitava Mitra, Xuefeng Zhu, Yahu A Liu, Francis Burrows, Shivani Malik","doi":"10.1158/0008-5472.CAN-25-2764","DOIUrl":"10.1158/0008-5472.CAN-25-2764","url":null,"abstract":"<p><p>Resistance remains a key issue limiting the clinical benefit from RAS-targeting therapeutic agents and necessitates combination approaches. In this study, we identified persistent mTORC1 activity in preclinical KRAS-mutant non-small cell lung cancer (NSCLC) and colorectal cancer models as a frequent, nongenetic driver of inherent and adaptive resistance to RAS inhibition. This vulnerability was targetable with the farnesyl transferase inhibitor darlifarnib (KO-2806), which blocks mTORC1 activation via RHEB while sparing mTORC2 to limit associated toxicities. The addition of KO-2806 to NSCLC or colorectal cancer tumors progressing on mutant-selective RAS inhibitors led to rapid and durable tumor regression. In contrast, switching from mutant-selective to pan-RAS inhibitor monotherapy resulted in only stasis of NSCLC tumors and had no effect on colorectal cancer tumor progression. Furthermore, the addition of KO-2806 rescued sensitivity of progressing tumors to the pan-RAS inhibitor RMC-6236. These results establish mTORC1 as an important mediator of escape from RAS inhibition and highlight KO-2806 as a promising RAS companion inhibitor in patients with prior RAS inhibitor exposure.</p><p><strong>Significance: </strong>KO-2806 salvages RAS inhibitor activity by controlling parallel mTORC1 in RAS inhibitor-resistant tumors in which vertical inhibition of MAPK is insufficient to restore sensitivity, providing a combination strategy for resistant patients.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"2273-2285"},"PeriodicalIF":16.6,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146141170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SAICAR Drives T Regulatory Cell Differentiation and FOXP3 Maintenance to Promote Immunotherapy Resistance.","authors":"Mao Li, Yaqi Chen, Anyi Liu, Qi Wu, Changsheng Huang, Da Song, Fuqing Hu, Jingqin Lan, Chen Huang, Junbo Hu, Guihua Wang","doi":"10.1158/0008-5472.CAN-25-4373","DOIUrl":"10.1158/0008-5472.CAN-25-4373","url":null,"abstract":"<p><p>Regulatory T (Treg) cells within the tumor microenvironment critically undermine the efficacy of PD-1 immune checkpoint blockade. Metabolic reprogramming has emerged as a critical determinant of antitumor immunity, highlighting the need to define the metabolic cues that program Treg differentiation in cancer. In this study, we identified the purine biosynthesis intermediate succinylaminoimidazole carboxamide ribose-5'-phosphate (SAICAR) as a key metabolic driver of Treg induction and resistance to anti-PD-1 immunotherapy. Mechanistically, SAICAR directly bound to the serine/threonine phosphatase PPM1A, inhibiting SMAD3 dephosphorylation and thereby sustaining TGFβ-SMAD3 signaling. Persistent SMAD3 activation enhanced FOXP3 transcription and stabilized the Treg lineage. In both human tumors and mouse models, elevated intratumoral SAICAR levels were associated with increased Treg accumulation, suppression of effector T-cell function, and failure of PD-1 blockade. Genetic or pharmacologic reduction of SAICAR restored antitumor immunity and sensitized tumors to PD-1 therapy. Notably, low-dose 6-mercaptopurine disrupted SAICAR-driven immunosuppression and synergized with anti-PD-1 treatment without inducing systemic immune toxicity. Together, these findings establish SAICAR as an immunometabolic regulator that links purine metabolism to immune evasion and highlight a therapeutically actionable pathway to overcome metabolite-driven resistance to immune checkpoint blockade.</p><p><strong>Significance: </strong>SAICAR is necessary and sufficient to drive Treg-mediated immunosuppression in the tumor microenvironment, linking tumor metabolism and immunosuppression and providing mechanistic insights for metabolism-guided combination immunotherapy.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"2218-2236"},"PeriodicalIF":16.6,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146164252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FOSL1 Orchestrates Epigenetic Reprogramming of Anaplastic Thyroid Cancer and Suppresses NK Cell-Mediated Antitumor Immunity.","authors":"Yanfei Huo, Yizhou Huang, Xinyuan Yu, Linyu Han, Long Zhang, Linying Huang, Yanting Yang, Nasha Zhang, Ming Yang","doi":"10.1158/0008-5472.CAN-25-2781","DOIUrl":"10.1158/0008-5472.CAN-25-2781","url":null,"abstract":"<p><p>Anaplastic thyroid cancer (ATC) is the most aggressive type of thyroid cancer with survival time of only 7 to 10 months. Previous work revealed reduced proportions and cytotoxicity of NK cells in the ATC tumor microenvironment (TME). In this study, we investigated the role of super-enhancers (SE), clusters of adjacent enhancers that drive high expression of genes, in reshaping the TME in ATC. Comprehensive profiling of the SE landscapes in ATC revealed the activation of oncogenic SEs as a mechanism underlying the dedifferentiation and anaplastic transformation of thyroid cancer. An SE signature based on recurrent SEs in ATC was associated with significantly shortened overall patient survival. FOSL1 was identified as an SE-driven transcriptional factor that was crucial for epigenetic remodeling of ATC cells. Interestingly, FOSL1 bound to its own SE, promoted chromatin looping and spatial proximity of the distal SE with its promoter, and maintained its high expression, forming a positive feedback self-regulation circuit. During ATC progression, FOSL1 boosted the expression of metalloproteinases ADAM9 and MMP14 via binding to their SEs, which promoted MICA shedding from the cell surface and led to subsequent immune escape from NK-cell killing. Silencing FOSL1, ADAM9, or MMP9 sensitized ATC cells to NK cell-mediated cytotoxicity in vitro and suppressed ATC growth in vivo. Together, these findings highlight the role of FOSL1 in chromatin remodeling of ATC and in dampening cytotoxic functions of NK cells, thereby providing insights into the development of potential cancer therapeutics.</p><p><strong>Significance: </strong>Profiling oncogenic super-enhancers underlying dedifferentiation and anaplastic transformation of thyroid cancer reveals FOSL1 as a driver of epigenetic remodeling and immune escape, highlighting the potential of targeting FOSL1 in anaplastic thyroid cancer.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"2184-2201"},"PeriodicalIF":16.6,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146050461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell and Nuclear Size Is Associated with Chromosomal Instability and Tumorigenicity in Cancer Cells That Undergo Whole Genome Doubling.","authors":"Mathew Bloomfield, Sydney M Huth, Daniella S McCausland, Ron Saad, Nazia Bano, Tran N Chau, Megan L Sweet, Nicolaas C Baudoin, Andrew McCaffrey, Kai Fluet, Eva M Schmelz, Uri Ben-David, Daniela Cimini","doi":"10.1158/0008-5472.CAN-24-3718","DOIUrl":"10.1158/0008-5472.CAN-24-3718","url":null,"abstract":"<p><p>Whole genome doubling (WGD) is a frequent event in cancer evolution associated with chromosomal instability, metastasis, and poor prognosis. Whereas the genomic consequences of WGD are well documented, nongenetic alterations that accompany WGD, such as changes to cell and nuclear size, may also play an important role in tetraploid (4N) cancer cell physiology. In this study, we showed that cell and nuclear volume does not always scale with DNA content after WGD in cancer cells, resulting in 4N cells that differ in size. Small size was associated with enhanced cell fitness, mitotic fidelity, and tumorigenicity in 4N cancer cells and with poor patient survival in WGD-positive human cancers. Overall, these results suggest that cell and nuclear size may contribute to the tumorigenic potential of 4N cancer cells and could be an important prognostic marker in human tumors that undergo WGD.</p><p><strong>Significance: </strong>Cancer cell size varies after whole genome duplication, with smaller cells exhibiting high tumorigenicity and correlating with poor patient survival, demonstrating the clinical relevance and highlighting the biomarker potential of cell size.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"2126-2142"},"PeriodicalIF":16.6,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"VGF-Mediated Mitochondrial Remodeling Fuels Lung Adenocarcinoma Brain Metastasis.","authors":"Yibei Wang, Xinyue Sheng, Yi Yang, Chen Liu, Shubao Wang, Ruixi Guo, Yue Gu, Ming Chen, Hongyan Zhang, Jingjing Du, Xiaoxue Qin, Ziwei Miao, Pengfei Wu, Xiujuan Qu, Bo Li","doi":"10.1158/0008-5472.CAN-25-2712","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-25-2712","url":null,"abstract":"<p><p>Lung adenocarcinoma cells exhibit a marked propensity for brain metastasis, in which they face unique metabolic challenges imposed by the microenvironment. The mechanisms that enable lung adenocarcinoma cells to adapt to these constraints represent potential therapeutic targets. In this study, we identified the neuropeptide VGF as a clinically relevant driver of brain metastatic progression. VGF expression was markedly upregulated in lung adenocarcinoma brain metastases, and elevated VGF expression was associated with an increased risk of brain metastasis and poor survival outcomes. Moreover, brain-derived signals induced VGF expression in lung adenocarcinoma cells, promoting cell survival and proliferation through enhanced mitochondrial oxidative phosphorylation and ATP production. Mechanistically, the N-terminal domain of VGF-a nonclassically secreted peptide-interacted with the hydrolase domain of ABHD12B to suppress cardiolipin degradation, leading to increased cardiolipin levels, stabilization of mitochondrial membranes, and a shift toward mitochondrial fusion over excessive fission. These changes helped meet the heightened energetic demands of metastatic cells in the brain. Genetic deletion of the VGF N-terminal domain disrupted mitochondrial fusion, impaired oxidative metabolism, and significantly reduced brain colonization in mouse models of brain metastasis. Together, these findings uncover a role for VGF and establish the VGF-ABHD12B-cardiolipin axis as a critical mechanism underlying metabolic adaptation in lung adenocarcinoma brain metastases, highlighting the potential of this pathway as a therapeutic target for intervention.</p><p><strong>Significance: </strong>The N-terminal domain of VGF is required for sustaining mitochondrial fusion and oxidative phosphorylation to support metabolic adaptation in lung cancer brain metastases, underscoring a potentially targetable mechanism to impair brain colonization.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"86 9","pages":"2104-2125"},"PeriodicalIF":16.6,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147811217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}