bims-meract 2026-11-01 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–11–01
twenty-two papers selected by
Andrea Morandi, Università degli Studi di Firenze

Multi-omic profiling reveals metabolic vulnerabilities in enzalutamide resistant prostate cancer.
Survival of cancer cells following taxol-induced apoptosis is supported by ZEB1-mediated ferroptosis sensitivity.
Dual targeting of DHODH and SLC29A1 overcomes metabolic resistance and enhances antitumor immune responses in PDAC.
pH-Responsive Nanoplatform-Mediated Lipid Hijacking and Metabolic Collapse for Synergistic Starvation-Immunotherapy.
Co-targeting ASAH1 and the histone reader BRD1 potently suppresses TNBC growth through the transcriptional repressor BCL6.
IAP inhibition enhances response to radiotherapy and chemotherapy in preclinical models of rectal cancer.
A protein modification of TIGAR Fuels HCC Growth by Boosting Tumor Glucose Metabolism.
CRAT-mediated acetylcarnitine shuttling sustains p65 acetylation and NF-κB-associated radioresistance in colorectal cancer.
Metabolic targeting of cyst(e)ine enhances carboplatin responsiveness in ovarian cancer.
Targeting SLC6A14-mediated nutrient competition reverses an immunosuppressive metabolic niche in pancreatic cancer.
Strategies for Overcoming Acquired Resistance of Tumor Cells to MDM2 Inhibitors.
ADP-ribose induces neuronal ferroptosis through ENT2-mediated nucleotide rewiring.
Sodium Butyrate Inhibits Glyoxalase 1 to Reverse D-Lactate-associated Drug Resistance in Cancer Cells.
Targeting ERO1α triggers tumor immunosurveillance in triple-negative breast cancer.
PSAT1 integrates ferroptosis resistance and immune evasion to drive hepatocellular carcinoma progression.
Fatty acid-binding protein 2 suppresses liver metastasis by cytoplasmic sequestration of β-catenin to enhance ferroptosis sensitivity in colon cancer.
BAZ2A-induced epigenetic states in cancer cells fuel palmitate accumulation in the tumor microenvironment driving CAR-T cell exhaustion.
CD47 blockade augments anti-GD2 driven phagocytosis in vitro but fails to improve in vivo efficacy in immunocompetent, chemoresistant neuroblastoma preclinical models.
Macrophage lipid signaling drives glioblastoma invasion and represents a therapeutic vulnerability.
Epigenetic adaptations and vulnerabilities in ovarian cancer drug-tolerant persister cells.
Targeting Branched-Chain Amino Acid Transamination Sensitizes Clear Cell Renal Cell Carcinoma to Glutaminase Inhibition.
Mitochondrial metabolic reprogramming by a glutamine antagonist radioenhancer conjugate drives pyroptosis and antitumor immunity.

Cell Death Discov. 2026 Sep 09. pii: 431. [Epub ahead of print]12(1):

Multi-omic profiling reveals metabolic vulnerabilities in enzalutamide resistant prostate cancer.

Olivia Lee, Gio Fidelito, Qing Zhao, Bingshou Liu, Hyungwon Choi, Renea A Taylor, Matthew J Watt.

Resistance to the androgen receptor inhibitor enzalutamide (ENZ) is a major barrier to durable control of advanced prostate cancer. Given the central role of metabolic reprogramming in tumour survival under therapeutic stress, we investigated whether ENZ resistance is associated with adaptive metabolic rewiring that promotes stress tolerance and evasion of cell death. Multi-omic profiling of ENZ-sensitive (C4-2B and V16D) and ENZ-resistant (MR49F) cells revealed extensive metabolic reprogramming, with lipid metabolism emerging as a dominant axis. ENZ-resistant cells displayed depletion of long-chain polyunsaturated fatty acids (PUFAs) and increased resistance to lipid peroxidation and ferroptosis. Restoring PUFA availability or activating lipid regulatory pathways via treatment with a liver X receptor (LXR) agonist re-sensitised resistant cells to ferroptotic cell death. In parallel, nitrogen metabolism was altered in ENZ-resistant cells, including increased carbamoyl phosphate synthetase 1 (CPS1) and resistance to ammonium exposure. Treatment with the CPS1 inhibitor H3B-120 reduced proliferation of MR49F cells and increased their sensitivity to ammonium stress. Together, these findings identify coordinated lipid and nitrogen remodelling as targetable metabolic adaptations that support resistance to cellular stress and death in ENZ-resistant prostate cancer cells.

DOI: https://doi.org/10.1038/s41420-026-03332-3
Cell Death Dis. 2026 Sep 02. pii: 912. [Epub ahead of print]17(1):

Survival of cancer cells following taxol-induced apoptosis is supported by ZEB1-mediated ferroptosis sensitivity.

Rachel Hausman, Wells S Brown, Shannon J Awrey, Hossein Tavakoli, Denise J Montell, Paul C McDonald, Shoukat Dedhar.

Chemotherapy remains the mainstay treatment of many solid cancers; however, resistance and recurrence compromise patient outcomes. We investigated chemotherapy resistance mechanisms in Triple Negative Breast Cancer (TNBC) by examining cells that survive chemotherapy-induced apoptotic caspase activation. Using a biosensor that permanently labels cells surviving executioner caspase activation with GFP, we identified a GFP+ population that survives transient paclitaxel treatment. These GFP+ cells display a stem-like invasive phenotype, altered mitochondrial metabolism, and increased drug resistance. Metabolomics profiling identified defects in TCA cycle metabolites and accumulation of polyunsaturated fatty acids (PUFAs). Mechanistically, surviving GFP+ cells exhibited Epithelial to Mesenchymal Transition (EMT) and ZEB1-regulated repression of GPX4 expression, resulting in increased sensitivity to ferroptotic cell death. Consistent with this, transforming growth factor- beta induced EMT also suppressed GPX4 and increased ferroptosis sensitivity in Normal Mouse Mammary epithelial cells. ZEB1 knockdown strongly reduced the GFP+ surviving fraction, identifying ZEB1 as a key regulator of apoptotic survival. Supplementation with arachidonic acid restored survival in ZEB1 knockdown cells, while the ferroptosis-protective drug, Ferrostatin-1, prevented the accumulation of GFP+ survivors, demonstrating that ferroptosis sensitivity is required for the survival of TNBC cells from chemotherapy-induced apoptosis. Together, these findings reveal a previously unrecognized link between ferroptosis and apoptosis and identify potential biomarkers and therapeutic vulnerabilities in a subset of chemotherapy-resistant TNBC.

DOI: https://doi.org/10.1038/s41419-026-09242-7
Mol Cancer Ther. 2026 Oct 29.

Dual targeting of DHODH and SLC29A1 overcomes metabolic resistance and enhances antitumor immune responses in PDAC.

Rajgopal Govindarajan, Shivam Vij, Arnav Joshi, Sandip M Vibhute, Chengyu Gao, Reena Shakya, Jeffrey Patrick, Chad E Bennett, Christopher C Coss, Meixiao Long, Mitch A Phelps, Shafia Rahman, Fredrik I Thege.

Pancreatic ductal adenocarcinoma (PDAC) displays profound metabolic plasticity that sustains rapid proliferation through heightened demands for nucleotide biosynthesis. Here, we characterize HOSU-53 (JBZ-001), a dihydroorotate dehydrogenase (DHODH) inhibitor demonstrating potent antitumor activity in preclinical PDAC models and define the metabolic determinants of sensitivity and resistance. In HOSU-53-sensitive PDAC cells, DHODH inhibition induces G₂/M cell cycle arrest and triggers apoptotic and ferroptotic cell death. In contrast, resistant cells evade metabolic stress by activating compensatory nucleoside transport and macropinocytosis pathways. Integrated functional and genetic analyses reveal that nucleoside salvage via the equilibrative nucleoside transporter SLC29A1 constitutes a dominant resistance mechanism, enabling uptake of extracellular nucleosides to bypass de novo pyrimidine synthesis. Unbiased metabolomic profiling demonstrates that combined inhibition of DHODH and SLC29A1 precipitates mitochondrial dysfunction, oxidative stress, lipid remodeling, and amino acid depletion, culminating in metabolic collapse and energetic failure. Consistent with these findings, dual inhibition markedly suppresses tumor growth and metastatic burden in xenograft and syngeneic orthotopic PDAC models while reprogramming the tumor microenvironment toward a pro inflammatory, immune activated state. Furthermore, co targeting DHODH and SLC29A1 synergizes with anti-PD 1 immune checkpoint blockade, enhancing immunotherapeutic efficacy. Together, these results establish dual targeting of de novo and salvage nucleotide metabolism as a compelling strategy to overcome metabolic resistance, remodel tumor-immune interactions and potentiate therapeutic responses in PDAC.

DOI: https://doi.org/10.1158/1535-7163.MCT-26-0461
Adv Sci (Weinh). 2026 Oct 28. pii: e78459. [Epub ahead of print]

pH-Responsive Nanoplatform-Mediated Lipid Hijacking and Metabolic Collapse for Synergistic Starvation-Immunotherapy.

Xianlong Zong, Haochen Yao, Danyang Shen, Furu Gong, Zixuan Wang, Haoyang Qin, Yang Yang, Ruirui Qiao, Yongjuan Li, Rui Li.

  Tumor starvation therapy is a promising metabolism-targeting intervention, yet its efficacy is largely counteracted by lipid droplet (LD)-driven compensatory metabolism in malignant cells. Existing LDs-targeted approaches are further hampered by off-target systemic metabolic disturbances and inherent immunosuppressive adverse effects. Here, we construct a zeolitic imidazolate framework-8 (ZIF-8)-based nanomedicine loaded with 2-deoxy-D-glucose (2-DG) and surface-decorated with copper-tannic acid (Cu-TA, ZIF-8/2-DG@Cu-TA). This nanosystem reroutes intracellular LDs from tumor cells to adjacent cancer-associated fibroblasts (CAFs) to realize synergistic tumor starvation and immunotherapy. In the acidic tumor microenvironment, the degradable Cu-TA coating activates connexin 43 (Cx43) hemichannels on CAFs. After internalization by tumor cells, ZIF-8/2-DG releases 2-DG to suppress glycolysis, while dissociated zinc ions disrupt mitochondrial bioenergetics and further trigger Cx43 hemichannels activation on tumor cells. Fully assembled Cx43 gap junctions mediate directional LDs trafficking from tumor cells to CAFs, restricting intracellular lipid energy pools sustaining malignant metabolic demands. Simultaneous blockade of glycolysis, mitochondrial respiration and lipid metabolism induces profound tumor-cell metabolic collapse. The resulting metabolic stress strongly amplifies antitumor immunity and markedly suppresses both subcutaneous and orthotopic MOC1 tumors. Overall, this study establishes a gap-junction-driven triple metabolic starvation paradigm and offers mechanistic insights for next-generation metabolic immunotherapies.

Keywords:  cancer‐associated fibroblasts (CAFs); connexin‐43 (Cx43); lipid droplets (LDs); metabolic compensation; starvation‐immunotherapy

DOI:  https://doi.org/10.1002/advs.78459
Oncogenesis. 2026 Oct 24. pii: 56. [Epub ahead of print]15(1):

Co-targeting ASAH1 and the histone reader BRD1 potently suppresses TNBC growth through the transcriptional repressor BCL6.

Siva Chander Chabattula, Patrick T Ball, Alok Kartha, Kiran Kumar Reddi, Yvonne J K Edwards, Romi Gupta.

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype with limited targeted therapeutic options, leading to higher mortality rates compared to other breast cancer subtypes. In our previous study, we identified that N-acyl sphingosine amidohydrolase 1 (ASAH1) is overexpressed in TNBC cells, and its genetic and pharmacological targeting suppresses TNBC growth and progression. In the current study, we performed a small-molecule screen using epigenetic inhibitors in combination with the ASAH1 inhibitor carmofur to identify potential epigenetic regulators that can be co-targeted to enhance the antitumor effect of carmofur. We identified the bromodomain containing protein 1 (BRD1) inhibitors (BAY-299, NI57 and OF1), which when combined with carmofur led to stronger inhibition of TNBC tumor growth in cell culture and in in vivo model compared to either single agent alone. Mechanistically, BAY-299 in combination with carmofur induced higher expression of the transcriptional repressor B-cell lymphoma 6 (BCL6), resulting in stronger inhibition of the anti-apoptotic gene, B-cell lymphoma 2 (BCL2) than either treatment alone. This consequently led to enhanced apoptosis in TNBC cells treated with both BAY-299 and carmofur. Collectively, these results identify a previously undocumented therapeutic combination of BRD1 inhibitors and ASAH1 inhibitor carmofur as a promising treatment strategy for TNBC.

DOI: https://doi.org/10.1038/s41389-026-00667-5
Radiother Oncol. 2026 Oct 24. pii: S0167-8140(26)00672-9. [Epub ahead of print]226 111832

IAP inhibition enhances response to radiotherapy and chemotherapy in preclinical models of rectal cancer.

Timothy O'Brien, Thomas Wright, Matilda Downs, Shaun Sharkey, Catherine Higgins, Jaine Blayney, Fiza M F Ishaqwala, Liang Tang, Ashley K McCulloch, Chia Y Kong, Lily V S Hillson, Ross K McMahon, Sean M O'Cathail, Kathryn Pennel, Joanne Edwards, Karl Butterworth, Tomoko Smyth, George Ward, Melissa LaBonte-Wilson, Simon McDade, Catherine Hanna, Campbell Roxburgh, Victoria M Coyle, Daniel B Longley.

   INTRODUCTION: The modern management of locally advanced rectal cancer (LARC) involves sequential radiotherapy and chemotherapy, termed Total Neoadjuvant Therapy (TNT). Although TNT significantly improves tumour regression and achieves complete response rates of approximately 30 %, treatment efficacy remains limited in part by tumour-intrinsic resistance to apoptosis. We therefore sought to investigate the effects of radiotherapy on TNFα-associated apoptotic signalling in rectal cancer and evaluate whether inhibition of Inhibitor of Apoptosis Proteins (IAPs) could enhance treatment response.
METHODS: Transcriptomic profiling was performed on rectal tumour biopsies obtained before and after two weeks of neoadjuvant radiotherapy (n = 42). Gene Set Enrichment Analysis was used to identify pathways altered following radiotherapy. The clinically relevant IAP antagonist, tolinapant, was evaluated in rectal cancer models to assess effects on cIAP1/2 degradation, radiation- and chemotherapy-induced apoptosis, and formation of 5-fluorouracil (5FU)-induced drug-tolerant persister (DTP) cells. Mechanistic studies were performed in the presence of TNFα, and in vivo efficacy was assessed in SW837 xenograft models.
RESULTS: Radiotherapy induced robust upregulation of TNFα/TNFR1 signalling and apoptosis-associated gene sets. Gene Set Enrichment Analysis confirmed enrichment of both "TNFα signalling via NFκB" and "Apoptosis" pathways. Upregulation of TNF, TNFRSF1A, RIPK1, TRADD, and CFLAR (FLIP) was observed alongside downregulation of DIABLO, suggesting that radiotherapy primes tumours for TNFα-mediated apoptosis but that elevated antiapoptotic signalling may suppress this response. Tolinapant degraded cIAP1/2 and significantly enhanced radiation-induced apoptosis in rectal cancer models. Co-treatment with TNFα further amplified apoptosis through a caspase-8-dependent mechanism. The combination of tolinapant and radiation was well-tolerated in vivo and reduced SW837 xenograft tumour volume compared to radiation alone; however, this difference did not meet statistical significance. Tolinapant also potentiated chemotherapy-induced apoptosis and prevented the emergence of 5FU-induced DTP rectal cancer cells.
CONCLUSION: These findings identify TNFα-associated apoptotic signalling as a potential radiation-induced vulnerability in rectal cancer and provide a mechanistic rationale for combining radiotherapy with IAP antagonists. Tolinapant also enhanced apoptosis induced by chemotherapy whilst suppressing drug-tolerant persisters, supporting further investigation of IAP antagonism as a strategy to improve TNT efficacy in the neoadjuvant management of rectal cancer.

Keywords:  Apoptosis; Inhibitor of apoptosis proteins; Radiotherapy; Rectal neoplasms; Tolinapant; Tumour necrosis factor-alpha

DOI:  https://doi.org/10.1016/j.radonc.2026.111832
JHEP Rep. 2026 Oct 28. pii: S2589-5559(26)00355-1. [Epub ahead of print] 102084

A protein modification of TIGAR Fuels HCC Growth by Boosting Tumor Glucose Metabolism.

Claudia M Rejano-Gordillo, Carolina Conter, Patricia Peña-Sanfélix, Laura Mosca, Miguel Ángel Merlos-Rodrigo, Joaquín Tamargo-Azpilicueta, Carlos Díaz-Cuevas, Sofía Lachiondo-Ortega, L Estefanía Zapata-Pavas, Nerea Ferreiro, Eleonora Davoli, Naiara Gutiez, Juan Anguita, Marco Piva, Pietro Guerra, Irene González-Recio, Naroa Goikoetxea-Usandizaga, Marc Beltrà, Mikel Azkargorta, Félix Elortza, Natalia Herman Sánchez, Patrizia Pontisso, Jesús M Banales, Rubén Nogueiras, José J G Marín, Maite G Fernandez-Barrena, Matías A Ávila, Antonio Zorzano, Raúl M Luque, Zbynek Heger, Manuel D Gahete, Erica Villa, Miguel Lafarga, Irene Díaz-Moreno, María Luz Martínez-Chantar.

   BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is characterized by profound metabolic reprogramming. TIGAR (TP53-induced glycolysis and apoptosis regulator) regulates glucose metabolism and redox balance by redirecting glucose flux toward the pentose phosphate pathway. Although TIGAR is frequently upregulated in HCC, the mechanisms controlling its activity remain poorly understood. We investigated whether SUMOylation regulates TIGAR function and HCC progression.
METHODS: TIGAR SUMOylation was evaluated in two independent HCC patient cohorts (n=86 and n=19), HCC cell lines and mouse models. Seahorse assays, metabolomic profiling, 13C-glucose tracing, mitochondrial analyses and in vivo tumor models were used to investigate its effects on glucose metabolism, oxidative stress and tumor growth.
RESULTS: TIGAR was found to be SUMOylated in HCC tissues, cultured cells and murine tumor models. SUMOylation enhanced the pro-tumorigenic activity of TIGAR by promoting its interaction with glycolytic enzymes, including PFKFB3 and HK2, resulting in increased glycolytic activity and pentose phosphate pathway flux. Conversely, SUMOylation-deficient K82R cells exhibited increased oxidative stress, mitochondrial dysfunction and reduced proliferation and invasion compared with WT TIGAR. In the orthotopic liver model (n=4 per group), K82R expression was associated with reduced tumor growth. In the CAM assay, SUMOylation-deficient K82R clones showed significantly reduced tumor weight (n=8 per group, p < 0.0001) and volume (n=4 per group, p < 0.05) compared with WT TIGAR cells.
CONCLUSIONS: This study identifies Lys82 SUMOylation as a novel mechanism regulating TIGAR-mediated metabolic reprogramming and HCC progression. Targeting TIGAR SUMOylation may represent a novel therapeutic strategy for HCC.
IMPACT AND IMPLICATIONS: This study identifies TIGAR SUMOylation as a new mechanism driving metabolic adaptation in hepatocellular carcinoma. SUMOylated TIGAR promotes glycolysis, pentose phosphate pathway activity and mitochondrial function. Loss of TIGAR SUMOylation increases oxidative stress and reduces tumor growth and invasion. These findings highlight TIGAR SUMOylation as a potential biomarker and therapeutic target in liver cancer. Overall, our data support targeting this pathway to improve therapeutic strategies for hepatocellular carcinoma.

Keywords:  HCC; SUMOylation; TIGAR; Warburg effect; metabolism; mitochondrial dysfunction; oxidative stress; pentose phosphate pathway

DOI:  https://doi.org/10.1016/j.jhepr.2026.102084
Mol Cancer. 2026 Jul 31. pii: 258. [Epub ahead of print]25(1):

CRAT-mediated acetylcarnitine shuttling sustains p65 acetylation and NF-κB-associated radioresistance in colorectal cancer.

Yixuan Liu, Yu Xiao, Yiran Chen, Chaoxiong Huang, Feifei Lin, Qingyang Zhuang, Hui Li, Peicheng Lin, Lirui Tang, Jinluan Li.

   BACKGROUND: Neoadjuvant chemoradiotherapy is a standard treatment for locally advanced rectal cancer, yet acquired resistance limits durable tumor control. Whether stress-adaptive acetyl-group metabolism contributes to this resistance remains unclear.
METHODS: We performed a genome-wide CRISPR-Cas9 loss-of-function screen under fractionated irradiation and integrated the results with transcriptomic and proteomic profiling of radioresistant colorectal cancer models established by stepwise irradiation. CRAT function was interrogated using genetic perturbation, catalytic-dead reconstitution, acetylation-mimetic p65 rescue, RELA depletion, stable-isotope tracing, free coenzyme A quantification, NF-κB reporter assays, chromatin immunoprecipitation-qPCR, and xenograft and syngeneic tumor models.
RESULTS: CRAT was prioritized through cross-platform convergence of the CRISPR screen with transcriptomic and proteomic signatures of radioresistant cells, and post-treatment tumors with poorer pathological regression showed higher CRAT and nuclear p65 immunohistochemical scores. CRAT manipulation had limited, model-dependent effects on basal proliferation but more pronounced effects after irradiation, where CRAT loss reduced clonogenic survival and was associated with increased oxidative stress and persistent DNA damage. Stable-isotope tracing showed that irradiation increased acetate-to-acetylcarnitine flux and expanded the free coenzyme A pool in control cells, whereas CRAT loss disrupted this acetyl-group buffering. Mechanistically, CRAT catalytic activity helped maintain irradiation-induced p65 Lys310 acetylation, H3K27ac enrichment at NF-κB-responsive loci, and NF-κB-associated transcriptional output through a p300/CBP-sensitive acetylation axis. p65-K310Q rescue and RELA depletion supported p65 acetylation and RELA-dependent transcription as downstream contributors to, rather than sole mediators of, CRAT-dependent radioprotection. In syngeneic MC38 tumors, Crat deletion enhanced the response to fractionated radiotherapy.
CONCLUSIONS: These findings support CRAT-dependent acetyl-group metabolism as a contributor to an NF-κB-associated radioprotective program and nominate this metabolic dependency as a candidate vulnerability for radiosensitization in colorectal cancer.

Keywords:  Acetyl-group metabolism; CRAT; Colorectal cancer; NF-κB; Radiotherapy resistance

DOI:  https://doi.org/10.1186/s12943-026-02753-z
Cancer Metab. 2026 Jul 29. pii: 34. [Epub ahead of print]14(1):

Metabolic targeting of cyst(e)ine enhances carboplatin responsiveness in ovarian cancer.

Ina Yoon, Sinae Oh, Seo Young Park, Jisu Park, Hyelim Jang, Eunji Park, Kyung Ah You, Kibum Kim, Soonjae Hwang, Hyeong Yun Kim, Seongmin Cho, Jung Min Han, Sunghoon Kim.

BACKGROUND: Metabolic rewiring enables cancer cells to adapt to nutrient stress, making amino acid deprivation an attractive therapeutic strategy. However, cancer type-specific responsiveness to individual amino acid deprivation remains incompletely characterized.
METHODS: We profiled the viability of 60 cancer cell lines from six tissue origins under deprivation of each of the 20 proteinogenic amino acids. Based on the screening, we evaluated the therapeutic interaction between cyst(e)ine deprivation or pharmacological inhibition of cyst(e)ine metabolism and carboplatin in ovarian cancer models. Transcriptomic analyses together with functional validation experiments were performed to explore potential molecular mechanisms.
RESULTS: The unbiased screen revealed a relative sensitivity of ovarian cancer cells to cyst(e)ine deprivation. Cyst(e)ine starvation enhanced responsiveness to carboplatin in both carboplatin-sensitive and -resistant ovarian cancer cell lines. Pharmacological inhibition of cyst(e)ine metabolism showed a similar effect, supporting pharmacological targeting of cyst(e)ine metabolism as a potential alternative to dietary deprivation. Activating transcription factor 3 (ATF3) was identified as a candidate stress-responsive factor, and its suppression partially attenuated apoptotic marker induction, suggesting that ATF3 contributes, at least in part, to the stress-associated apoptotic response.
CONCLUSION: These findings suggest that cyst(e)ine metabolism may represent a therapeutically relevant metabolic target for enhancing carboplatin response in ovarian cancer. This screening framework provides a systematic approach to identify amino acid-associated metabolic dependencies with potential relevance in cancer therapy.

DOI: https://doi.org/10.1186/s40170-026-00450-5
Exp Hematol Oncol. 2026 Aug 14. pii: 118. [Epub ahead of print]15(1):

Targeting SLC6A14-mediated nutrient competition reverses an immunosuppressive metabolic niche in pancreatic cancer.

Lihong He, Zihao Lin, Lingyue Liu, Shicheng Yao, Jiawei Wang, Jingpeng Guo, Changxin Zhong, Hanjia Zhang, Xiaozhen Zhang, Tingbo Liang, Xueli Bai.

   BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) exhibits an immunosuppressive and nutrient-deficient tumor microenvironment (TME), where solute carrier (SLC) transporters are critical in metabolic reprogramming and intercellular communication. However, the precise mechanisms by which specific SLCs contribute to therapeutic resistance through the TME remain unclear.
METHODS: We integrated transcriptomic data from clinical cohorts with computational analysis and expression validation to identify the SLC family members most closely linked to PDAC patient outcomes. Using in vitro and in vivo experiments along with multi‑omics approaches, we further clarified its functional roles in stromal-immune-metabolic networks within the TME. Following virtual screening of a million‑compound library and validated by binding assays, two target‑specific inhibitors were identified. Using pharmacological and genetic methods, the therapeutic potential of targeting this pathway was systematically evaluated.
RESULTS: SLC6A14 is identified as a prognostic biomarker and functional driver of PDAC progression, with higher expression levels correlating with poor patient outcomes; it facilitates tumor growth by modifying amino acid metabolic reprogramming and exerting immunosuppressive effects by competitively impairing amino acid uptake in dendritic cells and CD8⁺ T cells. STOCK1N-75990 is a specific SLC6A14 inhibitor that competitively blocks amino acid binding, induces intracellular nutrient deprivation, and causes profound metabolic collapse; it exhibits marked anti-tumor activity and limited toxicity in preclinical models, synergizing with anti-PD1 therapy.
CONCLUSION: These findings establish SLC6A14 as a potent multifunctional therapeutic target and demonstrate the clinical relevance of its inhibitors as a metabolic immunotherapy for PDAC.

Keywords:  Immune metabolism; Immunotherapy; Metabolic remodeling; SLC6A14; STOCK1N-75990; Sophoricoside; Tumor microenvironment

DOI:  https://doi.org/10.1186/s40164-026-00818-9
Biochemistry (Mosc). 2026 Oct;91(10): 1937-1950

Strategies for Overcoming Acquired Resistance of Tumor Cells to MDM2 Inhibitors.

Nikolay V Pervushin, Ekaterina S Prosandeeva, Boris Zhivotovsky, Gelina S Kopeina.

  Emergence of drug resistance remains a major challenge in oncology and is closely associated with tumor progression. Activation of the tumor-suppressive activity of p53 through selective inhibition of its negative regulator MDM2 is a promising strategy for anticancer therapy. MDM2 antagonists, which have been extensively evaluated in clinical trials over the past two decades, could lose efficacy because tumor cells acquire resistance to these agents. We found that SH-SY5Y neuroblastoma cells resistant to the MDM2 antagonist RG7388 were less sensitive to ferroptosis induction and showed alterations in cell cycle distribution. In addition, both parental and resistant cells were highly sensitive to autophagy induction. Finally, combining RG7388 with various inhibitors of cellular metabolism and other anticancer compounds increased its cytotoxicity and could facilitate partial or complete overcoming of this type of resistance.

Keywords:  MDM2; RG7388; chemotherapy; drug resistance; p53; tumor cells

DOI:  https://doi.org/10.1134/S0006297926601875
Nat Chem Biol. 2026 Oct 28.

ADP-ribose induces neuronal ferroptosis through ENT2-mediated nucleotide rewiring.

Haoqi Ni, Yingying He, Qiao Ye, Peng Cui, Jieyuan Yuan, Guoqing Lv, Huiyan Lei, Qian Wang, Feng Wang, Qichuan ZhuGe, Baodong Chen, Ling Liang, Yong Zhang, Lin Yuan.

Excessive nicotinamide adenine dinucleotide (NAD+) consumption fuels neurological pathogenesis, yet the limited benefit of NAD+ supplementation hints at unresolved toxicity from its catabolism. Here, we identify ADP-ribose, a neglected NAD+ catabolite generated by poly(ADP-ribose) polymerase 1 (PARP1) and poly(ADP-ribose) glycohydrolase, as an inducer of neuronal ferroptosis through nucleotide metabolic rewiring. We discovered that extracellular ADP-ribose directly binds and inhibits the nucleoside transporter equilibrative nucleoside transporter 2 (ENT2; SLC29A2), suppressing nucleotide salvage and driving compensatory hyperactivation of de novo purine and pyrimidine biosynthesis. This metabolic rerouting engages xanthine oxidase (XO) and dihydroorotate dehydrogenase (DHODH) to unleash superoxide bursts, triggering lipid peroxidation and ferroptotic neuronal death. ADP-ribose accumulates across neurological disease models and its acute administration recapitulates ferroptotic neurodegeneration in vivo. Targeting ADP-ribose signaling through PARP1 knockdown, NUDT9-mediated hydrolysis or dual XO/DHODH inhibition rescues delayed cognitive deficits in intracerebral hemorrhage models. These findings define the ADP-ribose-ENT2 axis as a metabolic driver of neuronal ferroptosis and reveal a druggable vulnerability in disorders marked by NAD+ hyperconsumption.

DOI: https://doi.org/10.1038/s41589-026-02355-2
J Biol Chem. 2026 Oct 26. pii: S0021-9258(26)02566-4. [Epub ahead of print] 113694

Sodium Butyrate Inhibits Glyoxalase 1 to Reverse D-Lactate-associated Drug Resistance in Cancer Cells.

Davide Gnocchi, Rosa Rita Paparella, Patrizia Leone, Silvia De Santis, Tamara Meňhertová, Mária Bugajová, Antonio Mazzocca.

  Drug resistance remains a major limitation to effective cancer therapy, and its metabolic basis is incompletely understood. We recently developed models of acquired drug resistance through chronic exposure of tumor cells to anticancer agents and identified a metabolic phenotype characterized by impaired mitochondrial bioenergetics, increased L-lactate production, and decreased oxygen consumption rate (OCR). Here, we investigated the contribution of D-lactate metabolism to this phenotype. Compared with their parental (P) counterparts, drug-resistant (R) cell lines showed increased D-lactate production together with increased glyoxalase 1 (GLO1) expression and activity. Sodium butyrate (NaB) reduced GLO1 expression and activity in tumor cell lines with higher expression of D-lactate pathway components, and NaB treatment was associated with reduced intracellular D-lactate levels and increased sensitivity to the corresponding anticancer treatments in selected cell models. These findings support a biochemical link between NaB-mediated modulation of the GLO1/D-lactate pathway and drug response, without excluding additional NaB-dependent mechanisms. Furthermore, NaB enhanced the effects of pro-differentiation agents in the tested in vitro models. Together, our data identify the GLO1/D-lactate pathway as a metabolic feature associated with drug resistance and support further investigation of NaB-based strategies in appropriate preclinical models.

Keywords:  D-lactate; cancer; drug resistance; glyoxalases; oxidative phosphorylation; sodium butyrate

DOI:  https://doi.org/10.1016/j.jbc.2026.113694
Redox Biol. 2026 Oct 23. pii: S2213-2317(26)00450-7. [Epub ahead of print]98 104451

Targeting ERO1α triggers tumor immunosurveillance in triple-negative breast cancer.

Alessandro Cherubini, Ersilia Varone, Sara Irene Malandrin, Alice Marrazza, Giorgia Maria Renna, Serena Germani, Stefano Fumagalli, Angela Bachi, Angela Cattaneo, Michele Retini, Giovanni Piersanti, Marco Bolis, Ilaria Craparotta, Arianna Vallerga, Chiara Grasselli, Manuela Milani, Daniele Generali, Augusto Bleve, Ester Zito.

  Triple-negative breast cancer (TNBC) remains a highly aggressive malignancy with limited responsiveness to immune checkpoint blockade. Here, we identify endoplasmic reticulum oxidoreductase 1 alpha (ERO1α; ERO1A), a key regulator of oxidative protein folding, as a determinant of tumor immunogenicity and immunotherapy response in TNBC. Unbiased proteomic profiling demonstrated that ERO1α deficiency remodels the TNBC glycoproteome, leading to enrichment of pathways associated with immune signaling. Although ERO1α loss did not affect tumor cell growth, it reshaped the immune tumor microenvironment, enhancing antigen presentation, altering myeloid-cell composition, and modulating PD-1/PD-L1-associated signaling. Functionally, ERO1α deficiency sensitized otherwise refractory TNBC tumors to PD-1 blockade, resulting in durable tumor regression in immunocompetent hosts. In contrast, ERO1α deletion in bone marrow-derived immune cells had minimal effects on tumor growth or therapeutic response, supporting an ERO1α tumor-intrinsic mechanism. Pharmacologic inhibition of ERO1α with the novel small-molecule inhibitor I29 phenocopied ERO1α genetic deletion and enhanced the efficacy of anti-PD-1 therapy. Together, these findings identify ERO1α-dependent glycoproteome remodeling as a regulator of antitumor immunity and a therapeutically actionable mechanism of immune checkpoint responsiveness in TNBC.

Keywords:  ERO1; Immune-check points; Immunosurveillance; Protein N-glycosylation; Stress of the endoplasmic reticulum (ER stress); Triple negative breast cancer; UPR (unfolded protein response)

DOI:  https://doi.org/10.1016/j.redox.2026.104451
Sci Adv. 2026 Oct 30. 12(44): eaei7877

PSAT1 integrates ferroptosis resistance and immune evasion to drive hepatocellular carcinoma progression.

Chi Zhang, Yue Yang, Wei Tian, Jia Zhang, Chao Ge, Lili Meng, Yuqi Liu, Zhujun Wei, Hua Tian.

The serine/glycine biosynthesis pathway plays a critical role in tumor progression and has emerged as a promising therapeutic target in cancer. Phosphoserine aminotransferase 1 (PSAT1) is a key enzyme in this pathway and has been implicated in the progression of multiple malignancies. However, the functional significance and underlying mechanisms of PSAT1 in hepatocellular carcinoma (HCC) remain largely undefined. In this study, we identify PSAT1 as a critical determinant of ferroptosis resistance in HCC. Elevated PSAT1 expression was positively associated with ferroptosis resistance and poor clinical outcomes in patients with HCC. Both in vitro and in vivo functional assays demonstrated that PSAT1 promotes HCC cell proliferation and suppresses ferroptosis through an HSPA5-mediated adaptive endoplasmic reticulum response. Mechanistically, PSAT1 interacts with and stabilizes BCLAF1, thereby enhancing HSPA5 messenger RNA stability and translation in HCC cells. In addition, PSAT1 remodels the tumor immune microenvironment by promoting M2 tumor-associated macrophage polarization and regulatory T cell infiltration. PSAT1 up-regulates NRF2 expression, which directly binds to the CCL5 promoter to enhance CCL5 production and secretion by tumor cells, thereby fostering an immunosuppressive microenvironment. Therapeutically, pharmacological inhibition of PSAT1 with aminooxyacetic acid markedly potentiated the antitumor efficacy of anti-PD-1 immunotherapy. Our study reveals a previously unrecognized role of PSAT1 in coordinating ferroptosis resistance and immune escape in HCC and highlights therapeutic targeting of PSAT1 as a promising strategy for HCC treatment.

DOI: https://doi.org/10.1126/sciadv.aei7877
Cell Death Dis. 2026 Aug 01. pii: 921. [Epub ahead of print]17(1):

Fatty acid-binding protein 2 suppresses liver metastasis by cytoplasmic sequestration of β-catenin to enhance ferroptosis sensitivity in colon cancer.

Long Wu, Huan Wu, Yu-Tong Zhou, Guang-Ling Ou, Yong Sun, Xiao-Yun Li, Yun-Huan Zhen, Kun Cao, Hai-Yang Li.

Metastatic colon cancer commonly exhibits resistance to ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation. However, the mechanisms linking metabolic regulation to ferroptosis during metastatic progression remain incompletely understood. Here, we identified fatty acid-binding protein 2 (FABP2) as a regulator associated with ferroptosis sensitivity and liver metastatic phenotypes in colon cancer. Multi-omics analyses of clinical specimens showed reduced FABP2 expression in advanced colon cancer, which was associated with metastatic progression and poor survival. Mechanistically, FABP2 interacted with β-catenin, altered its intracellular localization, and was associated with reduced β-catenin/TCF4-dependent transcription of glutathione peroxidase 4 (GPX4), a key regulator of ferroptosis resistance. FABP2 overexpression increased ferroptosis sensitivity, whereas FABP2 downregulation promoted GPX4-dependent ferroptosis evasion and metastatic phenotypes. Pharmacological inhibition of Wnt/β-catenin signaling or GPX4 activity partially attenuated the effects of FABP2 loss. Together, these findings identify FABP2 as a factor associated with ferroptosis regulation and metastatic progression in colon cancer, and provide additional insight into the interplay between lipid metabolism, Wnt/β-catenin signaling, and ferroptosis.

DOI: https://doi.org/10.1038/s41419-026-09161-7
Nat Cancer. 2026 Oct 30.

BAZ2A-induced epigenetic states in cancer cells fuel palmitate accumulation in the tumor microenvironment driving CAR-T cell exhaustion.

Hongye Wang, Haigang Geng, Jingtong Zhao, Haodong Ge, Yan Shen, Zhaorong Wu, Linke Bian, Jinlu Zuo, Zhen Sun, Ying Yang, Jiufei Zhu, Weiming Shen, Jiaojiao Zheng, Dan Cui, Jiawei Ding, Shuxian Yang, Hongchao He, Hai Huang, Yi Gao, Keke Gao, Mengfei Huo, Hanqing Liu, Yixun Liu, Jun Xiao, Dan-Feng Xu, Qiang He, Yihao Zhang, Feng Liu, Lianxin Liu, Minghua Zheng, Haojie Jin, Bo Zhai, Chuanjie Zhang.

Chimeric antigen receptor T (CAR-T) cell therapy shows limited efficacy in solid tumors, partly owing to poorly defined tumor-intrinsic resistance mechanisms. Here we show that the epigenetic regulator BAZ2A drives resistance to CD70-targeted CAR-T therapy by reprogramming tumor lipid metabolism. Using an in vivo CRISPR screen in a mouse renal cell carcinoma model, we identify BAZ2A as a key mediator that promotes the production and accumulation of palmitic acid, a saturated fatty acid in the tumor microenvironment. Excess palmitic acid is taken up by CAR-T cells and impairs mitochondrial fitness by inhibiting PGC-1α activity, thereby enforcing a dysfunctional state. Pharmacologic inhibition of BAZ2A reduces lipid accumulation and restores CAR-T cell activity in vivo. These findings reveal an epigenetic-metabolic mechanism of immune resistance and suggest that targeting tumor lipid remodeling represents a therapeutic strategy to overcome CAR-T resistance in solid tumors.

DOI: https://doi.org/10.1038/s43018-026-01267-3
PLoS One. 2026 ;21(10): e0353900

CD47 blockade augments anti-GD2 driven phagocytosis in vitro but fails to improve in vivo efficacy in immunocompetent, chemoresistant neuroblastoma preclinical models.

Courtney Himsworth, Thomas Jackson, Chantelle Bowers, Sophie Munnings-Tomes, Gaya Nair, Henrike Muller, Elizabeth Tucker, Amy K Erbe-Gurel, Paul M Sondel, Louis Chesler, Robbie Mazjner, John Anderson.

CD47 delivers a dominant "Don't Eat Me" signal that inhibits macrophage‑mediated clearance of tumour cells. Using immunocompetent, chemoresistant neuroblastoma (NB) models, we tested a Fc‑silent CD47 blocker (ALX301) with anti‑GD2 antibody alone and in combination with a clinically aligned temozolomide/irinotecan chemoimmunotherapy backbone. Tumours expressed GD2 and CD47, and bound ALX301. In macrophage coculture assays, anti-GD2 antibody induced dose-dependent phagocytosis, whereas ALX301 or an anti-CD47 antibody alone did not. CD47 blockade in combination with a suboptimal concentration of anti-GD2 antibody showed an additive effect on phagocytosis in vitro. In vivo, however, ALX301 failed to improve tumour control or survival when added to anti‑GD2 or to chemoimmunotherapy in the dosing regimens and two independent models tested. Toxicity was acceptable, showing only mild, expected red‑cell changes without overt organ injury. This form of CD47 inhibition is therefore mechanistically active in vitro but insufficient to enhance anti‑GD2 antibody-based therapy in immunocompetent mice bearing a chemoresistant NB, highlighting the potential need for myeloid‑reprogramming partners.

DOI: https://doi.org/10.1371/journal.pone.0353900
Cancer Cell. 2026 Oct 27. pii: S1535-6108(26)00472-1. [Epub ahead of print]

Macrophage lipid signaling drives glioblastoma invasion and represents a therapeutic vulnerability.

Carla Pallarés-Moratalla, Mélanie Guyot, Krish Skandha Gopalan, Bernhard Robl, Jakub Idkowiak, Jonas Dehairs, Nina Ravoet, Tim F E Hendriks, Kinga Anna Nowak, Nikolina Dubroja Lakić, Linqian Weng, Vasileios Konstantakos, Xander Spotbeen, Lutgarde Serneels, Sarah-Maria Fendt, Stein Aerts, Frederik De Smet, Eva Cuypers, Johannes V Swinnen, Gabriele Bergers.

  Glioblastoma (GBM) is characterized by diffuse infiltration into the surrounding brain, limiting complete surgical resection, the strongest determinant of patient survival. The mechanisms driving this invasive growth remain incompletely understood. Here, we identify a lipid-mediated paracrine signaling axis through which tumor-associated microglia/macrophages promote glioma invasion. Integrating single-cell transcriptomics, spatial lipidomics, and functional perturbation across mouse models and human GBM samples, we show that invading tumor cells engage and reprogram myeloid cells via colony-stimulating factor-1 receptor (CSF1R)-PI3K signaling. This induces lipid metabolic reprogramming and secretion of bioactive lipids, including lysophosphatidylcholines (LPCs) and lysophosphatidic acids (LPAs), which promote GBM invasion through distinct downstream pathways. Disruption of this myeloid-GBM axis reduces lipid secretion and suppresses invasion. Targeting downstream LPA-LPA receptor (LPAR) or YAP/TAZ signaling further constrains invasion in a context-dependent manner. Together, these findings define a lipid-driven circuit linking the tumor microenvironment to glioma invasion and identify strategies to reduce infiltration and improve surgical resection.

Keywords:  CSF1-CSF1R signaling; LPC/LPA; TAM; YAP/TAZ signaling; glioblastoma; invasion; lipid metabolism; spatial lipidomics; tumor-associated microglia/macrophage

DOI:  https://doi.org/10.1016/j.ccell.2026.10.006
NAR Cancer. 2026 Dec;8(4): zcag030

Epigenetic adaptations and vulnerabilities in ovarian cancer drug-tolerant persister cells.

Mihai G Dumbrava, Sierra J Hamernick, Shariska P Harrington, Alexandre Gaspar-Maia.

High-grade serous ovarian carcinoma (HGSOC) recurs in most patients despite initial responses to chemotherapy and poly(ADP-ribose) polymerase inhibition. A leading explanation for the high rates of recurrence is the presence of minimal residual disease (MRD) comprised of drug-tolerant persister (DTP) cells that survive therapy through reversible epigenetic reprogramming. DTPs have various adaptations that enable them to tolerate therapy and eventually develop into resistant clones, including quiescence, metabolic and hypoxic stress responses, epithelial-mesenchymal plasticity, and immune evasion. Here, we discuss evidence from ovarian cancer of epigenetic mechanisms that coordinate DTP phenotypes, including DNA methylation, histone post-translational modifications, enhancer rewiring, and transcription factor gene-regulatory networks. Based on therapeutic vulnerabilities identified from increased resolution of DTPs, we highlight epigenetic therapies that are currently in clinical trials aimed at depleting MRD to delay or prevent relapse in HGSOC. Finally, we outline emerging technologies that have the potential to detect and monitor persister states in patients, including single-cell transcriptomic and epigenomic profiling, long-read sequencing, and spatial mapping of tumor biopsies.

DOI: https://doi.org/10.1093/narcan/zcag030
Cancer Res. 2026 Oct 27.

Targeting Branched-Chain Amino Acid Transamination Sensitizes Clear Cell Renal Cell Carcinoma to Glutaminase Inhibition.

Nathan J Coffey, Sara M Demczyszyn, Yizheng Xue, Zian Zhang, Nicolas Skuli, Nicholas P Lesner, Romain Riscal, Yanqing Jiang, Xu Han, Madeleine Carens, Morgan Brown, Laura C Kim, Brian Keith, Zoltan Arany, M Celeste Simon.

Metabolic reprogramming is a well-described hallmark of clear cell renal cell carcinoma (ccRCC). Gene copy number variation and altered gene expression data suggest enhanced branched-chain amino acid (BCAA) transamination and reduced BCAA oxidation are highly selected traits in ccRCC. Surprisingly, we found that genetic modulation of BCAA oxidation had little effect on experimental ccRCC cell growth in vitro and in vivo. In contrast, BCAA transamination in ccRCC cells was essential for the generation of glutamate-derived glutathione and cell viability when glutamine was limiting. Thus, BCAA transamination conferred resistance to states of low glutamine or treatment with the glutaminase inhibitor CB-839 by providing glutathione independent of glutamine breakdown. Targeting BCAA transamination in vitro and in vivo sensitized ccRCC to CB-839 mediated glutaminase inhibition by decreasing glutathione biosynthesis and redox homeostasis. These findings reveal that BCAA transamination maintains critical glutamate and glutathione levels in glutamine-deprived ccRCC, explaining why CB-839 treatment has been ineffective in ccRCC clinical trials and demonstrate an approach to treat ccRCC by targeting BCAA transamination to create a vulnerability to glutaminase inhibition.

DOI: https://doi.org/10.1158/0008-5472.CAN-26-0563
Sci Adv. 2026 Oct 30. 12(44): eaeh5903

Mitochondrial metabolic reprogramming by a glutamine antagonist radioenhancer conjugate drives pyroptosis and antitumor immunity.

Rundi Song, Jinhong Li, Chaoyu Wang, Langston Tillman, Yibin Mao, Yuxuan Xiong, Xuan Li, Ralph R Weichselbaum, Wenbin Lin.

Aberrant glutamine metabolism undermines the efficacy of cancer radiotherapy (RT) by promoting DNA repair, increasing oxygen consumption, and imposing metabolic stress that compromises the viability and function of cytotoxic T lymphocytes (CTLs). Here, we report a mitochondria-enriched, metabolism-regulating monolayered metal-organic framework (MOF) nanoplatform, Hf-Ir/DON, constructed by incorporating the glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) into a radiosensitizing hafnium-iridium (Hf-Ir) MOF to inhibit glutaminolysis. This design markedly sensitizes tumor cells to RT and, upon x-ray irradiation, enables mitochondria-targeted RT-radiodynamic therapy with substantially enhanced reactive oxygen species accumulation. The resulting oxidative stress induces extensive DNA damage, mitochondrial dysfunction, and immunogenic tumor cell pyroptosis. Concurrently, Hf-Ir/DON alleviates metabolic constraints on activated T cells, preserving CTL viability while sustaining effector and memory functions. In a murine colon cancer model, low-dose RT combined with Hf-Ir/DON achieved >95% tumor growth inhibition. Further combination with anti-PD-L1 therapy induced regression of bilateral triple-negative breast tumors and prevented lung metastasis. These results establish a radiometabolic MOF nanoplatform that potentiates RT while promoting durable antitumor immunity.

DOI: https://doi.org/10.1126/sciadv.aeh5903