bims-meract Biomed News
on Metabolic reprogramming and anti-cancer therapy
Issue of 2026–10–18
nineteen papers selected by
Andrea Morandi, Università degli Studi di Firenze
  1. Carboxylesterase 1 is a core metabolic vulnerability of platinum-resistant high-grade serous ovarian carcinoma.
  2. Targeting metabolic cell death in cancer to reverse drug resistance.
  3. Mitochondria-targeted tetraoxanes initiate lipid peroxidation to drive ferroptosis and tumor suppression.
  4. Targeting the HIF-1α-BSG metabolic circuit reverses enzalutamide resistance in prostate cancer.
  5. Targeting MMGT1 enhances immunotherapy efficacy in triple-negative breast cancer.
  6. ARID2 Loss Reprograms the Kynurenine-AhR Pathway to Restore Antitumor Immunity in CTNNB1-Mutant Hepatocellular Carcinoma.
  7. Dynamic changes in the metabolic network and signalling pathways of cancer stem cells in therapy resistance.
  8. Macrophage-induced ferritin expression protects pancreatic cancer cells from ferroptosis.
  9. Regulation of PDH via cysteine oxidation on DLAT.
  10. MDK+ cancer-associated fibroblasts promote immunotherapy resistance through mitochondrial reprogramming in breast cancer.
  11. GLS2 reshapes glycolytic metabolism and bioenergetic homeostasis in glioblastoma cells.
  12. Lactylation-Mediated HER2 Stabilization Promotes Trastuzumab Resistance in Gastric Cancer.
  13. PINK1-mediated mitophagy supports lung cancer initiation and limits the efficacy of KRAS-targeted therapy.
  14. Antagonistic roles of histone H3 lysine methyltransferases dictate tumor immune surveillance.
  15. Inhibition of PHB2/PINK1-mediated mitophagy potentiates venetoclax activity in acute myeloid leukemia.
  16. Hepatocellular Carcinoma Overcomes Lipid Depletion by Utilizing Serine for Phospholipid Synthesis and Enhanced Survival.
  17. Pharmacological protection from a sugar-rich diet through inhibition of Ras/MAPK signaling.
  18. Metabolic signature of phosphoethanolamine and arginine pathways predicts prognosis and immunotherapy resistance in lung adenocarcinoma.
  19. Selective lipid Metabolic remodelling in radiosensitive normal tissues after FLASH radiotherapy.
  1. J Exp Clin Cancer Res. 2026 Jul 24. pii: 217. [Epub ahead of print]45(1):
    Carboxylesterase 1 is a core metabolic vulnerability of platinum-resistant high-grade serous ovarian carcinoma.
    Irene Flati, Davide Vecchiotti, Fiorenza Di Giovanni, Daniela Verzella, Francesca Dall'Aglio, Angelo Sarra, Chiara Battistini, Melissa Zambuto, Giuseppe Frisullo, Jessica Cornice, Ilaria Nunzi, Mauro Di Vito Nolfi, Harry J Whitwell, Francesca Veglianti, Hafiz Nadeem Khan, Saverio Marchi, Guido Franzoso, Ugo Cavallaro, Daniel D'Andrea, Edoardo Alesse, Francesca Zazzeroni, Daria Capece.
       BACKGROUND: Platinum-resistant high-grade serous ovarian carcinoma (HGSOC) is a major clinical challenge, with high mortality rates and no effective therapeutic options. Metabolic adaptations-including enhanced lipid catabolism, oxidative phosphorylation (OXPHOS), and autophagy-are major drivers of chemoresistance; however, the molecular mechanisms underpinning this metabolic reprogramming remain poorly understood. Carboxylesterase 1 (CES1), an NF-κB-regulated neutral lipase, supports malignant cell survival under nutrient-depleted conditions in other cancers, but its role in HGSOC has not been explored.
    METHODS: We investigated the role of CES1 in i) epithelial ovarian cancer (EOC) cell lines across different histological subtypes, ii) primary HGSOC cells, iii) syngeneic and platinum-resistant HGSOC mouse models. Glucose and serum limitation was used to model metabolic stress associated with platinum resistance. CES1 activity was blocked both genetically and pharmacologically using the specific CES1 inhibitor GR-148672X. Metabolic profiling, survival analysis, lipid-droplet dynamics and autophagy assays were performed. Clinical significance was evaluated by analyzing The Cancer Genome Atlas (TCGA) cohort, stratified by chemotherapy response.
    RESULTS: Metabolic stress induced a shift from glycolysis to OXPHOS and promoted platinum resistance in EOC cells. This adaptation was coincident with an upregulation of CES1, which supported lipolysis, fatty acid oxidation, and autophagy/lipophagy. CES1 inhibition disrupted these processes leading to apoptosis/ferroptosis in platinum-resistant EOC lines. Oleate supplementation effectively reversed CES1-mediated biological effects, confirming their dependence on CES1-driven lipid mobilization. CES1 blockade also killed primary HGSOC cells with oxidative dependency for survival, impaired tumor growth and metastatic dissemination in Trp53-/- ID8-Luc allografts and retained robust antitumor activity in platinum-resistant HGSOC xenografts. Further, in the TCGA dataset, an elevated CES1/Carnitine Palmitoyl-transferase 1A (CPT1A) gene signature correlated with shorter overall survival (OS) and disease-specific survival (DSS) in chemoresistant, but not chemosensitive patients with HGSOC, underscoring the clinical significance of this metabolic axis in platinum resistance.
    CONCLUSIONS: CES1 is a key checkpoint governing metabolic plasticity in EOC including HGSOC, by linking lipid catabolism, OXPHOS, and autophagy to chemoresistance under conditions of metabolic pressure. Targeting CES1 selectively compromises tumor cell survival under nutrient deprivation, uncovering a metabolic vulnerability that may be exploited to treat aggressive platinum-resistant HGSOC that rely on OXPHOS to thrive.
    Keywords:  Autophagy; Carboxylesterase 1; Chemoresistance; High Grade Serous Ovarian Carcinoma; Metabolic adaptation
    DOI:  https://doi.org/10.1186/s13046-026-03766-8
  2. Biochim Biophys Acta Rev Cancer. 2026 Oct 16. pii: S0304-419X(26)00209-X. [Epub ahead of print] 189737
    Targeting metabolic cell death in cancer to reverse drug resistance.
    Tingting Liu, Yixiong Dang, Wen Zhang, Yanting Liu, Yinghua Ji, Ping Lu, Haimin Zou, Wenyong Yang, Jingwen Jiang.
      Evasion of apoptosis is a typical feature of malignant tumors developing to survive therapeutic stress. As a result, chemotherapeutic drugs that primarily induce apoptosis can no longer effectively kill tumor cells, which brings challenges to clinical cancer treatment. Recent evidence indicates that targeting key nodes in cellular metabolic pathways can bypass apoptotic routes and induce metabolic cell death in tumor cells to overcome drug resistance. Different from the traditional ways of defining cell death that rely on morphological features, metabolic cell death focuses more on the inducing factors and the associated dysregulation of cellular metabolic pathways. Metabolic cell death can be classified into four categories based on the driver factors of cell death: (1) metal ion dyshomeostasis-mediated cell death; (2) redox-collapse cell death; (3) pH dyshomeostasis-driven cell death; and (4) metabolic byproduct accumulation-mediated cell death. According to these metabolic cell death patterns, several therapeutic strategies targeting the metabolic vulnerabilities have attracted considerable attention. Here, we summarize the major metabolic cell death patterns of tumor cells, examine how these death modalities engage anti-tumor immunity, and discuss how exploiting them can reverse drug resistance. We further discuss the therapeutic window, tumor metabolic heterogeneity, and metabolic network therapeutic implications.
    Keywords:  Drug resistance; Metabolic cell death; Redox system; Tumor metabolism; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189737
  3. Cell. 2026 Oct 15. pii: S0092-8674(26)01141-4. [Epub ahead of print]
    Mitochondria-targeted tetraoxanes initiate lipid peroxidation to drive ferroptosis and tumor suppression.
    Zijian Pan, Ming-Kwan Wong, Yang Lu, Jingxuan Mao, Fengxiang Wang, Xin Gu, Kaiyin Huang, Taotao Shi, Tianshu William Wu, Yuxuan Zhu, Yuan Zhang, En Chen, Jingrong Regina Han, Yunfei Qiu, Lei Zhou, Yinxin Li, Peng Lin, Zhibin Li, Shan Deng, Yingshan Fang, Qi Xie, Jian Cao, Nathchar Naowarojna, Dan Yang, Yilong Zou.
      Ferroptosis is implicated as a vulnerability in multiple cancers, yet approaches for effectively inducing ferroptosis in vivo are limited. Bypassing conventional strategies targeting the antiferroptotic glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) proteins, we designed metabolic initiators of lipid peroxidation (MILPOs) and developed the compounds WMK-1/2, which contain tetraoxane radical-generating and mitochondria-targeting groups, as de novo ferroptosis inducers. WMK-1 localizes primarily to mitochondria, induces local lipid peroxidation, and impairs oxidative phosphorylation. WMK-1 induces a "mito-ferroptosis" sub-pathway that skips GPX4 inhibition as a prerequisite, can be rescued by lipophilic radical-trapping antioxidants, yet is minimally sensitive to acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) perturbation and long-chain polyunsaturated fatty acid (PUFA) supplementation, and evades retinol-mediated protection. Instead, WMK-1-induced cell death requires labile Fe2+ and can be selectively suppressed by ɑ-lipoic acid, an endogenous, mitochondria-resident antioxidant. WMK-1/2 are bioavailable and exhibit significant efficacy in tumor suppression by eliciting ferroptosis in multiple cancer models and augmenting the antitumor effects of immune-checkpoint blockers. Our work provides a protein-targeting-independent metabolic ferroptosis induction strategy for potential cancer therapy.
    Keywords:  cancer and metastasis; ferroptosis induction; iron metabolism; metabolic initiator of lipid peroxidation; mito-ferroptosis; mitochondria; tetraoxanes
    DOI:  https://doi.org/10.1016/j.cell.2026.09.040
  4. Cell Signal. 2026 Oct 13. pii: S0898-6568(26)00607-8. [Epub ahead of print]149 112947
    Targeting the HIF-1α-BSG metabolic circuit reverses enzalutamide resistance in prostate cancer.
    Xiuchen Guo, Jiacheng Huang, Zhiwei Chen, Haihong Liao, Yulin Xu, Yongjiang Yu.
       BACKGROUND: Enzalutamide resistance limits durable control of castration-resistant prostate cancer (CRPC), but the mechanisms coordinating metabolic adaptation, cellular plasticity, and residual androgen receptor (AR) signaling remain incompletely understood. We investigated whether BSG, encoding basigin/CD147, contributes to this resistant state.
    METHODS: We integrated reanalysis of an androgen-responsive reporter-based CRISPR activation screen with bulk and single-cell transcriptomic datasets, clinical specimens, and outcome data. Reciprocal BSG loss- and gain-of-function experiments were performed in parental and enzalutamide-resistant LNCaP and C4-2 cells. Drug response, cellular plasticity, glycolytic activity, hypoxia/HIF1A perturbation, pathway-directed inhibition, and resistant xenografts were evaluated.
    RESULTS: BSG-activating guides were enriched in unsorted and androgen-responsive, but not androgen-independent, enzalutamide-resistant populations. BSG was elevated in resistant models and high-Gleason-score tumors, and high expression was associated with shorter progression-free survival. Single-cell analysis identified a CRPC-enriched tumor-cell state with high BSG and SLC16A3 expression, increased glycolysis and hypoxia-related activity, enhanced developmental plasticity, and retained AR-target gene expression. BSG depletion increased enzalutamide responsiveness and suppressed proliferation, clonogenic survival, migration, invasion, sphere formation, and stemness and epithelial-mesenchymal transition programs in resistant cells, whereas BSG overexpression produced reciprocal effects in parental cells. BSG depletion reduced AR and PSA abundance in LNCaP EnzR cells. It also reduced extracellular acidification, lactate production, glucose uptake, and the abundance of HK2, LDHA, MCT1, and MCT4. Hypoxia or HIF1A overexpression increased BSG-associated metabolic and plasticity programs, whereas BSG depletion attenuated most HIF-1α-induced changes without materially reducing HIF-1α. In resistant xenografts, BSG depletion or PX-478 enhanced tumor suppression by enzalutamide.
    CONCLUSIONS: BSG contributes to an AR-retaining, hypoxia-associated glycolytic and plastic state that supports enzalutamide resistance.
    Keywords:  Basigin; Castration-resistant prostate cancer; Cellular plasticity; Enzalutamide resistance; Glycolysis; scRNA-seq
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112947
  5. Cell Rep Med. 2026 Oct 16. pii: S2666-3791(26)00537-9. [Epub ahead of print] 103120
    Targeting MMGT1 enhances immunotherapy efficacy in triple-negative breast cancer.
    Shaoqing Liu, Hongbing Liu, Mengying Zhang, Kaiyuan Guo, Shilin Tong, Nuo Jiang, Jinxue Zhou, Linlin Yan, Mien-Chie Hung, Chenhao Zhou, Yanzhao Zhou, Min Xu.
      The role of senescent tumor cells in modulating the immune microenvironment and influencing immunotherapy efficacy remains poorly understood. In this study, we investigate the function of the senescence-associated gene membrane magnesium transporter 1 (MMGT1) in triple-negative breast cancer (TNBC) immunotherapy. MMGT1 is upregulated in TNBC and correlates with poor prognosis. Mammary gland-specific knockout of Mmgt1 significantly impedes tumor growth. Mechanistically, MMGT1 promotes lipid metabolism by facilitating translocation of the SCAP-SREBP1 complex to the Golgi apparatus, thereby suppressing cellular senescence. Notably, senescent TNBC cells enhance CD8+ T cell proliferation and cytotoxicity through CCL20 secretion. Furthermore, a positive feedback loop exists between MMGT1 and SREBP1. In vivo, AZ191 downregulates MMGT1 expression, which suppresses tumor growth and enhances the efficacy of anti-PD-1 therapy. Collectively, these findings reveal a critical role for MMGT1 in shaping the TNBC immune microenvironment and suggest that targeting MMGT1 represents a promising strategy to improve anti-PD-1 immunotherapy outcomes.
    Keywords:  CD8(+) t; cellular senescence; immunotherapy; membrane magnesium transporter 1; triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.xcrm.2026.103120
  6. Cancer Res. 2026 Oct 14.
    ARID2 Loss Reprograms the Kynurenine-AhR Pathway to Restore Antitumor Immunity in CTNNB1-Mutant Hepatocellular Carcinoma.
    Qianyu Li, Yunfeng Yuan, Ning Liu, Linfeng Li, Yifei Qian, Fan Wang, Songling Li, Wenli Qin, Quankun Lin, Hongmin Lu, Yuliang Rao, Qiang Xia, Yanan Wang, Yanfeng Liu.
      Hepatocellular carcinoma (HCC) driven by gain-of-function mutations in CTNNB1 (CTNNB1GOF) that stabilize β-catenin exhibits a profoundly immunosuppressive tumor microenvironment (TME), rendering it resistant to immune checkpoint blockade (ICB). Metabolic reprogramming is increasingly recognized as a crucial mediator of immune activity, highlighting the need to elucidate the specific metabolic mechanisms underlying immune exclusion in CTNNB1GOF HCC. Here, we identified a critical metabolic-immune network orchestrated by co-mutations of CTNNB1 and ARID2. Integrative analysis of HCC patient cohorts and a de novo MYC/CTNNB1GOF HCC mouse model revealed that tumors harboring concurrent CTNNB1 and ARID2 mutations exhibited a more immune-active TME and improved survival compared to tumors with CTNNB1 mutations alone. Mechanistically, β-catenin and ARID2 cooperatively enhanced the transcription of tryptophan 2,3-dioxygenase (TDO2), leading to accelerated kynurenine production and activation of the aryl hydrocarbon receptor (AhR) in myeloid-derived suppressor cells (MDSCs). This metabolic axis established an immunosuppressive milieu characterized by MDSC accumulation and impaired T cell function. Genetic ablation of Arid2 in CTNNB1GOF HCC attenuated TDO2-dependent kynurenine synthesis, reduced MDSC infiltration, and enhanced CD8⁺ T cell cytotoxicity, thereby sensitizing tumors to anti-PD-1 therapy. Clinically, co-mutations of CTNNB1 and ARID2 correlated with elevated immune infiltration and favorable ICB responses across multiple human cancers, including HCC. Importantly, pharmacological inhibition of AhR phenocopied the immunomodulatory effect of ARID2 loss and, when combined with anti-PD-1, robustly reversed the immune-cold phenotype of CTNNB1GOF HCC. These findings reveal TDO2-kynurenine-AhR signaling as a pivotal metabolic pathway enforcing immune evasion in CTNNB1-mutant HCC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-0860
  7. Biochim Biophys Acta Rev Cancer. 2026 Oct 15. pii: S0304-419X(26)00210-6. [Epub ahead of print] 189738
    Dynamic changes in the metabolic network and signalling pathways of cancer stem cells in therapy resistance.
    Onyisi C Didamson, Sajan George, Heidi Abrahamse.
      Cancer stem cells (CSCs) play a pivotal role in therapeutic resistance, metastasis, and tumour recurrence. During treatment, these cells undergo dynamic changes that enable survival and metabolic adaptation, leading to poor clinical outcomes. CSCs are capable of developing resistance to drugs by alterations in the metabolic and signalling pathways. They exhibit metabolic adaptations that enable therapy resistance, tumour recurrence, and metastasis. These adaptations involve shifts in glycolysis, oxidative phosphorylation (OXPHOS), lipid and amino acid metabolism, mitochondrial dynamics, and interactions with the tumour microenvironment to support energy production. Depending on the biological contexts and the energy needs, CSCs can switch to different metabolic phenotypes. CSCs drive energy production and biogenesis via glycolysis in hypoxic conditions. OXPHOS is essential for sustaining cell dormancy, survival and carcinogenesis. In addition to glycolysis and OXPHOS, CSCs employ lipid metabolism for energy production via fatty acid oxidation and amino acids metabolism via glutamine metabolism promoting redox balancing and epigenetic modifications. Taken together, this metabolic plasticity facilitates CSC survival and treatment resistance. Besides, CSCs are capable of metabolically rewiring their niche to evade apoptosis, enhance DNA repair, and promote immune evasion, which are considered hallmarks of drug resistance and cancer relapse. An in-depth understanding of the metabolic network and signalling pathways of CSCs may help in developing combination or targeted therapies against them, thereby increasing the potential to formulate effective treatment approaches for the complete eradication of cancer/CSCs. This review addresses dynamic changes in the CSCs' metabolism and signalling leading to the development of drug-resistance phenotype, causing survival and relapse in the tumours. Therapeutic strategies targeting CSC metabolism and signalling via metabolic modulators and stemness inhibitor were discussed. Overall, CSC metabolic adaptation promotes drug resistance and tumour proliferation. Hence targeting these metabolic adaptations offers new perspective for the elimination of CSCs and enhanced therapy.
    Keywords:  Apoptosis; Metabolism; Resistance; Signalling; Stemness; cancer
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189738
  8. Cell Rep. 2026 Oct 13. pii: S2211-1247(26)01158-7. [Epub ahead of print]45(10): 118079
    Macrophage-induced ferritin expression protects pancreatic cancer cells from ferroptosis.
    Eric C Cheung, Meng-Han Wu, Wen-Chi Cheng, Jack Coomes, Karen Blyth, Karen H Vousden.
      Reactive oxygen species (ROS) drive pro-tumorigenic signaling but also promote lipid peroxidation and ferroptosis, making ROS regulation critical during high oxidative stress stages of tumor progression, such as metastasis. Loss of the antioxidant TIGAR in pancreatic ductal adenocarcinoma (PDAC) cells raises ROS and enhances metastatic behavior but also sensitizes cells to ferroptosis. To understand how TIGAR-null cells survive to metastasize, we examine the role of macrophage infiltration, which is increased in TIGAR-null tumors. Co-culturing TIGAR-null PDAC cells with macrophages protects them from ferroptosis. The tumor cells induce macrophage IL-6 secretion, which leads to the activation of STAT3 and upregulation of the iron-sequestering protein ferritin (FTH1) in cancer cells. FTH1 depletion in TIGAR-null cells restores ferroptosis sensitivity and reduces lung metastasis. These results suggest that the outcome of increased ROS in tumors may depend on the activation of mechanisms that selectively prevent ferroptosis while preserving ROS-induced oncogenic signaling and metastasis-promoting pathways.
    Keywords:  CP: cancer; CP: immunology; PDAC; ferritin; ferroptosis; macrophages; metastasis; oxidative stress; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1016/j.celrep.2026.118079
  9. Nat Commun. 2026 Oct 14. pii: 10784. [Epub ahead of print]17(1):
    Regulation of PDH via cysteine oxidation on DLAT.
    Fabiola Garcia-Cortizo, Tobias Weber, Hana Nůsková, Daniel Pfaff, Michael Büttner, Angela Wirth, Elisabeth Kliemank, Gernot Poschet, Marc Freichel, Thomas Fleming, Alba Sulaj, Peter Paul Nawroth, Julia Szendroedi, Aurelio A Teleman.
      Pyruvate dehydrogenase (PDH) complex is a key regulator of metabolism, controlling flux from glycolysis into the tricarboxylic acid (TCA) cycle. PDH is often dysregulated in metabolic diseases and cancer. We discover here that in addition to its well characterized regulation by phosphorylation, PDH activity is also regulated via inhibitory oxidation of three cysteines of the DLAT subunit - Cys488, Cys586 and Cys618. Oxidation of these cysteines increases under oxidative stress, and is highly prevalent in mouse and human tissues. This mechanism enables cells to efficiently fight oxidative stress. Under oxidative stress, cells execute a metabolic shift, blocking glycolytic flux into the TCA cycle to shunt glycolytic carbons toward the pentose phosphate pathway. This generates NADPH which cells use to detoxify H2O2 and to reduce oxidized cysteines. We find that DLAT oxidation is required for cells to mount an effective antioxidant response. Mutations preventing DLAT oxidation render PDH resistant to oxidative inhibition, impair NADPH generation, reduce peroxide detoxification, and sensitize cells to oxidative damage and death. DLAT oxidation also drives a Warburg-like metabolic phenotype of increased glucose uptake, elevated lactate secretion, and reduced TCA cycle activity. Thus DLAT oxidation is a redox-sensing mechanism that regulates PDH activity and central carbon metabolism.
    DOI:  https://doi.org/10.1038/s41467-026-78266-6
  10. Cancer Lett. 2026 Oct 14. pii: S0304-3835(26)00648-8. [Epub ahead of print] 218884
    MDK+ cancer-associated fibroblasts promote immunotherapy resistance through mitochondrial reprogramming in breast cancer.
    Wei Deng, Yidan Fan, Hanqi Zhang, Song Wu, Kaiying Zhang, Yongzhou Luo, Wenwen Tian, Huajie Guan, Hailin Tang, Lewei Zhu, Zikun Ma, Rongfang He, Yutian Zou.
      Immunotherapy has improved outcomes for patients with breast cancer, yet therapeutic resistance remains a major clinical challenge. Therefore, we integrated single-cell and spatial transcriptomic data from breast cancer cohorts treated with immune checkpoint inhibitors to identify resistance-associated cellular populations and pathways, with validation across eight independent bulk RNA-seq immunotherapy cohorts. Cancer-associated fibroblasts (CAFs) were isolated from anti-PD-1-resistant breast tumors for functional studies, including in vitro co-culture and in vivo models. Mitochondrial function and metabolic alterations were assessed by flow cytometry, transmission electron microscopy, ATP and adenosine quantification, and JC-1 staining. Tumor mitochondrial metabolism was markedly upregulated in anti-PD-1 non-responders and consistently associated with poor therapeutic response across validation cohorts. MDK-expressing CAFs were enriched in resistant tumors, exhibited strong interactions with tumor cells, and were negatively associated with intratumoral CD8+ T cell infiltration. Single-cell source contribution and depletion analyses identified CAF-derived MDK as the major paracrine mediator linking stromal signaling to tumor metabolic adaptation and immune suppression. Mechanistically, MDK activated SDC1-dependent PI3K/AKT/mTOR signaling in cancer cells, promoting mitochondrial metabolic reprogramming, ATP production, and CD38/CD73-dependent extracellular adenosine accumulation, thereby suppressing CD8+ T cell cytotoxicity. Receptor-depletion experiments further identified SDC1 as the principal functional receptor mediating these effects. Importantly, CAF-specific MDK depletion or pharmacological MDK inhibition enhanced anti-PD-1 efficacy and restored CD8+ T cell effector activity in vivo. Collectively, MDK+ CAFs facilitate anti-PD-1 resistance via mitochondrial rewiring and adenosine-mediated immunosuppression, supporting the MDK-SDC1 axis as a potential therapeutic target for overcoming resistance and improving immunotherapy efficacy in breast cancer.
    Keywords:  Anti-PD-1 resistance; Breast cancer; Cancer-associated fibroblasts; Immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2026.218884
  11. Pharmacol Rep. 2026 Oct 14.
    GLS2 reshapes glycolytic metabolism and bioenergetic homeostasis in glioblastoma cells.
    Juan De Los Santos-Jiménez, José A Campos-Sandoval, Jessica Sudderth, Lauren G Zacharias, João Santos Patricio, Francisco J Alonso, Javier Márquez, Thomas P Mathews, Ralph J DeBerardinis, José M Matés.
       BACKGROUND: Glioblastoma (GBM) exhibits extensive metabolic reprogramming, including glucose and glutamine (Gln) addiction, with Gln being converted into glutamate by glutaminase, encoded by the GLS and GLS2 genes. GLS2 acts as a context-dependent tumor suppressor, although the underlying mechanisms remain poorly understood. GLS2 is silenced in GBM, and we previously showed that its re-expression modulates pyruvate dehydrogenase (PDH) activity and tricarboxylic acid cycle (TCAC) metabolism, suggesting a distinct metabolic rewiring associated with its tumor-suppressive function.
    METHODS: LN229 and T98G GBM cell lines were used as experimental models. Metabolomic profiling by liquid chromatography-mass spectrometry was performed to compare changes in central metabolic pathways following GLS2 or GLS overexpression. Glutaminase and PDH enzymatic activities were measured, and Western blotting was performed to assess GLS, GLS2, and PDHA1 protein levels and PDHA1 phosphorylation. A Seahorse analyzer was employed to quantify real-time ATP production derived from glycolysis and oxidative phosphorylation.
    RESULTS: Overexpression of GLS2, but not GLS, in LN229 cells caused the accumulation of TCAC-related metabolites, except for citrate, whose depletion is attributed to GLS2's effect on PDH phosphorylation, causing reduced PDH activity. This was accompanied by decreased levels of several acyl-carnitines. Furthermore, GLS2 induced the accumulation of glucose/fructose, while reducing levels of glucose-6-phosphate and pentose-phosphates, consistent with altered glycolysis. GLS2 also diminished the ATP/AMP ratio, confirmed by a reduced ATP synthesis rate, particularly glycolytic ATP, whereas mitochondrial ATP production remained unaltered.
    CONCLUSIONS: GLS2 exerts an isoenzyme-specific effect on Gln and glucose metabolism in GBM, likely modulating the glycolysis/pentose-phosphate pathway (PPP)-TCAC-axis.
    Keywords:  Cancer metabolism; GLS2; Glioblastoma; Glutaminase; Glutamine; Pyruvate dehydrogenase
    DOI:  https://doi.org/10.1007/s43440-026-00908-9
  12. Adv Sci (Weinh). 2026 Oct 11. e77955
    Lactylation-Mediated HER2 Stabilization Promotes Trastuzumab Resistance in Gastric Cancer.
    Meng Qian, Tongguan Tian, Zhenxiang Wang, Huihui Sun, Ming Zong, Ying Chen, Jie Xiong, Ye Chen, Zhiqian Hu, Tianming Li, Yanping Xu, Shuchang Xu.
      Trastuzumab is the standard first-line targeted therapy for human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). Unfortunately, its clinical efficacy is often compromised by the development of drug resistance. The Warburg effect, a hallmark of cancer metabolism, leads to substantial lactate accumulation. Nevertheless, the impact of metabolic reprogramming on the response to HER2-targeted therapy remains poorly understood. Here, we demonstrate that AARS1-mediated lactylation of HER2 promotes trastuzumab resistance in GC. Mechanistically, lactylation at lysine 1171 (K1171) promotes USP11-mediated deubiquitination and stabilization of HER2 and also enhances the interaction between HER2 and EGFR. Clinically, elevated HER2 K1171 lactylation levels are associated with poor prognosis in GC patients. Inhibiting HER2 K1171 lactylation with L-alanine or stiripentol-a lactate dehydrogenase inhibitor (LDHi) clinically approved for epilepsy-significantly sensitizes tumor cells to trastuzumab. Furthermore, a cell-penetrating peptide designed to specifically block HER2 K1171 lactylation potently enhances antitumor efficacy in vivo. In summary, our findings identify HER2 lactylation as a critical mechanism underlying trastuzumab resistance and highlight lactate metabolism as a promising therapeutic target for HER2-positive GC.
    Keywords:  gastric cancer; human epidermal growth factor receptor 2 (HER2); lactylation; resistance mechanism; trastuzumab
    DOI:  https://doi.org/10.1002/advs.77955
  13. Sci Adv. 2026 Oct 16. 12(42): eaef8820
    PINK1-mediated mitophagy supports lung cancer initiation and limits the efficacy of KRAS-targeted therapy.
    Diogo Gonçalves, Emma Guilbaud, Léa Di Mascio, Camille Guerrier, Linda Mejri, Sonia Núñez-Vázquez, Lucie Levasseur, Rachel Paul, Corinne Menigot, Christophe Bontoux, Guylène Rignol, Véronique Hofman, Paul Hofman, Marin Truchi, Bernard Mari, Laurent Yvan-Charvet, Johanna Chiche, Sandrine Marchetti, Jean-Ehrland Ricci.
      Mitophagy, the selective degradation of mitochondria by lysosomes, is a major mitochondrial quality-control pathway, yet its role in lung cancer initiation and therapeutic response remains poorly understood. We investigated PINK1-dependent mitophagy in human lung adenocarcinoma and directly monitored mitophagy in vivo using mito-QC reporter mice during lung tumor development. We found that PINK1 activity and mitophagy are increased in human tumors and are activated from the earliest stages of tumorigenesis. Genetic inhibition of PINK1 impaired oncogenic transformation but had little impact once tumor cells were established, identifying mitophagy as a critical early adaptation during lung cancer initiation. PINK1 deficiency markedly enhanced the efficacy of KRAS-targeted therapy in vitro and in vivo. Together, our findings identify PINK1-dependent mitophagy as an early vulnerability in KRAS-driven lung cancer and provide a rationale for targeting mitophagy to improve the efficacy of KRAS-targeted therapies.
    DOI:  https://doi.org/10.1126/sciadv.aef8820
  14. Nat Commun. 2026 Sep 14. pii: 10810. [Epub ahead of print]17(1):
    Antagonistic roles of histone H3 lysine methyltransferases dictate tumor immune surveillance.
    Amy C Gladstein, Akino Mercy Charles Solomon, Carson D Poltorack, Sharan Venkatesh, Keren M Adler, Maggie R Robertson, Stephanie Stransky, Valerie M Irizarry-Negron, Dain A Ruiz, Dingwen Tao, Nelson F Freeburg, Simone Sidoli, Irfan A Asangani, Sydney M Shaffer, David M Feldser.
      SETD2 is a critical tumor suppressor in lung cancer that catalyzes histone H3 lysine 36 (H3K36) trimethylation. Oncogenic histone H3 alleles, including H3K36M, causally drive cancer formation by dominantly inhibiting SETD2 and other H3K36 methyltransferases. Here we show that expression of the H3K36M oncogene paradoxically suppresses tumor growth in KRAS-driven lung cancer by promoting transcription of repetitive elements and accumulation of cytoplasmic dsRNA, activating antiviral-like immune clearance. Unexpectedly, all attendant effects of H3K36M expression require SETD2 activity despite widespread loss of H3K36 trimethylation. Reducing H3K36 dimethylation through genetic or pharmacologic attenuation of NSD2 phenocopies H3K36M expression, revealing NSD2 as the relevant target through which H3K36M triggers immune activation. Mechanistically, H3K36M expression or NSD2 attenuation reveals a SETD2-dependent mechanism that limits EZH2-mediated repression of repetitive elements, enabling dsRNA accumulation and immune activation. These findings establish opposing roles for NSD2- and SETD2-dependent H3K36 methylation in lung tumor immunity and reveal an NSD2-SETD2-EZH2 axis that can be targeted to modulate viral mimicry and immune surveillance in cancer.
    DOI:  https://doi.org/10.1038/s41467-026-76657-3
  15. Leukemia. 2026 Oct 13.
    Inhibition of PHB2/PINK1-mediated mitophagy potentiates venetoclax activity in acute myeloid leukemia.
    Romain Vazquez, Maxime Sajot, Jad Nasrallah, Rudy Birsen, Ismaël Boussaid, Morgane Plevenage, Zubaidan Tuerdi, Axelle Guedon, Lilia Cantero Aguilar, Tony Huynh, Natacha Johnson, Chloé Friedrich, Eric Grignano, Justine Decroocq, Lise Willems, Carole Almire, Marie-Clotilde Alves-Guerra, Evelyne Lauret, Yannick Simoni, Michaela Fontenay, Olivier Kosmider, Didier Bouscary, Clement Larrue, Nicolas Chapuis.
      Acute myeloid leukemia (AML) cells are highly dependent on mitochondrial activity for survival, with this metabolic reliance driven in part by BCL-2, which is therapeutically targeted by venetoclax-based therapies. The regulation of mitochondrial dynamics in leukemic cells is therefore essential for maintaining mitochondrial homeostasis. However, the mechanisms that enable selective degradation of damaged mitochondria (mitophagy) are still poorly understood in AML. In this study, we sought to elucidate the role of PTEN-induced putative kinase 1 (PINK1), a key sensor of mitochondrial stress, in regulating mitophagy in leukemic cells. Our results identified PINK1 as a central modulator of mitophagy. Genetic depletion of PINK1 reduced both basal and stress-induced mitophagy, leading to mitochondria accumulation and functional impairment. Additionally, we discovered that PINK1 stabilization during mitochondrial stress is regulated by Prohibitin 2 (PHB2), and that depletion or inhibition of PHB2 mirrored the biological effects of PINK1 loss. Notably, both genetic depletion of PINK1 or PHB2, as well as pharmacological inhibition of PHB2, significantly increased AML cell sensitivity to venetoclax both in vitro and in vivo. Together, these findings highlight the potential of targeting the PHB2/PINK1 signalling pathway to improve the efficacy of venetoclax-based therapies in AML by disrupting the mitophagy process.
    DOI:  https://doi.org/10.1038/s41375-026-03160-5
  16. JHEP Rep. 2026 Oct 12. pii: S2589-5559(26)00334-4. [Epub ahead of print] 102063
    Hepatocellular Carcinoma Overcomes Lipid Depletion by Utilizing Serine for Phospholipid Synthesis and Enhanced Survival.
    Bichitra Paul, Monika Lewinska, Juan F Lafuente-Barquero, Ekaterina Zhuravleva, Mikel Ruiz de Gauna, Matthias Mattanovich, Xabier Buqué, Dawei Geng, Raissa Novais Rodrigues, Martin Woergaard Kjær, Sebastian Weber Nielsen, Blanca I Aldana, Jens U Marquardt, Patricia Aspichueta, Thomas Moritz, Jesper B Andersen.
       BACKGROUND & AIMS: Metabolic vulnerabilities of hepatocellular carcinoma (HCC) remain largely unexplored functionally, though their deregulation is a major cancer hallmark. This study aims to investigate HCC tumor cells marked lipid-dependency and explore their distinct responses when grown in lipid starved conditions.
    METHODS: We challenged 8 HCC tumor cell lines by lipid depletion, studying their functional phenotypes through lipidomics, metabolomics, transcriptomics, and metabolic fluxes to define how tumor cells may survive metabolic challenges such as lipid depletion.
    RESULTS: HCC cell lines were functionally grouped as lipid-depletion sensitive (LD-S), characterized by high triglycerides and cholesterol esters, or lipid-depletion resistant (LD-R), marked by increased membrane lipids like phosphatidylcholine and phosphatidylethanolamine. Separation of these cell models was based on ranked functional phenotypes, including clonogenicity (P<0.0001), population doubling time (P<0.01), viability (P<0.001), and senescence (P<0.01) in LD-S at acute 48-hour lipid starvation. During lipid depletion, LD-R tumor cells survive by promoting serine uptake (serine utilization, P<0.0001) and carbon-donor incorporation into their lipid synthesis pathways such as membrane lipids (P<0.05) and fatty acids (P<0.01). Based on the mechanistic difference between LD-S and LD-R models, a lipid-response signature consisting of 150 distinct genes was constructed, distinguishing 519 HCC patients into two subgroups based on their lipid-dependency genotypes, correlating LD-R traits with lower survival (P<0.0001), higher vascular invasion (P<0.001), and distinct immune compositions based on cell deconvolution and single cell transcriptomics.
    CONCLUSIONS: Distinct sensitivity to lipid depletion underscores lipid metabolism as a therapeutic target offering new treatment options for HCC patients.
    IMPACT AND IMPLICATIONS: This study shows that hepatocellular carcinoma displays distinct lipid metabolic dependencies, with some tumors being highly sensitive to lipid depletion while others adapt through increased membrane lipid synthesis and extracellular serine utilization. These findings highlight a potential vulnerability in HCC metabolic reprogramming, suggesting that targeting lipid and serine-dependent pathways may offer new therapeutic strategies. Although the MASLD-associated HCC sample size was limited, the work provides important insight into tumor heterogeneity and establishes a foundation for future basic and clinical studies aimed at exploiting metabolic weaknesses in HCC.
    Keywords:  HCC; lipid dependence; lipid depletion; lipidomics; metabolic rearrangements
    DOI:  https://doi.org/10.1016/j.jhepr.2026.102063
  17. iScience. 2026 Oct 16. 29(10): 117656
    Pharmacological protection from a sugar-rich diet through inhibition of Ras/MAPK signaling.
    Mihails Laskovs, Jacob S Cook, Andrew R Pitt, Corinne M Spickett, Cathy Slack.
      Consumption of sugar-rich diets adversely affects health and reduces life expectancy through the excessive production and storage of triacylglycerides (TAGs), leading to metabolic dysfunction. Here, we show that in Drosophila, pharmacological inhibition of Ras/mitogen-activated protein kinase (MAPK) signaling using the highly specific MEK inhibitor, trametinib, mitigates several of the detrimental effects of a high-sugar diet by reducing TAG accumulation, restoring TAG composition, and increasing survival. Notably, Ras/MAPK activity is required for the transcriptional response to elevated sugar intake, including expression of the glucagon-like hormone, Akh. We further demonstrate that adipokinetic hormone (AKH) is essential for the protective effects of trametinib under high-sugar conditions. Together, our findings support Ras/MAPK signaling as an important link between dietary sugar and metabolic dysfunction and show that its pharmacological inhibition can uncouple excess sugar intake from adverse metabolic outcomes.
    Keywords:  Drosophila; Ras/MAPK signaling; lifespan; lipidomics; metabolism
    DOI:  https://doi.org/10.1016/j.isci.2026.117656
  18. Transl Cancer Res. 2026 Sep 30. 15(9): 706
    Metabolic signature of phosphoethanolamine and arginine pathways predicts prognosis and immunotherapy resistance in lung adenocarcinoma.
    Tao Wang, Hongwei Li, Fei Ding.
       Background: Metabolic reprogramming is a hallmark of lung adenocarcinoma (LUAD). However, the prognostic significance of phosphoethanolamine (pEtn) and arginine metabolism-related genes remains poorly defined. This study aimed to develop and externally validate a pEtn- and arginine metabolism-related gene signature for predicting prognosis in LUAD and to characterize its associations with tumor biology, immune response, and therapeutic sensitivity.
    Methods: We analyzed transcriptomic data from The Cancer Genome Atlas (TCGA) LUAD (TCGA-LUAD, n=514) and independent Gene Expression Omnibus (GEO) cohorts. Candidate genes were identified from Molecular Signatures Database (MSigDB) gene sets, followed by differential expression, Cox regression, and protein-protein interaction (PPI) analyses. An 18-gene metabolic signature was constructed using least absolute shrinkage and selection operator (LASSO) regression and validated across three external datasets. Functional enrichment, immune infiltration profiling, Tumor Immune Dysfunction and Exclusion (TIDE) analysis, and drug sensitivity prediction, Cancer Therapeutics Response Portal (CTRP), and Genomics of Drug Sensitivity in Cancer (GDSC) were performed to explore biological and therapeutic implications.
    Results: We identified 114 metabolism-related genes, of which 27 were significantly associated with overall survival (OS). An 18-gene prognostic signature stratified patients into high- and low-risk groups, with high-risk patients showing significantly poorer survival [TCGA: hazard ratio (HR) =2.81, P<0.001; external validation: HR 2.60-3.24, all P<0.01]. High-risk tumors were enriched in cell cycle, glycolysis, and epithelial-mesenchymal transition (EMT) pathways, and exhibited elevated but dysfunctional CD8+ T cell infiltration, consistent with immune exclusion and reduced immunotherapy response. Drug sensitivity analysis suggested that high-risk patients may benefit from dasatinib, lovastatin, irinotecan, and talazoparib.
    Conclusions: An 18-gene metabolic signature demonstrates robust prognostic value in LUAD, linking metabolic reprogramming with tumor aggressiveness, immunotherapy resistance, and drug vulnerability. This model provides a potential tool for risk stratification and personalized treatment.
    Keywords:  Lung adenocarcinoma (LUAD); arginine metabolism; immunotherapy resistance; phosphoethanolamine metabolism (pEtn metabolism); prognostic signature
    DOI:  https://doi.org/10.21037/tcr-2026-1553
  19. Radiother Oncol. 2026 Oct 14. pii: S0167-8140(26)00665-1. [Epub ahead of print] 111825
    Selective lipid Metabolic remodelling in radiosensitive normal tissues after FLASH radiotherapy.
    Shuhei Aramaki, Maxime Dubail, Mathieu Sertorio, Md Muedur Rahman, Mst Sayela Afroz, Chi Zhang, Liang Tang, Kohei Wakabayashi, Kenta Konishi, Tomoaki Kahyo, Gael Boivin, Marta Vilalta, Ricky A Sharma, Katsumasa Nakamura, Mitsutoshi Setou.
       BACKGROUND AND PURPOSE: FLASH radiotherapy, delivered at ultra-high dose rates, spares normal tissues while maintaining tumor control, but the molecular basis of this differential response remains poorly defined, particularly at timepoints relevant to tissue repair. We investigated whether lipid metabolism contributes to the FLASH effect in head and neck cancer.
    MATERIALS AND METHODS: MOC2 tumor-bearing mice received a single 10 Gy fraction of conventional (CONV) or ultra-high dose-rate FLASH protons, with non-irradiated controls (CTRL). Tongue and contralateral tumors were collected two weeks later and analyzed by bulk lipidomics, spatial lipidomics and proteomics. After biochemical filtering, 1,547 lipid species across 37 classes were quantified.
    RESULTS: At two weeks, CONV irradiation was associated with a triglyceride-catabolic, oxidative-stress signature in tongue tissue, marked by loss of the lipid-droplet hydrolase Ces1d alongside induction of the peroxisomal β-oxidation enzyme Acox1. FLASH irradiation was instead associated with a distinct lipid-remodelling signature: suppression of Mgll, induction of Apoe, membrane phospholipid remodelling (increased phosphatidylcholine and phosphatidylethanolamine), and Lypla2 upregulation. Spatial lipidomics provided illustrative spatial context consistent with concentration of these changes in minor salivary gland acini. Tumor tissue showed no comparable modality-specific divergence.
    CONCLUSIONS: These correlative multi-omics data indicate that FLASH is associated with remodelling of lipid metabolism in radiosensitive normal tissue, beyond a simple reduction of acute oxidative damage. We propose a Lipid Metabolic Remodelling Hypothesis for testing: the remodelling of lipid metabolism observed after FLASH may contribute to normal-tissue sparing rather than representing solely a downstream consequence of reduced acute oxidative damage. This model complements existing physicochemical models and offers a basis for radioprotection strategies in head and neck radiotherapy.
    Keywords:  FLASH radiotherapy; Head and neck radiotherapy; Lipid metabolism; Normal tissue protection; Proton therapy; Salivary gland; Spatial lipidomics
    DOI:  https://doi.org/10.1016/j.radonc.2026.111825
This page is being maintained by Thomas Krichel. It was last updated on 2026‒10‒18 at 7:05.