bims-meract 2026-10-25 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–10–25
twenty papers selected by
Andrea Morandi, Università degli Studi di Firenze

Mevalonate Biosynthesis is a Metabolic Vulnerability of Gemcitabine-resistant Pancreatic Cancer.
PHGDH Sustains Oncometabolite Production to Drive Resistance to Mutant IDH Inhibition in Glioma that can be Monitored by Metabolic Imaging.
Targeting the mitochondrial complex I subunit NDUFS2 potentiates FLT3 inhibition in acute myeloid leukaemia with FLT3 internal tandem duplication.
Absolute Quantification of Intravesicular Adenosine Triphosphate in Single Extracellular Vesicles Reveals Mitochondrial Bioenergetic Rewiring in Chemoresistance.
TP53 mutations drive therapy resistance through post-mitochondrial caspase blockade.
Targeting SLC1A5-mediated glutamine metabolism overcomes PARP inhibitor resistance in ovarian cancer.
Fatty acid 2-hydroxylation restrains gastric cancer by blocking CD36 palmitoylation and fatty acid uptake.
Metabolic plasticity underlies ferroptosis resistance driven by mutant p53 in pancreatic ductal adenocarcinoma.
Primary tumor-derived lactate primes prostate cancer cells for a dormant fate.
The NEK8/ALYREF axis promotes cisplatin resistance in bladder cancer by stabilizing CDK18 mRNA to facilitate DNA damage repair.
Epigenetic and metabolic plasticity of tumor cells in immunotherapy resistance.
A Metabolic Nanoplatform Potentiates Triple-Negative Breast Cancer Radiosensitivity via Disrupting Carbonic Anhydrase IX/Pentose Phosphate Pathway Crosstalk.
FABP4 drives gastric cancer peritoneal metastasis by inhibiting ferroptosis via UBR4/ALOX15-mediated arachidonic acid metabolism.
Obesity-Induced PLPE-PTK6-FASN Feedback Loop Drives Enzalutamide Resistance by Exacerbating Lipid Metabolic Dysregulation in Castration-Resistant Prostate Cancer.
VCP-Regulated LMF2 Stabilizes the Cholesterol Biosynthesis Enzyme HMGCS1 to Drive Cancer Progression and Confer Capecitabine Resistance in Triple-Negative Breast Cancer.
Adaptive drug resistance in melanoma is characterised by lipidome remodelling while maintaining cell membrane biophysical properties.
Targeting CDC7 Overcomes Gemcitabine Resistance in Cholangiocarcinoma by Inducing Cellular Senescence.
Propionate promotes MHC class I antigen presentation and anti-tumor immunity.
Targeting PGAM1 overcomes paclitaxel resistance and restores cuproptosis sensitivity in non-small cell lung cancer.
Inhibition of ACSS2 enhances cabozantinib sensitivity by blocking TFEB-induced autophagic flux in hepatocellular carcinoma.

Gastroenterology. 2026 Oct 21. pii: S0016-5085(26)07348-8. [Epub ahead of print]

Mevalonate Biosynthesis is a Metabolic Vulnerability of Gemcitabine-resistant Pancreatic Cancer.

Alica K Michels, Sabrina Calderon, Ethan Nghiem, Eleni Zimmer, Leonor Schubert Santana, Rima Singh, Tim Eiseler, Chantal Allgöwer, Gregory Tong, Sharon Wu, Kevin Gulay, Mumina Sadullozoda, Austin Silva, Cecily Anaraki, Natalie Yousefian, Devon F Pendlebury, Cameron Geller, Alina Chao, Dennis Juarez, Thomas Seufferlein, Cholsoon Jang, Aimee L Edinger, Marcus Seldin, Alexander Muir, Thomas F Martinez, Alexander Kleger, David K Chang, Herve Tiriac, Jennifer B Valerin, David A Fruman, Christopher J Halbrook.

   BACKGROUND & AIMS: Gemcitabine remains a cornerstone of systemic therapy for pancreatic ductal adenocarcinoma (PDAC) but acquired resistance limits its efficacy. While both microenvironment-derived metabolites and intrinsic metabolic reprogramming have been implicated in gemcitabine resistance, the relationship between these mechanisms remains poorly understood. We investigated the metabolic adaptations accompanying acquired gemcitabine resistance and identified therapeutically actionable vulnerabilities.
METHODS: Acquired gemcitabine-resistant PDAC models were generated and characterized. The effects of physiological pyrimidines on gemcitabine response were evaluated alongside changes in pyrimidine metabolism. Sensitivity to inhibition of the mevalonate pathway was assessed in vitro and in immunocompetent mouse models. Metabolite rescue experiments were performed to identify critical downstream mediators of statin activity and HMGCR expression was analyzed for its association with clinical response to gemcitabine.
RESULTS: PDAC cells with acquired gemcitabine resistance exhibited diminished sensitivity to physiological extracellular pyrimidines due to suppression of the pyrimidine salvage pathway. This metabolic rewiring created a selective dependency on the mevalonate biosynthesis pathway, rendering gemcitabine resistant cells highly sensitive to statins. Statin treatment selectively inhibited the growth of gemcitabine-resistant tumors in mice. Metabolite rescue studies identified geranylgeranyl pyrophosphate depletion, not cholesterol limitation, as a principal mediator of statin sensitivity. HMGCR expression declined progressively during the acquisition of gemcitabine resistance and low HMGCR expression levels predicted poor response to gemcitabine-based therapy in PDAC patients.
CONCLUSIONS: Acquired gemcitabine resistance drives metabolic reprogramming that suppresses pyrimidine salvage while creating a therapeutically exploitable dependence on the mevalonate pathway. These findings identify pharmacological inhibition of HMGCR as a metabolic vulnerability in gemcitabine resistance and support HMGCR expression as a candidate biomarker for treatment stratification in PDAC patients.

Keywords:  3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR); Chemotherapy resistance; Pancreatic ductal adenocarcinoma; Statin

DOI:  https://doi.org/10.1053/j.gastro.2026.09.027
Cancer Res. 2026 Oct 22.

PHGDH Sustains Oncometabolite Production to Drive Resistance to Mutant IDH Inhibition in Glioma that can be Monitored by Metabolic Imaging.

Céline Taglang, Georgios Batsios, Anne Marie Gillespie, Joanna J Phillips, Jennie W Taylor, Pavithra Viswanath.

Mutations in isocitrate dehydrogenase (IDHm) define a distinct molecular class of gliomas. IDHm converts α-ketoglutarate (α-KG) to the oncometabolite D-2-hydroxyglutarate (D-2HG), which drives tumorigenesis. The IDHm inhibitor vorasidenib suppresses D-2HG production and prolongs progression-free survival in some, but not all, patients. Here, using patient-derived models, genetically engineered glioma cells, orthotopic xenografts, and patient tissue, we showed that phosphoglycerate dehydrogenase (PHGDH) mediates intrinsic resistance to vorasidenib by sustaining D-2HG production despite IDHm inhibition. Silencing PHGDH suppressed residual D-2HG synthesis and restored vorasidenib sensitivity in resistant models, whereas PHGDH overexpression restored D-2HG production and induced resistance in sensitive models. Importantly, restoration of intracellular D-2HG rescued growth despite continued vorasidenib treatment, demonstrating a causal role for residual D-2HG production in the resistant phenotype. Mechanistically, a permissive chromatin state characterized by increased H3K4me3, reduced H3K27me3, and enhanced ATF4 occupancy at the PHGDH promoter facilitated PHGDH upregulation in resistant models. Pharmacologic induction of this chromatin state induced PHGDH expression, restored D-2HG production, and conferred resistance to vorasidenib in sensitive models. Consistently, tumor tissue from patients with poor response to IDHm inhibitor treatment exhibited higher PHGDH expression, coupled with the ATF4-enriched permissive chromatin state observed in resistant models. Finally, deuterium metabolic imaging of D-2HG production from diethyl-[3,3'-2H]-α-KG provided an early, non-invasive readout of response and resistance to vorasidenib in vivo. Collectively, this study identifies a chromatin-regulated ATF4-PHGDH-D-2HG axis as a mechanism of intrinsic resistance to IDHm inhibition and establishes diethyl-[3,3'-2H]-α-KG as a metabolic imaging probe for interrogating treatment response in IDHm gliomas.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-4071
Leukemia. 2026 Oct 19.

Targeting the mitochondrial complex I subunit NDUFS2 potentiates FLT3 inhibition in acute myeloid leukaemia with FLT3 internal tandem duplication.

Xiqin Tong, Guopeng Chen, Yuzhe Pan, Yanling Chen, Yuxin Tan, Hongqiang Jiang, Qian Wang, Linlu Ma, Ruihang Li, Yuxing Liang, Xiaoyan Liu, Fuling Zhou.

Acute myeloid leukaemia (AML) with FLT3 internal tandem duplication (FLT3-ITD) frequently relapses after FLT3 tyrosine kinase inhibitor (TKI) therapy, highlighting the need to define mechanisms of drug tolerance. Here, we identify the mitochondrial complex I core subunit NDUFS2 as a determinant of FLT3 TKI tolerance in FLT3-ITD AML. A metabolism-focused CRISPR-Cas9 sensitiser screen, integrated with transcriptomic profiling of gilteritinib-resistant cells and primary samples, identified NDUFS2 as upregulated in acquired resistance and preferentially expressed in FLT3-ITD AML. NDUFS2 knockdown impaired complex I activity, oxidative phosphorylation, mitochondrial membrane potential and ATP production, thereby promoting apoptosis and sensitising FLT3-ITD AML cells to gilteritinib. Pharmacologic complex I inhibition with IACS-010759 similarly enhanced gilteritinib activity in FLT3-ITD AML cell lines and primary FLT3-ITD samples, activated AMPK-PERK-ATF4-CHOP stress signalling, promoted apoptosis, and reduced leukaemia burden in a patient-derived xenograft model. Genetic NDUFS2 knockdown also prolonged survival in a xenograft model. A preliminary murine safety assessment showed no overt toxicity under the tested short-term dosing schedule. These findings identify NDUFS2-dependent complex I activity as an adaptive metabolic dependency supporting FLT3 inhibitor tolerance and provide mechanistic insight for further preclinical evaluation.

DOI: https://doi.org/10.1038/s41375-026-03170-3
ACS Nano. 2026 Oct 13. 20(40): 27508-27525

Absolute Quantification of Intravesicular Adenosine Triphosphate in Single Extracellular Vesicles Reveals Mitochondrial Bioenergetic Rewiring in Chemoresistance.

Xu Xiao, Yuqing Luo, Chenxi Liu, Haonan Di, Yunyun Hu, Cheng Lu, Hao Chen, Xiaozhen Zhan, Guoqiang Su, Xiaomei Yan.

  The inability to quantify specific metabolites within individual extracellular vesicles (EVs) represents a fundamental analytical gap, precluding a mechanistic understanding of how cellular metabolic states are encoded into vesicular cargo. Here, we introduce single-particle adenosine triphosphate (ATP) quantification by nano-flow cytometry (SPAQ-nFCM), a laboratory-constructed dual-laser platform that overcomes particle size heterogeneity by integrating ATP-loaded liposome standards with a size-corrected "ATP fluorescence density" metric, thereby enabling liposome-calibrated absolute measurement of intravesicular ATP. Applying SPAQ-nFCM, we find that compared to chemosensitive cancer cells, chemoresistant cancer cells secrete EVs highly enriched in ATP, as evidenced by both a higher proportion of ATP-positive EVs (ATP+ EVs) and an elevated intravesicular ATP content per EV. Targeted metabolomics and bioenergetic analyses trace this to a profound metabolic reprogramming toward enhanced mitochondrial oxidative phosphorylation, thereby expanding the cellular ATP pool in chemoresistant cells. Strikingly, single-particle multiparametric analysis reveals a distinct, ATP-enriched P-glycoprotein (P-gp)-positive EV subpopulation, providing direct evidence for the spatial coupling of mitochondrial energetics to drug efflux. Moreover, we demonstrate that ATP+ EVs predominantly exhibit high expression of the classical tetraspanin marker CD63. A targeted screen further identifies conserved molecular regulators (Rab27a/b, VPS35, DRP1) governing ATP+ EV biogenesis. Thus, SPAQ-nFCM provides a generalizable analytical framework for quantitative metabolite analysis at the single-vesicle level. The link between ATP-enriched EVs and chemoresistance further underscores the broader utility of SPAQ-nFCM for investigating EV-mediated metabolic communication.

Keywords:  chemoresistance; extracellular vesicles (EVs); metabolic reprogramming; nano-flow cytometry; single-particle metabolite quantification

DOI:  https://doi.org/10.1021/acsnano.6c15798
Cell Death Dis. 2026 Jul 28. pii: 902. [Epub ahead of print]17(1):

TP53 mutations drive therapy resistance through post-mitochondrial caspase blockade.

Ahmed M Mamdouh, Fizza Iftikhar, Elyse A Olesinski, Fang Qi Lim, Shaista Jasdanwala, Yuhan Wang, Yang Mi, Nicole Si En Lin, Daniel Tan En Liang, Md Al Nayem Chowdhury, Nishtha Chitkara, Leah Hogdal, Coleman R Lindsley, Anthony Letai, Koji Itahana, Shruti Bhatt.

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by a broad spectrum of molecular alterations that influence clinical outcomes. TP53 mutations define one of the most lethal subtypes of AML, driving resistance to nearly all available treatment modalities, including venetoclax plus azacitidine (VenAza). Yet, the molecular basis of this resistance, beyond affecting transactivation of BCL-2 family genes, has remained elusive. Here, we demonstrate that VenAza treatment leads to reduced transcriptional upregulation of the p53 signaling pathway in TP53 mutant/deficient AML compared to wild-type AML. Functionally, TP53 mutant/deficient AML exhibits selective failure in apoptosis induction rather than impaired G1 arrest or senescence. Despite inhibition of pro-apoptotic BAX and selective enrichment for MCL-1 in TP53 mutant isogenic AML cells, compensatory upregulation of BIM preserved functional mitochondrial outer membrane permeabilization (MOMP). TP53 mutant primary AML tumors at baseline also had retained capacity for MOMP. Instead, TP53 mutant AML exhibited disruption in caspase-3/7 activation to evade apoptosis after VenAza therapy - decoupling the mitochondrial and executioner phases of apoptosis. Importantly, this "post-MOMP brake" is not a bystander effect but itself a driver of VenAza and chemotherapy resistance in TP53 mutant/deficient AML. This previously unrecognized mechanistic insight shifts the focus from mitochondrial priming to terminal caspase blockade in TP53 mutant AML and opens the door for urgently needed therapeutic strategies that reignite apoptosis at its execution point.

DOI: https://doi.org/10.1038/s41419-026-09087-0
Cell Death Dis. 2026 Jul 22. pii: 890. [Epub ahead of print]17(1):

Targeting SLC1A5-mediated glutamine metabolism overcomes PARP inhibitor resistance in ovarian cancer.

Fang Han, Hongjie Du, Kunlin Tian, Gonghua Qi, Beihua Kong, Xia Luo, Hanlin Ma.

Poly(ADP-ribose) polymerase inhibitors (PARPi), such as olaparib, have significantly improved outcomes in ovarian cancer (OC); however, therapy resistance remains a major clinical challenge. Here, we showed that glutamine metabolism was upregulated in PARPi-resistant OC cells and identified the glutamine transporter SLC1A5 as a key mediator of this metabolic adaptation. Inhibition of SLC1A5 increased the sensitivity of OC cells to olaparib both in vitro and in vivo. Mechanistically, we demonstrated that the deubiquitinating enzyme USP14 directly interacted with and stabilized SLC1A5 by removing K48-linked polyubiquitin chains, thereby enhancing glutamine uptake, promoting glutathione synthesis, alleviating oxidative stress, and activating the mTORC1 pathway. This metabolic rewiring improved DNA damage repair capacity and ultimately contributed to PARPi resistance. Notably, combined treatment with the SLC1A5 inhibitor V-9302 and olaparib synergistically suppressed tumor growth in a patient-derived xenograft (PDX) model. Collectively, our findings identify the USP14-SLC1A5 axis as a novel regulator of PARPi resistance and suggest that targeting glutamine metabolism represents a promising therapeutic strategy to overcome PARPi resistance in ovarian cancer.

DOI: https://doi.org/10.1038/s41419-026-09123-z
Oncogene. 2026 Oct 21.

Fatty acid 2-hydroxylation restrains gastric cancer by blocking CD36 palmitoylation and fatty acid uptake.

Min Feng, Xiaoheng Huang, Chaofeng Wang, Huifang Wei, Nada A Abumrad, Xiong Su.

Fatty acid (FA)-induced internalization of the FA transporter CD36 normally functions as an intrinsic brake on FA uptake and lipid overload, but cancer cells can bypass this checkpoint to sustain lipid-fueled growth. The mechanism underlying this failure remains unclear. Here, we identify a FA 2-hydroxylase (FA2H)-CD36 signaling axis that operates as an endogenous brake on lipid fueling in gastric cancer cells. FA2H-derived (R)-2-hydroxy palmitic acid ((R)-2-OHPA) disrupts CD36 interaction with its palmitoyltransferase DHHC4, thereby limiting CD36 palmitoylation and trafficking to the plasma membrane. Loss of FA2H permits CD36 palmitoylation and establishes a feed-forward loop that amplifies FA uptake, lipid accumulation, and tumor growth. Restoring FA2H expression or supplementing cells with exogenous (R)-2-OHPA reinstates the lipid-sensing checkpoint. Moreover, FA2H activation sensitizes gastric cancer cells to inhibition of endogenous FA synthesis through blockade of FA synthase (FASN) or stearoyl-CoA desaturase 1 (SCD1). In vivo, (R)-2-OHPA treatment or expression of the palmitoylation-deficient CD36 AASS mutant attenuates FA2H deficiency-driven lipid accumulation and tumor growth, positioning CD36 palmitoylation as the critical effector in this metabolic circuit. Together, these findings establish FA 2-hydroxylation as a metabolic checkpoint that links FA structure to CD36 trafficking and FA utilization in gastric cancer, revealing a targetable vulnerability in lipid-driven tumor growth.

DOI: https://doi.org/10.1038/s41388-026-04021-2
Mol Cancer. 2026 Jul 23. pii: 248. [Epub ahead of print]25(1):

Metabolic plasticity underlies ferroptosis resistance driven by mutant p53 in pancreatic ductal adenocarcinoma.

Adriana Celesia, Filippo Piccoli, Tian Wang, Yushu Hu, Federica Danzi, Antonino Aparo, Barbara Cisterna, Raffaella Pacchiana, Maria Poles, Maria Teresa Scupoli, Claudio Luchini, Stefano Ugel, Massimo Donadelli, Alessandra Fiore.

   BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by late diagnosis, rapid progression, and resistance to conventional therapies. Mutations in the tumor suppressor gene TP53 are prevalent in this cancer and have been associated with gain-of-function activities that promote tumor survival. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, represents a potential therapeutic vulnerability. However, the influence of mutant p53 on ferroptosis susceptibility remains poorly understood.
METHODS: We employed isogenic pancreatic cancer cell models, including CRISPR-Cas9-mediated TP53 Knockout (TP53-KO) and transient overexpression of common mutant TP53 variants, to examine ferroptosis sensitivity. Cell viability, reactive oxygen species accumulation, lipid peroxidation, mitochondrial integrity, and metabolic profiling were assessed following treatment with ferroptosis inducers. Transcriptional changes were analysed by RNA sequencing, and functional contributions of glycolysis and mitochondrial respiration were evaluated using metabolic flux assays. Pharmacological reactivation of wild-type p53 was tested in combination with ferroptosis inducers in vitro and in orthotopic murine models.
RESULTS: Deletion of mutant TP53 sensitized pancreatic cancer cells to ferroptosis, accompanied by increased oxidative stress, lipid peroxidation and mitochondrial dysfunction. Mutant TP53 expression preserved mitochondrial integrity and sustained bioenergetic flexibility under ferroptotic stress. Transcriptomic analyses revealed a multi-layered adaptive program, including upregulation of antioxidant and metabolic genes, and activation of PI3K-AKT signaling, which is associated to a selective glycolytic shift to maintain ATP levels. Functional modulation confirmed that glucose supplementation enhanced, whereas glycolytic inhibition impaired, survival under ferroptotic conditions in mutant TP53-expressing cells, but not in TP53-KO cells. Pharmacological reactivation of wild-type p53 disrupted this adaptive network, abrogating glycolytic reprogramming and significantly increasing ferroptotic cell death both in vitro and in vivo.
CONCLUSIONS: Mutant p53 orchestrates transcriptional and metabolic plasticity that confers ferroptosis resistance in pancreatic cancer. Reactivating wild-type p53 in combination with ferroptosis induction overcomes this resistance, highlighting a therapeutically actionable vulnerability and supporting the development of combinatorial strategies for this aggressive malignancy.

Keywords:  Ferroptosis; Glycolysis; Mitochondria; Mutant p53; PDAC

DOI:  https://doi.org/10.1186/s12943-026-02746-y
Sci Adv. 2026 Oct 23. 12(43): eaeb8595

Primary tumor-derived lactate primes prostate cancer cells for a dormant fate.

Luigi Ippolito, Erica Pranzini, Giulia Gangarossa, Marta Iozzo, Giuseppina Comito, Giacomo Venditti, Sara Roccabianca, Elisa Pardella, Matteo Lulli, Alice Santi, Gabriella Nesi, Elisa Giannoni, Paola Chiarugi.

The metastatic outcome depends on the state of disseminated cancer cells (DCCs) leading to overt metastasis or undergoing dormancy. Before distant organ colonization, primary tumor microenvironment may shape the decision between proliferation and dormancy. Here, we identify lactic acid (LA), a highly abundant environmental metabolite at the primary site in prostate cancer (PCa), as a key inducer of dormant state. LA-uploading PCa cells undergo a proliferation delay, associated with stemness, therapy tolerance, and invasiveness through the nuclear receptor subfamily 2 group F member 1 (COUP-TF1/NR2F1) activation. These traits rely on LA-driven accumulation of lipid droplets (LDs), which serve as reservoirs of lipid-derived acetyl moieties essential for histone acetylation. Notably, the epigenetic reader BRD4 is essential for COUP-TF1 expression and for establishing and maintaining dormancy. In metastatic sites, where LA levels are low, dormant features are lost, allowing DCCs to support metastatic growth. Last, targeting LA-mediated LD formation or BRD4 activation prevents dormancy entry, reducing PCa cell adaptability and increasing vulnerability to antiproliferative therapies.

DOI: https://doi.org/10.1126/sciadv.aeb8595
Cell Death Differ. 2026 Oct 19.

The NEK8/ALYREF axis promotes cisplatin resistance in bladder cancer by stabilizing CDK18 mRNA to facilitate DNA damage repair.

Jia-Yin Chen, Zhi-Bin Ke, Bin Lin, Meng-Xin Liu, Zi-Heng Yan, Yu-Xuan Zhao, Chao-Ran Chen, Xue-Yi Xue, Qing-Shui Zheng, Yong Wei, Hai Cai, Ning Xu.

Cisplatin-based chemotherapy remains a standard treatment for advanced bladder cancer (BCa), however, the development of chemoresistance substantially compromises its clinical efficacy and patient prognosis. In this study, we investigated the functional role of NEK8 in cisplatin resistance in BCa and elucidated its underlying molecular mechanisms. We found that NEK8 was significantly upregulated in cisplatin-resistant BCa and was associated with unfavorable prognosis. Functional studies demonstrated that NEK8 promoted cisplatin resistance and tumor progression both in vitro and in vivo. Mechanistically, NEK8 directly interacted with ALYREF and promoted its phosphorylation and subsequent nuclear translocation. Nuclear ALYREF recognized m5C-modified CDK18 mRNA and enhanced its stability, resulting in increased CDK18 expression. Elevated CDK18 facilitated DNA damage repair, ultimately driving cisplatin resistance in BCa. Collectively, we identified a NEK8-mediated mechanism in which ALYREF phosphorylation and nuclear translocation enhance CDK18 mRNA stability and DNA damage repair, thereby driving cisplatin resistance in BCa.

DOI: https://doi.org/10.1038/s41418-026-01883-7
Front Immunol. 2026 ;17 1968997

Epigenetic and metabolic plasticity of tumor cells in immunotherapy resistance.

Jee-Eun Choi, Inwha Baek.

  Cancer immunotherapy has demonstrated remarkable efficacy across multiple tumor types. Despite their significant clinical benefits, most patients with solid tumors remain refractory to immunotherapy, and initial responders frequently develop acquired resistance. Tumor plasticity is a key driver of resistance to cancer immunotherapy. In this review, we discuss how epigenetic and metabolic plasticity of tumor contributes to immunotherapy resistance and highlight emerging strategies targeting these programs to overcome resistance and improve clinical outcomes.

Keywords:  cancer immunotherapy; chimeric antigen receptor-T cell therapy; drug resistance; epigenetic plasticity; immune checkpoint blockade; metabolic plasticity

DOI:  https://doi.org/10.3389/fimmu.2026.1968997
ACS Nano. 2026 Sep 15. 20(36): 24736-24753

A Metabolic Nanoplatform Potentiates Triple-Negative Breast Cancer Radiosensitivity via Disrupting Carbonic Anhydrase IX/Pentose Phosphate Pathway Crosstalk.

Zhili Ma, Bin Zhao, Yun Wang, Shuaishuai Ding, Yuhua Cao, Lijuan Zeng, Yunping Hu, Xiu-Wu Bian, Xiao Zhang, Gan Tian, Chuan Xu.

  Radiotherapy resistance in tumors driven by metabolic adaptations within acidic microenvironments involves the upregulation of both carbonic anhydrase IX (CA IX) and the pentose phosphate pathway (PPP) as well as the functional crosstalk between them. To overcome this, we developed a polyvinylpyrrolidone (PVP)-modified gadolinium acetazolamide (PGA) nanoradiosensitizer. PGA simultaneously inhibits CA IX to trigger intracellular acidification and tumor cell acidosis, suppresses PPP through regulation of glucose-6-phosphate dehydrogenase (G6PD), and depletes key radioresistance-sustaining metabolites, such as NADPH, lipids, and nucleotide precursors. In addition, the high-Z element Gd endows PGA with potent radiosensitizing properties by enhancing X-ray absorption and DNA damage. In orthotopic and metastatic triple-negative breast cancer (TNBC) mouse models, PGA combined with radiotherapy markedly improves the therapeutic efficacy. Mechanistically, this metabolic reprogramming amplifies radiation-induced apoptosis and immunogenic cell death (ICD) while inhibiting metastasis-associated matrix metalloproteinases (MMPs) and the epithelial-mesenchymal transition (EMT) process. Consequently, PGA effectively overcomes radioresistance and suppresses TNBC lung metastasis through the coordinated disruption of tumor metabolism and remodeling of the tumor immune microenvironment. This work advances the frontier of metabolism-targeted nanomedicine for precision cancer therapy, offering a promising strategy to combat radiotherapy resistance in aggressive breast cancer.

Keywords:  CA IX/PPP crosstalk; TNBC antimetastasis; metabolic reprogramming; radiosensitization; tumor acidosis

DOI:  https://doi.org/10.1021/acsnano.6c06716
Cell Signal. 2026 Oct 17. pii: S0898-6568(26)00618-2. [Epub ahead of print]149 112958

FABP4 drives gastric cancer peritoneal metastasis by inhibiting ferroptosis via UBR4/ALOX15-mediated arachidonic acid metabolism.

Chuanfu Ren, Xin Chen, Lifeng Zheng, Hong Chen, Zhi Yang, Xuefeng Xia, Xing Kang, Banxin Luo, Ziyun He, Zhihao Shi, Wenxian Guan, En Xu.

  Peritoneal metastasis (PM) significantly contributes to the high mortality rate in patients with advanced gastric cancer (GC) and indicates a poor prognosis. A hallmark of cancer is dysregulated lipid metabolism, and gastric cancer peritoneal metastasis (GCPM) is specifically associated with these metabolic alterations. While fatty acid binding protein 4 (FABP4) is a known crucial regulator of fatty acid metabolism in tumor cells, its precise role in GCPM remains unclear. In this study, we found that adipocytes induced FABP4 upregulation in GC cells through PPARγ-dependent signaling, and FABP4 was highly expressed in PM tissues from GCPM patients. FABP4 cooperated with CD36 to facilitate adipocyte-derived arachidonic acid (AA) acquisition while simultaneously limiting the peroxidation of AA that drives ferroptosis. Mechanistically, FABP4 stabilized UBR4 by limiting its lysosome-dependent degradation, thereby promoting UBR4-mediated ubiquitination and degradation of ALOX15, suppressing AA peroxidation and ferroptosis. Collectively, our findings reveal a FABP4-UBR4-ALOX15 axis that links adipocyte-derived lipid metabolism to ferroptosis resistance and peritoneal metastasis in GC cells, and identify FABP4 as a potential therapeutic target for GCPM.

Keywords:  Adipocytes; Arachidonic acid; FABP4; Ferroptosis; Gastric cancer; Peritoneal metastasis

DOI:  https://doi.org/10.1016/j.cellsig.2026.112958
Research (Wash D C). 2026 ;9 1461

Obesity-Induced PLPE-PTK6-FASN Feedback Loop Drives Enzalutamide Resistance by Exacerbating Lipid Metabolic Dysregulation in Castration-Resistant Prostate Cancer.

Zhuo Xing, Xuewen Jiang, Banking Shi, Ruilin Liu, Ruijiang Zeng, Shangqing Ren, Zexian Ding, Pingxia Lin, Xin Yang, Jinxiang Wang, Wenjun Mao, Xin Jin.

Obesity represents an independent risk factor for various malignancies, including prostate cancer. However, how specific lipid metabolites influence enzalutamide sensitivity in castration-resistant prostate cancer (CRPC) remains elusive. Here, we find that obesity is associated with poorer clinical outcomes during enzalutamide treatment. Lipidomic profiling reveals that 1-palmitoyl-2-linoleoyl phosphatidylethanolamine (PLPE) is markedly enriched in tumors from these individuals. Mechanistically, elevated PLPE directly binds to the SH2 domain of protein tyrosine kinase 6 (PTK6), driving its membrane translocation and functional activation. Furthermore, PLPE facilitates PTK6-fatty acid synthase (FASN) interaction, enabling PTK6 to mediate FASN phosphorylation at T976 via dual mechanisms: steric occupancy and kinase cascade amplification. This hyperactivation of FASN exacerbates lipid metabolic dysregulation, ultimately conferring enzalutamide resistance. Importantly, FASN-derived palmitic acid serves as a substrate for further PLPE synthesis, thereby reinforcing PTK6 membrane retention in a positive feedback loop. Collectively, this study identifies a PLPE-PTK6-FASN feedback loop that drives lipid metabolic reprogramming and enzalutamide resistance in CRPC with obesity, highlighting the therapeutic potential of cotargeting lipid metabolism and kinase signaling.

DOI: https://doi.org/10.34133/research.1461
Adv Sci (Weinh). 2026 Oct 20. e78301

VCP-Regulated LMF2 Stabilizes the Cholesterol Biosynthesis Enzyme HMGCS1 to Drive Cancer Progression and Confer Capecitabine Resistance in Triple-Negative Breast Cancer.

Qian Zhao, Lisa Andriani, Yin-Ling Zhang, Shao-Ying Yang, Yun-Xiao Ling, Min-Ying Huang, Jia-Yang Cai, Fang-Lin Zhang, Xin Hu, A-Yong Cao, Zhi-Min Shao, Guang-Yu Liu, Da-Qiang Li.

  Triple-negative breast cancer (TNBC) is the most therapeutically challenging breast cancer subtype owing to its aggressive nature and lack of effective targeted therapies. Here, we identify lipase maturation factor 2 (LMF2), a previously uncharacterized gene in human cancer, as a novel oncogenic driver that promotes tumor growth, metastasis, and resistance to capecitabine in TNBC both in vitro and in vivo. Mechanistically, LMF2 localizes predominantly to the endoplasmic reticulum membrane and is targeted for autophagic degradation mediated by the autophagy receptor NBR1. Valosin-containing protein (VCP) counteracts this process to stabilize LMF2 by impeding the LMF2-NBR1 interaction, and pharmacological inhibition of VCP effectively suppressed LMF2-driven TNBC progression and capecitabine resistance. LMF2, in turn, disrupts the interaction between the autophagy receptor NDP52 and HMGCS1, the rate-limiting enzyme in cholesterol biosynthesis, thereby shielding HMGCS1 from autophagic degradation and enhancing cholesterol production. Importantly, re-expression of HMGCS1 or exogenous cholesterol supplementation partially rescued the malignant and chemoresistant phenotypes impaired by LMF2 depletion. Clinically, the VCP-LMF2-HMGCS1 axis is significantly co-upregulated in TNBC patient specimens. Collectively, these findings unveil a previously unrecognized VCP-LMF2-HMGCS1 regulatory axis that drives TNBC progression and chemoresistance, and identify LMF2 as a promising therapeutic target for this recalcitrant disease.

Keywords:  autophagic degradation; cancer progression; chemoresistance; metabolic reprogramming; triple‐negative breast cancer

DOI:  https://doi.org/10.1002/advs.78301
Cancer Drug Resist. 2026 ;9 35

Adaptive drug resistance in melanoma is characterised by lipidome remodelling while maintaining cell membrane biophysical properties.

Aurélie H Benfield, Reuben S E Young, Grégoire J B Philippe, Nicholas D Condon, Nicolau Barbosa Palma Filho, Helmut Schaider, Stephen J Blanksby, Sónia Troeira Henriques.

  Aim: Cancer drug resistance is driven by dynamic, systems-level adaptations, including cellular state transitions, epigenetic reprogramming, metabolic rewiring, and proteome remodelling. Lipid metabolic reprogramming is increasingly recognised as a contributor to resistance through alterations in the membrane composition and has been hypothesised to promote resistance by increasing membrane rigidity and limiting drug permeability. Here we tested this hypothesis in melanoma using a cell state-resolved multi-omics approach. Methods: We combined lipidomics, surface-resolved phospholipid profiling, live-cell biophysical measurements, and whole-cell proteomics to characterise plasma membrane composition and function across drug-naïve, drug-tolerant persister, and permanently drug-resistant states in BRAFV600E metastatic melanoma cells treated with dabrafenib. Results: Lipidomic analyses revealed membrane remodelling, particularly in the drug-tolerant state, including altered fatty acid chain unsaturation, and increased cholesterol (Chol) and sphingomyelin levels. All cell states retained surface exposure of negatively charged phosphatidylserine and phosphatidylinositol. Despite compositional changes typically associated with membrane rigidification, plasma membrane fluidity and tension remain conserved across all resistance states. Proteomic analysis further revealed coordinated regulation of lipid metabolic pathways, including Chol homeostasis and sphingolipid turnover, indicating that lipid-metabolic adaptation supports survival under drug pressure without substantially altering membrane biophysical properties. Conclusion: These findings show that lipid metabolic rewiring supports drug tolerance while conserving core membrane features. By resolving resistance-associated changes across both molecular and biophysical layers, this study identifies shared plasma membrane features and vulnerabilities across heterogeneous melanoma cell populations, supporting the application of membrane-active therapeutic agents and of combination strategies targeting lipid-metabolic adaptations to delay or prevent resistance.

Keywords:  Proteome; cholesterol; glycerophospholipids; leaflet asymmetry; lipid metabolism; membrane lipids; metabolomics; phospholipase digestion

DOI:  https://doi.org/10.20517/cdr.2026.54
Cancer Lett. 2026 Oct 20. pii: S0304-3835(26)00666-X. [Epub ahead of print] 218902

Targeting CDC7 Overcomes Gemcitabine Resistance in Cholangiocarcinoma by Inducing Cellular Senescence.

Rong Xiao, Jing Han Hong, Peili Wang, Yi Zhong, Zhiwei Ye, Ziyu Hao, JiuPing Gao, Yu Jiang, Yu Peng, Siyu Chen, Jiaxin Yin, Lizhen Liu, Qiqing Xiong, Yaojun Zhang, Mei Li, Jianfeng Chen, Jing Tan.

  Advanced-stage cholangiocarcinoma (CCA) frequently develops resistance to chemotherapy, highlighting an urgent unmet need for novel therapeutic strategies. Here, we analyzed 16 pairs of CCA and adjacent non-tumor tissues, and demonstrated that dysregulation of the cell cycle machinery is a hallmark of CCA, closely associated with chemoresistance and poor prognosis. Targeting aberrant cell cycle regulation therefore represents a promising approach to improve current treatment outcomes. We identify the CDC7 inhibitor XL413 as an effective agent capable of re-sensitizing gemcitabine-resistant tumors across multiple preclinical models of CCA. Mechanistic analyses, including transcriptomic profiling, reveal that combination therapy activates senescence-associated pathways, with therapeutic efficacy is mediated via a ROS-DNA damage-senescence cascade. Notably, synergistic induction of cellular senescence is observed in CCA cells upon co-treatment with a CDC7 inhibitor and gemcitabine. Collectively, these findings provide robust preclinical evidence supporting the combination of gemcitabine and CDC7 inhibitors as a viable therapeutic strategy to enhance the clinical management of CCA.

Keywords:  CDC7 inhibitor; DNA damage; cellular senescence; cholangiocarcinoma; gemcitabine

DOI:  https://doi.org/10.1016/j.canlet.2026.218902
Cell Metab. 2026 Oct 21. pii: S1550-4131(26)00393-1. [Epub ahead of print]

Propionate promotes MHC class I antigen presentation and anti-tumor immunity.

Suyao Li, Dong Guo, Qingqing Yang, Yizhi Cao, Yu Dong, Xiaoming Jiang, Xinyao Tian, Dou Nie, Lihui Wu, Qingang Wu, Xuxiao He, Yanyan Hu, Rongxuan Zhu, Ning Zhu, Shudi Luo, Yinan Shen, Yuhao Wang, Zhexu Chi, Ying Yuan, Daqian Xu, Weilin Wang, Yuan Ding, Zhimin Lu.

  Defective tumor antigen presentation promotes immune evasion and resistance to immune checkpoint blockade. Here, we identified the short-chain fatty acid propionate as a potent enhancer of major histocompatibility complex class I (MHC class I) antigen presentation. Propionate stabilizes MHC class I on tumor cells, promotes CD8+ T cell infiltration and activation, and suppresses tumor growth. Mechanistically, the E3 ubiquitin (Ub) ligase STUB1 directly interacts with human leukocyte antigen (HLA)-A to mediate K168/K170 polyubiquitination and subsequent degradation. Propionate directly binds STUB1 through hydrogen bonds involving K30 and N34, residues that overlap with the MHC class I-binding interface. This interaction blocks STUB1-mediated MHC class I polyubiquitination, thereby stabilizing MHC class I, enhancing T cell receptor (TCR) engagement and T cell activation, and restraining tumor growth. Importantly, propionate or the propionate-producing probiotic Akkermansia muciniphila markedly enhanced anti-PD-1 efficacy. These findings uncover a non-metabolic moonlighting function of short-chain fatty acids in regulating tumor immunity and provide a rationale for leveraging dietary propionate or propionate-producing probiotics to enhance immune checkpoint therapy.

Keywords:  MHC class I; SCFA; STUB1; immune response; immune therapy; propionate; tumor; ubiquitination

DOI:  https://doi.org/10.1016/j.cmet.2026.09.018
Eur J Pharmacol. 2026 Oct 22. pii: S0014-2999(26)00928-3. [Epub ahead of print] 179446

Targeting PGAM1 overcomes paclitaxel resistance and restores cuproptosis sensitivity in non-small cell lung cancer.

Zhansheng Zhang, Peiheng Hu, Yiru Cong, Duo Song, Yibing Ma, Jiahong Wang, Yusheng Pei, Yanting Gu.

  Paclitaxel (PTX) resistance is a major obstacle in non-small cell lung cancer (NSCLC). The metabolic enzyme phosphoglycerate mutase 1 (PGAM1) is implicated in chemoresistance, but its role in PTX resistance and cuproptosis remains unknown. We analyzed PGAM1 expression in PTX-resistant NSCLC cells and patient cohorts, performed truncation mapping and co-immunoprecipitation, and evaluated the PGAM1/PP2A/AKT/β-catenin/ATP7B axis. Drug sensitivity and cuproptosis were assessed in vitro, in patient-derived organoids (PDOs), and in xenograft models using the PGAM1 inhibitor HKB99. We identified that PGAM1 is overexpressed in PTX-resistant NSCLC and correlates with poor prognosis. PGAM1 overexpression reduces PTX sensitivity and confers cuproptosis resistance. Mechanistically, PGAM1 binds PP2A via its 1-150 region (critical residues V81, R83, N135, D144), inhibiting PP2A and enhancing AKT/GSK3β phosphorylation. This stabilizes β-catenin and promotes its nuclear translocation, where β-catenin/TCF4 drives ATP7B transcription. Elevated ATP7B lowers intracellular copper, impairs DLAT oligomerization, and confers resistance to elesclomol-induced cuproptosis. Pharmacologic or genetic inhibition of PGAM1 restored PP2A activity, re-sensitized PTX-resistant NSCLC cells to paclitaxel, and re-engaged cuproptosis. These effects were rescued by reconstitution with wild-type PGAM1, but not with the PP2A-binding-deficient mutant, indicating that PTX resistance is driven by the scaffolding function of PGAM1. The therapeutic potential of this strategy was validated in PDOs and xenograft models, where HKB99 synergized with PTX to suppress the growth of resistant tumors. In conclusion, PGAM1 drives PTX resistance by enabling cuproptosis evasion through the PP2A/AKT/β-catenin/ATP7B axis; combining PGAM1 inhibition with PTX represents a promising strategy for refractory NSCLC.

Keywords:  Cuproptosis; HKB99; NSCLC; PGAM1; PP2A

DOI:  https://doi.org/10.1016/j.ejphar.2026.179446
Br J Cancer. 2026 Oct 21.

Inhibition of ACSS2 enhances cabozantinib sensitivity by blocking TFEB-induced autophagic flux in hepatocellular carcinoma.

Xuping Feng, Jiang Lan, Jinpeng Du, Chuang Jiang, Guoteng Qiu, Yujia Song, Xinyi Zhou, Zheng Zhang, Lin Xu, Die Hu, Yan Liang, Jiwei Huang, Yong Zeng, Kefei Yuan.

BACKGROUND: Cabozantinib, a promising tyrosine kinase inhibitor (TKI), has recently been approved by the Food and Drug Administration (FDA) to treat hepatocellular carcinoma (HCC). However, the objective response rate (ORR) of cabozantinib as monotherapy is low. Therefore, there is an urgent need to develop cabozantinib-based combination therapy.
METHODS: RNA-sequencing was used to analyse the gene expression alterations in HCC cells after cabozantinib treatment. A luciferase reporter assay was used to measure TFEB transcriptional activity. In vitro and in vivo studies were applied to assess the effect of cabozantinib in combination with autophagy inhibitors on HCC.
RESULTS: Our results showed that cabozantinib induces autophagic flux, which protects HCC cells from cabozantinib-induced growth inhibition and apoptosis. Further mechanistic studies showed that cabozantinib upregulates Acetyl-CoA Synthetase 2 (ACSS2) and promotes its nuclear translocation, which subsequently activates transcription factor EB (TFEB). TFEB then binds to lysosomal and autophagy gene promoter regions, thereby promoting lysosomal biogenesis and inducing autophagy. In addition, the combination use of an ACSS2 inhibitor or chloroquine (CQ) enhances the antitumor efficacy of cabozantinib in HCC both in vitro and in vivo.
CONCLUSION: Our study proposes a novel molecular mechanism of cabozantinib and provides insights into cabozantinib-based combination therapy for HCC.

DOI: https://doi.org/10.1038/s41416-026-03538-3