bims-meract 2026-09-13 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–09–13
fourteen papers selected by
Andrea Morandi, Università degli Studi di Firenze

NRF2 activation is required for chemotherapy resistance acquisition in medulloblastoma via metabolic and redox adaptation.
Adipocyte-derived β-hydroxybutyrate confers metabolic resilience in multiple myeloma.
Case Report: Synergistic potential of RANKL and ACLY inhibition in a breast cancer patient with acquired resistance to CDK4/6 inhibitors.
KRAS/ERK2-driven stabilization of AARS1 reprograms tumor metabolism and confers Sorafenib resistance in lung adenocarcinoma.
Targeting 3-mercaptopyruvate sulfurtransferase selectively eliminates colorectal cancer stem cells.
Targeting the KAT7/H3K14ac/RAC2 Axis Mediates OXPHOS to Promote Stemness Maintenance and Malignancy in Glioblastoma.
FOXD1 upregulates DARS2-mediated glycolysis to drive cisplatin resistance in bladder cancer.
CD84 expression stratifies venetoclax response and reveals a targetable vulnerability in resistant acute myeloid leukemia.
A fungal-derived benzothiazole derivative overcomes osimertinib resistance in NSCLC by targeting SCD1.
Glutamine-dependent biosynthetic pathways fuel autoreactive T and B cells in Foxp3 deficiency-mediated disease.
Estrogen promotes tumor phenotypes in ER+ and ER- breast cancer through UGDH-GPR30.
Mitochondrial DNA mutations are associated with impaired oxidative phosphorylation and enhanced imatinib response in chronic myeloid leukemia.
Macrophages transfer functional proteins to their surface during live-cell uptake.
Selenium serves as an immunomodulator adjunct to enhance the efficacy of anti-PD-1 therapy in non-small cell lung cancer.

Redox Biol. 2026 Sep 03. pii: S2213-2317(26)00379-4. [Epub ahead of print]97 104380

NRF2 activation is required for chemotherapy resistance acquisition in medulloblastoma via metabolic and redox adaptation.

Lorenzo Manfreda, Fatlum Rruga, Arianna Zanolli, Bryan P Marzullo, Lisa Vettore, Martina Mozzo, Martina Canton, Chiara Marchioro, Elena Rampazzo, Elena Mariotto, Serena Filiberti, Marta Turati, Roberto Ronca, Daniel A Tennant, Luca Persano, Giampietro Viola, Roberta Bortolozzi.

  This study explores the pivotal role of NRF2 signaling in conferring resistance to chemotherapy and ferroptosis in medulloblastoma (MB), a highly malignant pediatric brain tumor. Using newly developed in vitro models of MB cells, resistant to standard chemotherapeutics (vincistine, etoposide, cisplatin, and cyclophosphamide), we observed that chemotolerant cells exhibit an enhanced antioxidant response. Specifically, we found higher levels of glutathione, compared to sensitive cells, and increased thioredoxin reductase activity, both key components in maintaining redox homeostasis. Furthermore, we identified a metabolic shift in resistant cells, marked by increased flux through the pentose phosphate pathway (PPP), which boosts NADPH production and supports the antioxidant defense mechanisms. This adaptive antioxidant response is largely mediated by hyperactivation of the NRF2 transcription factor and the consequent upregulation of a set of antioxidant genes, thus effectively reducing intracellular reactive oxygen species (ROS) levels and enhancing cells' ability to tolerate oxidative stress. Intriguingly, our results suggest that NRF2 activation not only supports the acquisition of chemotherapy resistance but also confers protection against ferroptosis induction. Indeed, resistant cells upregulate iron sequestration proteins and ferroptosis-suppressing genes, directly controlled by NRF2, thereby reducing vulnerability to lipid peroxidation-induced cell death. Inhibition of NRF2 in resistant cells increased their sensitivity to both chemotherapy and ferroptosis inducers and, more interestingly, its knockdown prevented sensitive cells from acquiring resistance. Overall, our study underscores the crucial role of NRF2-controlled redox homeostasis in mediating resistance mechanisms in MB, highlighting the therapeutic potential of targeting this pathway. Targeting NRF2 signaling may provide a novel approach to overcome therapy resistance and improve treatment outcomes for patients with this challenging cancer.

Keywords:  Chemotherapy resistance; Ferroptosis resistance; Medulloblastoma; NRF2 signaling; Redox homeostasis

DOI:  https://doi.org/10.1016/j.redox.2026.104380
Nat Commun. 2026 Aug 11. pii: 9611. [Epub ahead of print]17(1):

Adipocyte-derived β-hydroxybutyrate confers metabolic resilience in multiple myeloma.

Chen Song, Peng Yang, Yu Li, Tao Xia, Rui Li, Mengmeng Guo, Wenjun Li, Chenfeng Liu, Tiantian Jia, Yansheng Wang, Xunxia Bao, Qi Wang, Yuan Yao, Qian Dai, Huan Liu, Zongwei Li.

Multiple myeloma (MM) remains an incurable blood cancer. Obesity is a known risk factor, but how adipocytes promote MM progression is not fully understood. Here, we uncover a metabolic crosstalk between adipocytes and MM cells that promotes MM cell survival under glucose deprivation. We show that glucose restriction activates AMPK, disrupting HSP90-IRF4 binding and rendering IRF4 susceptible to TRIM21-mediated proteasomal degradation. Paradoxically, the same stress stimulates adipocytes to produce β-hydroxybutyrate (β-OHB). MM cells utilize β-OHB through OXCT1-mediated ketolysis, fueling NAT10-dependent acetylation of IRF4 at K87, which restores IRF4-HSP90 binding and sustains tumor cell survival. Genetic ablation of the rate-limiting ketogenic enzyme Hmgcs2 in adipocytes abrogates this protective effect. Importantly, combining an AMPK activator (metformin) with an OXCT1 inhibitor (pimozide) or a NAT10 inhibitor (remodelin) shows synergistic anti-tumor activity in vivo. Our findings position adipocyte-derived β-OHB as a critical metabolic adaptor and highlight a potential combination therapy for MM.

DOI: https://doi.org/10.1038/s41467-026-76595-0
Front Oncol. 2026 ;16 1911207

Case Report: Synergistic potential of RANKL and ACLY inhibition in a breast cancer patient with acquired resistance to CDK4/6 inhibitors.

Anastasiia Samusieva, Ielizaveta Gorodetska, Oleg Socha, Yuliia Lytovchenko, Roman Kisielov, Borys Dons Koi, Daria Kozeretska, Vasyl Lukiyanchuk, Anna Dubrovska, Valeriy Cheshuk, Olga Ponomarova, Iryna Kozeretska.

   Background: The development of acquired resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) represents a major clinical challenge in the management of hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. Overcoming this resistance requires novel therapeutic strategies that target the underlying molecular escape pathways.
Case presentation: We report the case of a patient initially diagnosed in 2011 with pT2N0M0, ER+/HER2- invasive ductal carcinoma. Following multimodality treatment, she experienced disease progression with bone metastases after five years, followed by lymph node metastases at the ten-year mark. Subsequent treatment with the CDK4/6i ribociclib in combination with fulvestrant resulted in disease progression approximately one year later, indicating acquired resistance. Due to progressive bone loss, denosumab was initiated for skeletal support, and bempedoic acid was later added for dyslipidemia.
Discussion: This case provides a clinical basis for exploring two innovative therapeutic concepts to overcome resistance. First, we discuss the complex role of receptor activator of nuclear factor kappa-B ligand (RANKL) inhibition. Given that leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) functions as a decoy receptor for RANKL, we hypothesize that a patient's LGR4 expression status may dictate the efficacy and safety of denosumab, potentially serving as a predictive biomarker to personalize its use. Second, we propose that bempedoic acid, a supportive care medication, may exert a direct anti-neoplastic effect. Its dual mechanism, inhibiting ATP-citrate lyase (ACLY) to disrupt lipid synthesis and activating AMP-activated protein kinase (AMPK) to suppress mammalian target of rapamycin complex 1 (mTORC1) signaling, positions it as a potential agent to counteract the metabolic reprogramming associated with therapeutic resistance.
Conclusion: This case report illustrates the sequential development of acquired therapeutic resistance in the long-term management of metastatic breast cancer. Although a single clinical observation cannot establish definitive efficacy, this scenario generates compelling hypotheses for future studies. It highlights the potential need to explore biomarker-driven approaches-such as evaluating LGR4 expression to guide RANKL inhibition-to personalize treatment. Additionally, it raises the possibility that repurposed supportive care medications, such as bempedoic acid, might offer hypothetical anti-neoplastic benefits, warranting broader clinical validation to overcome complex resistance mechanisms.

Keywords:  ATP-citrate lyase; CDK4/6 inhibitor resistance; LGR4; RANKL inhibition; bempedoic acid; bone metastasis; breast cancer; lymph node metastasis

DOI:  https://doi.org/10.3389/fonc.2026.1911207
Cell Death Differ. 2026 Sep 09.

KRAS/ERK2-driven stabilization of AARS1 reprograms tumor metabolism and confers Sorafenib resistance in lung adenocarcinoma.

Wenxuan Hu, Zhike Chen, Jian Yang, Gaomeng Luo, Haoyang Yuan, Kang Hu, Xin Lv, Yin Wang, Jun Zhao, Chun Xu.

KRAS is the most frequently mutated oncogene in human cancers, and its G12C variant is highly prevalent in lung adenocarcinoma (LUAD) and predicts poor clinical outcomes. However, the metabolic mechanisms underlying KRAS-driven malignancy and therapeutic resistance remain incompletely understood. Here, we identify alanyl-tRNA synthetase 1 (AARS1) as a previously unrecognized metabolic effector of KRAS signaling. AARS1 protein-but not its mRNA-is markedly upregulated in LUAD tissues, owing to impaired selective autophagic degradation mediated by the E3 ligase TRIM21. Mechanistically, KRAS G12C activates ERK2-dependent phosphorylation of AARS1 at Ser882, disrupting its interaction with TRIM21 and preventing autophagic turnover. Stabilized AARS1 drives metabolic reprogramming by catalyzing lysine lactylation of PDHA1 (K336) and ENO1 (K71), thereby suppressing OXPHOS, enhancing glycolysis, and promoting tumor progression. Importantly, KRAS G12C-induced AARS1 phosphorylation confers resistance to Sorafenib. Blocking AARS1 phosphorylation using the natural compound Hypericin restores autophagic degradation of AARS1, reverses metabolic reprogramming, and markedly sensitizes KRAS-mutant LUAD organoids and PDX models to Sorafenib. These findings uncover AARS1 as a lactate-sensing oncogenic effector downstream of KRAS G12C and highlight the therapeutic potential of targeting AARS1 phosphorylation to overcome drug resistance in LUAD.

DOI: https://doi.org/10.1038/s41418-026-01862-y
Redox Biol. 2026 Sep 02. pii: S2213-2317(26)00375-7. [Epub ahead of print]97 104376

Targeting 3-mercaptopyruvate sulfurtransferase selectively eliminates colorectal cancer stem cells.

Kelly Ascenção, Olivia Oravecz, Csaba Szabo.

  Cancer stem cells (CSCs) contribute to therapeutic resistance, metastatic progression, and tumor recurrence, yet the metabolic pathways that sustain their survival remain incompletely understood. Here, we identify 3-mercaptopyruvate sulfurtransferase (3-MST), a hydrogen sulfide-producing enzyme encoded by MPST, as a metabolic dependency of colorectal CSCs. 3-MST expression was increased in human colorectal tumors and cancer cell lines and strongly correlated with proliferative capacity. HCT116-derived CSCs exhibited elevated 3-MST expression, increased hydrogen sulfide and reactive sulfur species production, altered membrane rigidity, and a metabolically restrained phenotype characterized by low basal oxidative phosphorylation and glycolysis. Genetic depletion of 3-MST preferentially impaired CSC proliferation, spheroid formation, stem-like properties, and migration, with less pronounced effects in differentiated parental cells. Pharmacological inhibition of 3-MST reproduced these effects across CSCs derived from several colorectal cancer cell lines and induced near-complete suppression of mitochondrial respiration and glycolytic activity. 3-MST inhibition also increased membrane fluidity, promoted cell death, and reduced CSC-derived tumor growth in mice. Integrated transcriptomic, proteomic, metabolomic, and lipidomic analyses demonstrated coordinated disruption of mitochondrial carbon metabolism, respiratory-chain maintenance, lipid desaturation, and membrane phospholipid homeostasis. These changes were accompanied by accumulation of free fatty acids and diacylglycerols and activation of antioxidants, integrated stress-response, endoplasmic-reticulum-stress, apoptotic, and p53-associated pathways. Ferroptosis-related molecular signatures were also enriched. These findings identify 3-MST as a critical regulator of colorectal CSC bioenergetics and membrane homeostasis and reveal a therapeutically exploitable metabolic vulnerability in treatment-resistant colorectal cancer.

Keywords:  3-Mercaptopyruvate sulfurtransferase; Bioenergetics; Colon cancer; Gasotransmitters; Hydrogen sulfide; Mitochondria

DOI:  https://doi.org/10.1016/j.redox.2026.104376
Adv Sci (Weinh). 2026 Sep 08. e77551

Targeting the KAT7/H3K14ac/RAC2 Axis Mediates OXPHOS to Promote Stemness Maintenance and Malignancy in Glioblastoma.

Jilong Liu, Yanfei Sun, Yuehua Zhu, Guangjing Mu, Jiazheng Wang, Liangliang Wang, Feihu Zhao, Zhimin Zhao, Jian Wang, Ying He, Zheng Jiang, Xingang Li, Mingzhi Han, Bin Huang.

  Glioblastoma multiforme (GBM), the most lethal type of primary brain tumor, exhibits profound metabolic plasticity driven by glioma stem cells (GSCs), which sustain therapeutic resistance and tumor recurrence. Here, we elucidate a novel epigenetic-metabolic axis mediated by the histone acetyltransferase KAT7 that orchestrates oxidative phosphorylation (OXPHOS) dominance in GSCs. Through a multi-omics analysis, we demonstrated that KAT7 is preferentially upregulated in GBM, particularly in the classical subtype and in GSC-enriched populations, where it activates Rac family samll GTPase 2 (RAC2) expression via H3K14 acetylation of its promoter. Mechanistically, KAT7-mediated RAC2 upregulation triggers PAK1/2/3 phosphorylation, increasing tricarboxylic acid cycle (TCA) and ATP production. Genetic ablation of KAT7 impairs GSCs self-renewal, induces apoptosis, and suppresses tumor growth in orthotopic xenograft models. Conversely, KAT7 overexpression or pharmacological activation of the KAT7-RAC2 axis restores metabolic fitness and malignant phenotypes. Notably, the small-molecule inhibitor WM-3835, which targets KAT7, exhibits potent anti-GBM efficacy by disrupting H3K14ac and mitochondrial respiration, leading to prolonged survival in mice. Our study identifies KAT7 as a master regulator of GSCs metabolism, revealing an actionable therapeutic target in GBM progression. Targeting the KAT7-RAC2-PAK axis may represent a precise strategy to overcome metabolic plasticity-driven therapeutic resistance in this recalcitrant malignancy.

Keywords:  GBM; GSCs; KAT7; OXPHOS; RAC2

DOI:  https://doi.org/10.1002/advs.77551
Urol Oncol. 2026 Sep 05. pii: S1078-1439(26)00619-8. [Epub ahead of print]

FOXD1 upregulates DARS2-mediated glycolysis to drive cisplatin resistance in bladder cancer.

Xianyong Li, Mingqiang Su, Jingxian Luo, Dengjun Han, Liangliang Qing, Dayong Zhang, Sheng Liu, Junfa Liu, Guangqing Fu.

   BACKGROUND: Chemotherapy remains the most effective systemic treatment for bladder cancer (BLCA), with cisplatin as the primary agent. However, the frequent development of cisplatin resistance limits its clinical efficacy. Forkhead box D1 (FOXD1) is implicated in BLCA progression, yet its role in mediating cisplatin resistance remains unexplored.
METHODS: FOXD1 expression and its correlation with patient prognosis in BLCA were analyzed using the TCGA database. Cisplatin-resistant BLCA cell lines (T24-R and HT-1376-R) were established by treatment with gradient concentrations of cisplatin. qRT-PCR and Western blot were performed to detect the expression levels of FOXD1, β-catenin, and Aspartyl-tRNA Synthetase 2 (DARS2). Cell viability, proliferation, cell cycle, and apoptosis were assessed using CCK-8, colony formation assays, and flow cytometry. Co-IP was performed to examine the interaction between FOXD1 and β-catenin. Glycolysis levels in BLCA cells were determined using specific assay kits.
RESULTS: FOXD1 was highly expressed in BLCA tissues and correlated with poor prognosis. Knockdown of FOXD1 inhibited proliferation and cell cycle progression, promoted apoptosis, and enhanced cisplatin sensitivity in T24-R cells, while reducing β-catenin nuclear translocation and DARS2 expression. Overexpression of FOXD1 exerted the opposite effects on HT-1376-R cells and increased DARS2 expression, which were reversed by β-catenin knockdown. Moreover, knockdown of TCFs/LEF suppressed DARS2 expression. DARS2 was enriched in the glycolysis pathway. Its overexpression promoted glycolysis, proliferation, and cell cycle progression, while inhibiting apoptosis and cisplatin sensitivity in HT-1376-R cells-effects were reversed by 2-DG.
CONCLUSION: FOXD1 facilitates β-catenin nuclear translocation and upregulates DARS2 to enhance glycolysis, thereby promoting cisplatin resistance in BLCA. These findings identify the FOXD1/β-catenin/DARS2 axis as a potential therapeutic target for overcoming cisplatin resistance in BLCA clinically.

Keywords:  Bladder cancer; Cisplatin resistance; DARS2; FOXD1; Glycolysis

DOI:  https://doi.org/10.1016/j.urolonc.2026.07.027
Exp Hematol Oncol. 2026 Sep 07. pii: 90. [Epub ahead of print]15(1):

CD84 expression stratifies venetoclax response and reveals a targetable vulnerability in resistant acute myeloid leukemia.

Xuemei Wang, Xiangjie Lin, Tianyi Chen, Yi Chen, Huafeng Wang, Yinghui Zhu.

  Venetoclax-based regimens have become increasingly integrated into the therapeutic landscape of acute myeloid leukemia (AML), yet primary resistance and relapses remain major barriers to durable benefits. Building on our previous discovery of CD84 as a critical survivor and redox regulator in AML, we here demonstrate that CD84 expression contributes to venetoclax sensitivity. Low CD84 expression is associated with favorable clinical response, whereas high CD84 expression correlates with primary resistance and is up-regulated at relapse in two of three paired samples. Functional perturbation of CD84 through genetic knockdown or CD84-targeted CAR-T cells sensitized AML cells to venetoclax in vitro and in vivo cell-derived xenograft models. Mechanistically, CD84 coordinates a pro-survival program with upregulating the antioxidant stress sensor SESN2, which suppresses mitochondrial reactive oxygen species and antagonizes venetoclax-induced apoptosis. SESN2 knockdown phenocopied CD84 depletion, while SESN2 overexpression partially restored venetoclax resistance in CD84-deficient cells. Our findings suggest that CD84-mediated upregulation of SESN2 contributes to venetoclax resistance and may represent a potential therapeutic target to enhance treatment efficacy in AML.

Keywords:  Acute myeloid leukemia; CAR-T cell therapy; CD84; Redox homeostasis; Venetoclax resistance

DOI:  https://doi.org/10.1186/s40164-026-00830-z
Nat Prod Bioprospect. 2026 Sep 11. pii: 86. [Epub ahead of print]16(1):

A fungal-derived benzothiazole derivative overcomes osimertinib resistance in NSCLC by targeting SCD1.

Boyin Li, Yuanyu Ke, Jinhua Zhu, Weisong Zhang, Mingjin Yang, Zhan Li, Mu Chen, Zhiling Liu, Jieyao Liu, Qiudi Deng, Peng Zhang, Xueping Lei.

  Osimertinib resistance remains a critical factor for treatment failure in non-small cell lung cancer (NSCLC), making it of great clinical significance to develop novel agents that can overcome this resistance. Natural products are invaluable sources for anti-drug discovery. In this study, we first report that 6-(2-hydroxyethyl) benzo[d]thiazol-4-ol (HBT), a benzothiazole derivative isolated from the endophytic fungus Aspergillus sp. 1022LEF, effectively reverses osimertinib resistance both in vitro and in vivo. Our results demonstrate that HBT effectively inhibits the proliferation of osimertinib-resistant cells by inducing ferroptosis, a novel form of iron-dependent cell death driven by lipid peroxidation. This effect is partially dependent on stearoyl-CoA desaturase 1 (SCD1). Further mechanistic studies revealed that HBT acts as a novel SCD1 inhibitor by directly binding to SCD1 and promoting its degradation, thereby leading to lipid peroxidation and ferroptosis. In vivo experiments showed that HBT treatment significantly suppressed tumor growth in PC9-OR xenograft models, as evidenced by reduced tumor volume and weight. In summary, our study not only identifies HBT as a promising therapeutic candidate for overcoming osimertinib resistance in NSCLC but also suggest that SCD1 is a potential target for combating such resistance.

Keywords:  6-(2-hydroxyethyl) benzo[d]thiazol-4-ol (HBT); Ferroptosis; Non-small lung cancer; Osimertinib resistance; SCD1

DOI:  https://doi.org/10.1007/s13659-026-00645-9
JCI Insight. 2026 Sep 08. pii: e200076. [Epub ahead of print]11(17):

Glutamine-dependent biosynthetic pathways fuel autoreactive T and B cells in Foxp3 deficiency-mediated disease.

Mohammad Adeel Zafar, Charlotte N Hill Machado, Jyotirmaya Behera, Yuelin Zhong, Xiao Li, Shakchhi Joshi, Yassine El Fazaa, Virginia Camacho, Peter Georgiev, Kiran Kurmi, Marcia Haigis, Louis-Marie Charbonnier.

  Foxp3 deficiency causes a profound loss of immune tolerance, unleashing autoreactive T and B cells, lymphoproliferation, cytokine-driven inflammation, and autoantibody production. This autoimmune pathology is fueled by increased glutamine usage, but it remains unresolved whether glutamine is necessary to produce energy or for intermediate metabolite biosynthesis responsible for immunomodulation. Here, we demonstrate that glutamine utilization for biosynthetic pathways supported autoimmune inflammation in the settings of Foxp3 deficiency and dextran sodium sulfate-induced colitis. By employing a model of autoimmunity driven by Treg-specific loss of Foxp3, we showed that this effect is independent of pathogenic Foxp3-deficient Treg reprogramming. Mechanistically, glutamine biosynthetic pathways sustained conventional T cell activation and proinflammatory cytokine production by preventing inosine accumulation and signaling, thus implicating adenosine pathway modulation in autoreactive T cell dysregulation. Conversely, autoreactive B cell activation and autoantibody production relied on glutamine-dependent asparagine availability, which we identified as a targetable vulnerability for autoantibody formation. These findings highlighted glutamine-driven biosynthetic processes as critical drivers of autoimmunity and revealed distinct metabolic vulnerabilities in autoreactive T and B cells that could be targeted for therapeutic intervention.

Keywords:  Autoimmune diseases; Autoimmunity; Inflammation; Metabolism; Mouse models; Therapeutics

DOI:  https://doi.org/10.1172/jci.insight.200076
JCI Insight. 2026 Sep 08. pii: e197357. [Epub ahead of print]11(17):

Estrogen promotes tumor phenotypes in ER+ and ER- breast cancer through UGDH-GPR30.

Meghan J Price, Annee D Nguyen, Corinne H Strawser, Trupti Trivedi, Cesar Cd Baeta, Catherine Lavau, Jovita K Byemerwa, Debarati Mukherjee, Suzanne E Wardell, Sandeep Artham, Vardhman Kumar, Shyni Varghese, C Rory Goodwin.

  Estrogen can promote aggressive tumor phenotypes in estrogen receptor-positive (ER+) breast cancer; however, ER- cell lines are not widely considered estrogen responsive. Noncanonical estrogen-stimulated pathways such as the membrane-bound G protein-coupled estrogen receptor (GPR30) can mediate migratory and proliferative phenotypes in breast cancer and are postulated to promote resistance to aromatase therapies. Moreover, dysregulation of UDP-glucose 6-dehydrogenase (UGDH), a ubiquitously expressed enzyme critical to the metabolism of UDP-glucuronic acid into extracellular matrix precursors and hormone regulation, is associated with tumorigenesis. Here, we illustrated the impact of estrogen stimulation on tumor phenotypes in ER+ and ER- cell models in vitro and in vivo. We then demonstrated UGDH's association with metastatic breast cancer via single-cell sequencing of patient specimens. Genetic knockdown of UGDH blunted estrogen-stimulated tumor phenotypes in vitro, ex vivo, and in vivo using both ER+ and ER- breast cancer lines. Finally, we demonstrated that UGDH knockdown blunted noncanonical estrogen stimulation through GPR30. Ultimately, our study validated prior studies demonstrating estrogen-responsive malignant phenotypes in ER- breast cancer and demonstrated that estrogen-stimulated breast cancer progression can be mediated through noncanonical pathways (e.g., UGDH/GPR30), regardless of ER status.

Keywords:  Breast cancer; Endocrinology; G protein-coupled receptors; Oncogenes; Oncology

DOI:  https://doi.org/10.1172/jci.insight.197357
Hemasphere. 2026 Sep;10(9): e70429

Mitochondrial DNA mutations are associated with impaired oxidative phosphorylation and enhanced imatinib response in chronic myeloid leukemia.

Ilaria S Pagani, Vaidehi Krishnan, John F Ouyang, Chung H Kok, BeiJun Chen, Kian Leong Lee, Cong M Pham, Paul Wang, Elyse Page, Phuong Dang, Verity A Saunders, Jane James, Kelly Lim, Stefano Mangiola, Yingnan Gao, Naranie Shanmuganathan, Agnes Yong, Susan Branford, Charles Chuah, David T Yeung, Deborah L White, Vignir G Helgason, Daniel Thomas, S Tiong Ong, Timothy P Hughes, David M Ross.

Mitochondrial DNA (mtDNA) mutations are frequently observed in cancer, but their clinical and functional significance in chronic myeloid leukemia (CML) remains incompletely defined. Here, we show that a distinct mtDNA mutational landscape is associated with mitochondrial metabolic programs and response to imatinib therapy in CML. We performed comprehensive profiling of somatic mtDNA mutations in 120 patients with chronic-phase CML. At diagnosis, 241 somatic mtDNA mutations were identified in 92 patients, including 29 homoplasmic mutations. In a clinically annotated cohort of 79 imatinib-treated patients, a higher number of mtDNA mutations (≥3 mutations) and higher variant allele frequency were associated with superior molecular responses, and remained significant in multivariable analyses. mtDNA mutational patterns were associated with distinct metabolic phenotypes in CD34+ leukemic stem/progenitor cells. Suboptimal responders exhibited increased mitochondrial respiration, spare respiratory capacity, mitochondrial content, and enrichment of mitochondrial biogenesis and lipid metabolic programs, consistent with enhanced oxidative phosphorylation dependence. In contrast, favorable responders displayed higher mtDNA mutational burden together with reduced respiratory reserve and increased mitophagy-related programs. Pharmacologic Complex I inhibition reduced clonogenic potential and enhanced imatinib sensitivity. Collectively, these findings identify mtDNA mutational states as a biomarker of metabolic fitness and therapeutic response in CML, while supporting further investigation of mitochondrial metabolism as a potential therapeutic vulnerability in CML.

DOI: https://doi.org/10.1002/hem3.70429
Nat Chem Biol. 2026 Sep 08.

Macrophages transfer functional proteins to their surface during live-cell uptake.

Regan F Volk, Amy C Fan, Sara W Casebeer, Vishnu R Tejus, Andrew C Condon, Bahar Zirak, Nayelis A Manon, Iryna Irkliyenko, Danielle M Torralba, Shao Tao, Tommaso Pollini, Vijay Ramani, Ajay V Maker, Matthew F Krummel, Hani Goodarzi, Balyn W Zaro.

A cell's proteome is assumed to reflect its transcriptional and translational activity. Macrophages regularly acquire xenobiotic material from neighboring cells, which is thought to result in degradation of the material. However, increasing lines of evidence suggest that not all taken up material is degraded and other transfer-like processes also occur. Field standard technologies are unable to rigorously report on precisely how and by whom the macrophage protein repertoire is altered during these interactions, leaving unresolved the extent to which nondegradative processes contribute to altered phenotypes. Here, we leveraged chemical tools and proteomics to show that intact target cancer cell surface proteins are transferred to the macrophage cell surface at functionally impactful levels in a manner associated with live-cell uptake. Widespread acquisition of proteins during cell uptake reengineers the macrophage cell surface proteome and is a transcriptionally silent, cell-nonautonomous process with the potential to alter metabolic uptake.

DOI: https://doi.org/10.1038/s41589-026-02292-0
J Immunol. 2026 Aug 29. pii: vkag241. [Epub ahead of print]215(9):

Selenium serves as an immunomodulator adjunct to enhance the efficacy of anti-PD-1 therapy in non-small cell lung cancer.

Kaiyuan Guo, Hongwei Hu, Naichen Yao, Qitai Zhao, Shasha Liu, Peng Wu, Yachang Huo, Pingchuan Ma, Tianran Chen, Xinfeng Chen, Guohui Qin, Yi Zhang.

  The role of selenium in tumor progression remains controversial, and its mechanisms of action in the context of immunotherapy are poorly understood. In this study, our findings indicate that selenium supplementation did not alter immune parameters, induce organ damage under healthy conditions, or affect the growth of Lewis lung cancer cells in vitro. In tumor-bearing mice, although selenium supplementation alone significantly enhanced the infiltration of CD8+ T cells into tumors, it failed to arrest tumor growth. Further analyses revealed that selenium treatment upregulated the expression of PD-1 on CD8+ T cells and PD-L1 on tumor cells. This finding suggests that PD-1/PD-L1 engagement may impair CD8+ T cell function, thereby preventing the effective elimination of tumor cells. Consequently, selenium supplementation exhibited a strong synergistic effect when combined with anti-PD-1 therapy, yielding enhanced antitumor responses. Single-cell RNA sequencing analysis revealed that the CD8-Prf1 subpopulation expanded and displayed enhanced proliferative and cytotoxic gene signatures after treatment with a combination of selenium and anti-PD-1. Clinically, a high abundance of this subpopulation was associated with prolonged survival in patients receiving anti-PD-1 treatment. Our results indicate that selenium is a promising immunomodulator adjunct that augments CD8+ T cell function and improves the response to anti-PD-1 therapy, supporting further clinical investigation of selenium supplementation in combination with immune checkpoint inhibitors for cancer treatment.

Keywords:  combination therapy; immune checkpoint inhibitors; non-small cell lung cancer; selenium

DOI:  https://doi.org/10.1093/jimmun/vkag241