bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–01–04
38 papers selected by
Christian Frezza, Universität zu Köln
  1. Growth factor-independent mTORC1 signaling promotes primary cilia length via suppression of autophagy.
  2. A simple, anesthesia-free infusion technique for in vivo metabolic tracing.
  3. Pexophagy meets physiology.
  4. Evaluation of Metabolic Characteristics of Cancer Cells.
  5. Mapping metabolic dependences and capacities using ATP as a biomarker.
  6. Exploring Splicing-Energy Axis Associations to Diet and Longevity.
  7. Perturbation of NAD(P)H metabolism with the LbNOX xenotopic tool extends lifespan and mitigates age-related changes.
  8. Cross-presentation of dead cell-associated antigens shapes the neoantigenic landscape of tumor immunity.
  9. Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation.
  10. Mechanistic insights make cancer cachexia a targetable syndrome.
  11. FSP1 and histone deacetylases suppress cancer persister cell ferroptosis.
  12. BATF2 is a glutamine-responsive tumour suppressor required for type-I interferon-dependent anti-tumour immunity.
  13. Dietary methionine deprivation enhances renal resilience against ischemia-reperfusion injury in mice through modulation of glucose oxidation.
  14. p53 inactivation drives breast cancer metastasis to the brain through SCD1 upregulation and increased fatty acid metabolism.
  15. Lipidomic changes in persister cancer cells drive enhanced ferroptosis sensitivity.
  16. Microcompartments in archaeal ancestors of eukaryotes: a bioenergetic engine that could have fuelled eukaryogenesis.
  17. Methionine Restriction, Not Cysteine Restriction, Is a Cancer-specific Vulnerability.
  18. The Janus framework of the integrated stress response: from homeostasis to maladaptation.
  19. Self-renewal of neuronal mitochondria through asymmetric division.
  20. An integrated single-cell and spatial transcriptomic atlas of thyroid cancer progression identifies prognostic fibroblast subpopulations.
  21. Translational Downregulation of 5' TOP mRNAs During T Cell Exhaustion.
  22. Real-Time Super-Resolution Tracking of mtDNA Remodeling and Inflammatory Release with a Selective Fluorescent Probe.
  23. Glioblastoma stem cells resist cuproptosis with circadian variation of copper levels.
  24. Regulatory T Cell Metabolism in Cancer.
  25. Spatial omics at the forefront: emerging technologies, analytical innovations, and clinical applications.
  26. Redox Modulation in Therapy of Cancer: Some Pros and Cons.
  27. Uridine depletion impairs CD8⁺ T cell antitumor activity through N-glycosylation.
  28. Targeting USP28 inhibits clear cell renal cell carcinoma growth.
  29. Inhibition of PAK2 in endothelial cells suppresses tumor angiogenesis and promotes immune sensitization through CXCL10.
  30. Systemically inducing trained immunity overcomes solid tumors' immunosuppressive microenvironment.
  31. Longevity of cardiac and skeletal muscle proteins is dependent on tissue and subcellular compartmentation patterns.
  32. T follicular helper cells transiently unlock a plasticity state in germinal centre B cells during the humoral immune response.
  33. Cancer cell death: Cell-autonomous and immunogenic dimensions.
  34. Lung Metastases in Pancreatic Cancer: Timing Their First Breath.
  35. How does cytoplasmic crowding affect reaction rates?
  36. Senescent cells secrete chromatin components via senescence-associated extracellular particles.
  37. Aneuploidy-driven vulnerabilities in breast cancer metastasis.
  38. Sex differences in bile acid homeostasis and excretion underlie the disparity in liver cancer incidence between males and females.
  1. iScience. 2025 Dec 19. 28(12): 114204
    Growth factor-independent mTORC1 signaling promotes primary cilia length via suppression of autophagy.
    Jong Shin, Khaled Tighanimine, Yann Cormerais, Dean M Rosenthal, Pratima Niroula, Samuel C Lapp, Krystle C Kalafut, Madi Y Cisse, Sandra Schrötter, Brendan D Manning.
      The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), a sensor of growth signals that control cell growth, has been studied mainly in proliferating cells. Primary cilia are sensory organelles present on most quiescent cells and are essential for receiving environmental and developmental signals. Given that ciliated cells are non-proliferative, we investigated whether mTORC1 signaling influences primary cilia growth. Here, we show that mTORC1 promotes cilia elongation without affecting ciliogenesis by suppressing autophagy. Inhibiting mTORC1 through pharmacological, nutritional, or genetic interventions shortened primary cilia, whereas activation of the pathway elongated them. Furthermore, pharmacological or genetic inhibition of autophagy-a key downstream process blocked by mTORC1-elongated primary cilia and rendered them resistant to mTORC1 inhibition. These mTORC1-mediated effects extend to mouse neurons ex vivo and in vivo. Thus, the mTORC1-mediated regulation of autophagy controls primary cilia length and may contribute to diseases in which ciliary function is altered, referred to as ciliopathies.
    Keywords:  Cell biology; Molecular physiology
    DOI:  https://doi.org/10.1016/j.isci.2025.114204
  2. bioRxiv. 2025 Dec 19. pii: 2025.12.17.694756. [Epub ahead of print]
    A simple, anesthesia-free infusion technique for in vivo metabolic tracing.
    Yumi Kim, Samantha Caldwell, Meredith Long, Dominique Abrahams, Margi Baldwin, Gina M DeNicola.
      Accurate metabolic flux analysis requires tracer delivery that preserves physiological metabolism. Current methods may distort metabolism through anesthesia, surgical stress, or complex procedures. We demonstrate that isoflurane anesthesia profoundly alters serum and tissue metabolism across multiple pathways. Glycolytic and TCA cycle intermediates, sulfur and aromatic amino acid metabolites, acylcarnitines, and nucleotide pools decreased, while branched-chain amino acids, their ketoacids, ketone bodies, and fatty acids increased. These coordinated changes were suggestive of mitochondrial complex I inhibition and reduced oxidative catabolism, leading to shifts in metabolite pool sizes that compromise isotopologue-based flux interpretation. We established a tail vein catheterization method completed in minutes under brief anesthesia that enables multi-hour tracer infusion in awake, freely moving mice. This method achieved steady-state labeling of cystine and downstream products comparable to jugular infusion without supraphysiologic cystine accumulation. This platform provides a practical, physiologically accurate method for in vivo steady-state isotope tracing.
    DOI:  https://doi.org/10.64898/2025.12.17.694756
  3. J Cell Biol. 2026 Feb 02. pii: e202511183. [Epub ahead of print]225(2):
    Pexophagy meets physiology.
    Michael J Clague.
      In this issue, Xiong et al. (https://doi.org/10.1083/jcb.202503169) introduce mouse models that enable tissue-resolved mapping of peroxisome turnover and pexophagy across development, metabolism, and disease. This study reveals striking cell type-specific differences in peroxisome dynamics and establishes a versatile platform for dissecting how pexophagy integrates with mitochondrial quality control and whole-body metabolic homeostasis.
    DOI:  https://doi.org/10.1083/jcb.202511183
  4. Methods Mol Biol. 2026 ;2983 159-167
    Evaluation of Metabolic Characteristics of Cancer Cells.
    Riddhi Mehta, Pritpal Kaur, Fatema Zohra Sadia, Patricia Maziarz, Ales Vancura.
      Cancer cells undergo a complex rearrangement of metabolic pathways that allows them to satisfy the needs of increased proliferation. Since many cancers are characterized by a high glycolytic rate regardless of oxygen availability, targeting glycolysis, electron transport chain (ETC), and oxidative phosphorylation (OXPHOS) have emerged as a potential therapeutic strategy. In this chapter, we describe a protocol that utilizes the Agilent Seahorse XFp Analyzer to assess mitochondrial respiration and glycolysis in ovarian cancer cells.
    Keywords:  Cancer metabolism; Extracellular acidification; Glycolysis; Mitochondrial respiration; Ovarian cancer; Oxygen consumption rate
    DOI:  https://doi.org/10.1007/978-1-0716-4901-5_15
  5. Res Sq. 2025 Apr 23. pii: rs.3.rs-4836421. [Epub ahead of print]
    Mapping metabolic dependences and capacities using ATP as a biomarker.
    Peter McGuire, Jose Marin, Amanda Fuchs, Tatiana Tarasenko, Emily Warren, Martha Kirby, Stacie Anderson, Eliza Gordon-Lipkin, Shannon Kruk, A West.
      Metabolic dependences highlight a cell's reliance on specific pathways to meet its bioenergetic needs, with these pathways being interrogated using chemical inhibitors to assess their significance. While surrogate markers of bioenergetics (e.g., oxygen consumption) have yielded important insights, we asked whether metabolic dependences could be defined using ATP as a biomarker. To address this gap, we developed Mitochondrial/Energy Flow Cytometry (MitE-Flo), a method that evaluates the contributions of glycolysis, fatty acid oxidation (FAO), and oxidative phosphorylation (OXPHOS) to cellular ATP content. In models of mitochondrial disease due to complex I or complex IV deficiency, we identified impaired OXPHOS with a compensatory shift to glycolysis. To define the utility of ATP monitoring in immunometabolism research, we analyzed previously inaccessible cell populations: light zone (LZ) and dark zone (DZ) germinal center (GC) B cells. Highly proliferative DZ B cells exhibited elevated ATP levels and a preference for FAO and OXPHOS over glycolysis, with uniform increased activity across ETC complexes. In contrast, less proliferative LZ B cells showed lower ATP levels and an equal reliance on glycolysis and OXPHOS. Using ATP as a biomarker to define metabolic dependences provides valuable insights into disease states and elusive immune cell subtypes, thereby enhancing the metabolism research toolkit.
    DOI:  https://doi.org/10.21203/rs.3.rs-4836421/v2
  6. Aging Cell. 2026 Jan;25(1): e70335
    Exploring Splicing-Energy Axis Associations to Diet and Longevity.
    Stefano Donega, Myriam Gorospe, Luigi Ferrucci.
      There is increasing evidence that nutrient composition, even without lowering total calorie intake, can shape lifespan through mechanisms independent of mitochondrial regulation. Brandon and colleagues recently reported that a low-protein, high-carbohydrate (LPHC) diet enriched with non-digestible cellulose, extends lifespan in mice by shifting the liver proteome through altered RNA splicing, a response different from the mitochondrial improvements typically seen with caloric restriction. The authors' findings support the "energy-splicing resilience axis," which proposes that changes in splicing help cells adapt to energetic and nutritional stress. We discuss how diet influences spliceosomal components such as SRSF1, linking nutrient sensing, AMPK signaling, and tissue-specific resilience pathways. We also consider the splicing paradox in aging, where beneficial isoforms increase despite a concomitant increase in splicing errors. Understanding how dietary and pharmacologic interventions modulate splicing may shed light on strategies to maintain homeostatic proteomes and support healthy longevity.
    DOI:  https://doi.org/10.1111/acel.70335
  7. Sci Adv. 2026 Jan 02. 12(1): eady0628
    Perturbation of NAD(P)H metabolism with the LbNOX xenotopic tool extends lifespan and mitigates age-related changes.
    Shweta Yadav, Xingxiu Pan, Shengxi Li, Paige LaRae Martin, Ngoc Hoang, Kejin Chen, Aditi Karhadkar, Jatin Malhotra, Austin L Zuckerman, Subrata Munan, Markus K Klose, Lin Wang, Valentin Cracan, Andrey A Parkhitko.
      Aging involves widespread metabolic dysregulation, including a decline in total nicotinamide adenine dinucleotide (NAD) levels. While NAD precursor supplementation elevates total NAD levels, it does not reveal tissue-specific effects of an altered NADH [reduced form of NAD+ (oxidized NAD)]/NAD+ balance. To address this, we generated transgenic Drosophila expressing the genetically encoded xenotopic enzyme LbNOX, which converts NADH to NAD+. LbNOX expression modulated both NAD(H) and NADP(H) (reduced form of NAD phosphate) metabolites in a sex-dependent manner and rescued neuronal cell death induced by mutant αB-crystallin-associated reductive stress. We demonstrate that tissue-specific targeting of redox NAD metabolism shows distinct outcomes: Muscle-specific LbNOX expression confers stronger protection against paraquat-induced oxidative stress than whole-body expression, emphasizing tissue-dependent redox sensitivity. Notably, LbNOX expression in nonneuronal tissues restored youthful sleep patterns in aged flies. Together, these findings establish LbNOX as an efficient xenotopic tool for in vivo redox manipulation and reveal tissue- and sex-specific NAD(P)H mechanisms underlying aging, stress resilience, and sleep regulation, providing a framework for NAD-based interventions in aging.
    DOI:  https://doi.org/10.1126/sciadv.ady0628
  8. Nat Immunol. 2026 Jan 02.
    Cross-presentation of dead cell-associated antigens shapes the neoantigenic landscape of tumor immunity.
    Kok Haw Jonathan Lim, Oliver Schulz, Irene Lobon, Tomas Castro-Dopico, Luis Zapata, Evangelos Giampazolias, Bruno Frederico, Carlos A Castellanos, Michael D Buck, William Stainier, Probir Chakravarty, Gavin Kelly, Neil C Rogers, Ana Cardoso, Sonia Lee, Brian Vash, Stephanie Maiocco, Raj Mehta, Jessica Strid, Samra Turajlić, Caetano Reis E Sousa.
      Type 1 conventional dendritic cells (cDC1s) acquire and cross-present tumor antigens to prime CD8⁺ T cells. Whether this selects for specific neoantigens is unclear. DNGR-1 (CLEC9A), a cDC1 receptor for F-actin exposed on dead cells, promotes cross-presentation of cell-associated antigens. Here we show that DNGR-1-deficient mice develop chemically induced tumors more rapidly and at higher incidence, and these are more frequently rejected on transplantation into wild-type recipients. Whole-exome sequencing reveals enrichment of predicted neoantigens derived from mutated F-actin-binding proteins. Consistent with this observation, tethering model antigens to F-actin enhances DNGR-1-dependent cross-presentation. These results suggest that DNGR-1-mediated recognition of F-actin exposed by dead cancer cells favors priming of CD8⁺ T cells specific for cytoskeletal neoantigens, which can then drive immune escape of cancer cells lacking or reverting those mutations. Thus, neoantigen cross-presentation by cDC1 can determine the immune visibility of the tumor mutational landscape and sculpt cancer evolution by immunoediting.
    DOI:  https://doi.org/10.1038/s41590-025-02354-w
  9. Science. 2026 Jan;391(6780): 52-58
    Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation.
    Gaurav Agarwal, Mateusz Antoszewski, Xueqin Xie, Yash Pershad, Uma P Arora, Chi-Lam Poon, Peng Lyu, Andrew J Lee, Chun-Jie Guo, Tianyi Ye, Laila Barakat Norford, Anna-Lena Neehus, Lucrezia Della Volpe, Lara Wahlster, Diyanath Ranasinghe, Tzu-Chieh Ho, Trevor S Barlowe, Arthur Chow, Alexandra Schurer, James Taggart, Benjamin H Durham, Omar Abdel-Wahab, Kathy L McGraw, James M Allan, Ruslan Soldatov, Alexander G Bick, Michael G Kharas, Vijay G Sankaran.
      Somatic mutations that increase the fitness of hematopoietic stem cells (HSCs) drive their expansion in clonal hematopoiesis (CH) and predispose individuals to blood cancers. Population variation in the growth rate and potential of mutant clones suggests that genetic factors may confer resilience against CH. Here, we identified a noncoding regulatory variant, rs17834140-T, that protects against CH and myeloid malignancies by selectively down-regulating the RNA-binding protein MSI2 in HSCs. By modeling variant effects and mapping MSI2 binding targets, we uncovered an RNA network that maintains human HSCs and influences CH risk. Variant rs17834140-T was associated with slower CH expansion, and stem cell MSI2 levels modified ASXL1-mutant HSC clonal dominance. These findings leverage natural resilience to illuminate posttranscriptional regulation in human HSCs, suggesting that inhibition of MSI2 or its targets could be rational strategies for blood cancer prevention.
    DOI:  https://doi.org/10.1126/science.adx4174
  10. Nat Med. 2026 Jan 02.
    Mechanistic insights make cancer cachexia a targetable syndrome.
    Ed Reznik, Martin H Voss, A Ari Hakimi.
      
    DOI:  https://doi.org/10.1038/s41591-025-04109-4
  11. Sci Adv. 2026 Jan 02. 12(1): eaea8771
    FSP1 and histone deacetylases suppress cancer persister cell ferroptosis.
    Masayoshi Higuchi, August F Williams, Anna E Stuhlfire, Ariel H Nguyen, David A G Gervasio, Claire E Turkal, Suejean Chon, Matthew J Hangauer.
      Cancer persister cells which survive oncogene targeted therapies are sensitized to ferroptosis, but mechanistic understanding of this vulnerability remains limited. Here, we found that while levels of iron, glutathione, and various ferroptosis-suppressing enzymes vary among persister cell types, ferroptosis suppressor protein 1 (FSP1) is down-regulated in multiple persister cell types, and persister cells which survive glutathione peroxidase 4 (GPX4) inhibition rely on residual FSP1 to survive. Furthermore, persister cells which survive GPX4 inhibition down-regulate oxidative phosphorylation, a key source of mitochondrial reactive oxygen species which are required for persister cell ferroptosis. We also found that persister cell treatment with histone deacetylase inhibitors induces reactive oxygen species and sensitizes multiple persister cell types to GPX4 inhibition. Together, these findings reveal that FSP1 and histone deacetylases suppress persister cell ferroptosis.
    DOI:  https://doi.org/10.1126/sciadv.aea8771
  12. Nat Commun. 2025 Dec 29.
    BATF2 is a glutamine-responsive tumour suppressor required for type-I interferon-dependent anti-tumour immunity.
    Wang Gong, Hülya F Taner, Yuesong Wu, Yumin He, Xingwu Zhou, Zaiye Li, Xin Hu, Charisse Ursin, Kala Chand Debnath, Kohei Okuyama, Qiang Hu, Christopher R Donnelly, Felipe Nör, Chamila D Perera, Emily Bellile, Arash Yunesi, Zhiqian Zhai, Mei Zhao, Wanqing Cheng, Zackary R Fitzsimonds, Luke Broses, Jiaqian Li, Shadmehr Demehri, Deepak Nagrath, Gregory T Wolf, Andrew G Sikora, Yanbao Yu, Haitao Wen, Lei Wei, Steven B Chinn, Jeffrey N Myers, Shizuo Akira, Yuying Xie, James J Moon, Yu Leo Lei.
      Recent evidence highlights the significance of a new type of tumour suppressors, which are not frequently mutated but inhibited by metabolic cues in cancers. Here, we identify BATF2 as a tumour suppressor whose expression is epigenetically silenced by glutamine in Head and Neck Squamous Cell Carcinomas (HNSCC). BATF2 correlates with type-I interferon and Th1 signatures in human HNSCC, with correlation coefficients even stronger than those of the positive control, STING. The phosphorylation of BATF2 at serine 227 promotes the oligomerization of STING. BATF2 deficiency or high glutamine levels result in higher oxygen consumption rates and metabolic profiles unfavorable for type-I interferon production. An isocaloric glutamine-rich diet abolishes STING-mediated effector cell expansion in tumours, weakening STING agonist-induced tumour control. Cancer cell-specific BATF2 expression promotes an Id2-centered T-cell effector signature, reduces T-cell exhaustion, and triggers spontaneous HNSCC rejection in a type-I interferon-dependent fashion. Utilizing syngeneic subcutaneous, orthotopic, and 24-week-long cigarette smoke carcinogen-induced HNSCC models, we demonstrate that host Batf2 deficiency results in increased infiltration of CD206+ myeloid cells and reduced effector CD8+ T-cells, accelerating the initiation of cancers. Overall, we reveal a tumour suppressor BATF2 whose loss is mediated by unique metabolic cues in the TME and drives cancer immune escape.
    DOI:  https://doi.org/10.1038/s41467-025-68027-2
  13. Commun Biol. 2025 Dec 31.
    Dietary methionine deprivation enhances renal resilience against ischemia-reperfusion injury in mice through modulation of glucose oxidation.
    Xiaofeng Peng, Yuanhao Xie, Hao Pan, Tianxin Ma, Yaoling Zou, Qun Su, Jianghua Chen, Hong Jiang, Cunqi Ye.
      Renal ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI) and presents significant challenges during kidney transplantation. Due to the detrimental effects of IRI on kidney function and the lack of effective intervention strategies, we conduct a multi-omics study in male mice with surgically induced renal IRI, revealing a modulatory role for the metabolite S-adenosylmethionine (SAM) in AKI development. Our metabolic analysis of clinical samples establishes a link between various AKI conditions and marked elevations in serum SAM, underlying its potential as a biomarker for diagnosis. Furthermore, we find that short-term dietary methionine deprivation, which reduces circulating methionine and kidney SAM levels, effectively enhances renal resilience against IRI. In vivo isotopic tracing demonstrates that this diet preconditions kidney metabolic programs, enhancing glucose and fatty acid oxidation in preparation for IRI. Particularly, the activation of pyruvate dehydrogenase, which produces acetyl-CoA to fuel the tricarboxylic acid (TCA) cycle, highlights an energy-efficient strategy of glucose metabolism that is essential for the protective effects of dietary methionine deprivation.
    DOI:  https://doi.org/10.1038/s42003-025-09447-0
  14. Nat Genet. 2025 Dec 29.
    p53 inactivation drives breast cancer metastasis to the brain through SCD1 upregulation and increased fatty acid metabolism.
    Kathrin Laue, Sabina Pozzi, Johanna Zerbib, Rebecca Bertolio, Yonatan Eliezer, Yael Cohen-Sharir, Tom Winkler, Manuel Caputo, Alessia A Ricci, Lital Adler, Rami Khoury, Giuseppe Longobardi, Rachel Slutsky, Alicia I Leikin-Frenkel, Shai Ovadia, Katharina Lange, Alessandra Rustighi, Silvano Piazza, Andrea Sacconi, Rayna Y Magesh, Faith N Keller, Jean Berthelet, Alexander Schäffer, Ron Saad, Sahar Israeli Dangoor, Karolina Szczepanowska, Iris Barshack, Yang Liao, Sergey Malitsky, Alexander Brandis, Thomas Broggini, Marcus Czabanka, Wei Shi, Delphine Merino, Emma V Watson, Giovanni Blandino, Ayelet Erez, Ruth Ashery-Padan, Hind Medyouf, Luca Bertero, Giannino Del Sal, Ronit Satchi-Fainaro, Uri Ben-David.
      Brain metastasis (BM) carries a poor prognosis, yet the molecular basis of brain tropism remains unclear. Analysis of breast cancer BM (BCBM) revealed pervasive p53 inactivation through mutations and/or aneuploidy, with pathway disruption already present in primary tumors. Functionally, p53 inactivation markedly increased BCBM formation and growth in vivo, causally linking p53 perturbation to BM. Mechanistically, p53 inactivation upregulated SCD1 and fatty acid synthesis (FAS), essential for brain-metastasizing cells; SCD1 knockout abolished the p53-dependent growth advantage. Molecularly, p53 suppressed SCD1 directly through promoter binding and indirectly by downregulating its co-activator DEPDC1. Astrocytes further enhanced FAS by secreting factors that were metabolized in a p53-dependent manner, promoting tumor survival, proliferation and migration. Finally, p53-deficient tumors were sensitive to FAS inhibition ex vivo and in vivo. Thus, we identify p53 inactivation as a driver of BCBM, reveal p53-dependent and astrocyte-dependent FAS modulation and highlight FAS as a therapeutically targetable BCBM vulnerability.
    DOI:  https://doi.org/10.1038/s41588-025-02446-1
  15. Ferroptosis Oxid Stress. 2025 ;pii: 202501. [Epub ahead of print]1(1):
    Lipidomic changes in persister cancer cells drive enhanced ferroptosis sensitivity.
    Eduard Reznik, Fereshteh Zandkarimi, Joleen M Csuka, Qiulin Zhu, Jenny Jin, Taruna Vani Neelakantan, Jiewen Zheng, Vasiliki Polychronidou, Mark Fongheiser, Ashley Brown, Baiyu Qiu, Megan Rodriguez, Lela DeVine, Prem S Subramaniam, Wei Gu, Andrea Califano, Brent R Stockwell.
       Aims: Unique in the broader category of drug-resistant cells, persister cancer cells (PSs) acquire their tolerance to compounds through reversible, chromatin-mediated changes, allowing them to 'persist' in the face of cancer therapeutic agents. PSs are implicated in minimal residual disease from which cancer relapse occurs, and given their established sensitivity to ferroptosis, PSs present a critical point through which identification and targeting of drug-resistant cancers may be possible. Ferroptosis sensitivity in drug-resistant cancers may be caused by the attainment of the persister state, or it may merely be correlative with this state and due instead to extended inhibition of oncogenic signaling or the induction of chemotherapy stress. Nonetheless, ferroptosis sensitivity has emerged as a common phenotype across multiple PS and drug-resistant cancer cell types. Identifying biomarkers for and drivers of ferroptosis sensitivity in drug-resistant and PS cells is therefore a high priority.
    Methods: We derived PS cells from the lung carcinoma cell line PC9 (PSPC9), performed transcriptomic analysis, and subsequently lipidomics on the PC9/PSPC9 system. Additionally, we reverted PSPC9 cells to the ferroptosis-resistant parental state (PC9PS -> PC9) and assessed the resulting lipid changes. We generated two additional PS-like cell models: PS-like prostate carcinoma (PSLNCaP) from LNCaP cells and PS-like fibrosarcoma (PSHT1080) from HT1080 cells, with lipidomics analysis. Finally, we performed a mitochondrial elimination assay and assessed its effect on ferroptosis sensitivity.
    Results: We observed enrichment of lipid and sugar metabolism gene expression in PSPC9; lipidomics revealed enrichment within PSPC9 for ferroptosis-driving diPUFA phospholipids (diPUFA-PL), as well as polyunsaturated free fatty acids (PUFA FFAs). Upon PSPC9 reversion to the ferroptosis-resistant parental state (PC9PS -> PC9), this lipid signature reverted. The LNCaP and HT1080 PS-like models individually showed features consistent with PS, including an increased labile-iron pool, reversibility, and enhanced ferroptosis sensitivity, and had lipid features consistent with those in PSPC9. Finally, mitochondrial elimination partially abrogated ferroptosis sensitivity and altered the PS lipid profile.
    Conclusion: In summary, lipidomic changes dependent on the presence of mitochondria are key to the ferroptosis sensitivity of drug-tolerant persister cancer cells.
    Keywords:  Polyunsaturated fatty acid; cancer; diPUFA; ferroptosis; lipids; mitochondria; persisters
    DOI:  https://doi.org/10.70401/fos.2025.0003
  16. bioRxiv. 2025 Nov 18. pii: 2025.11.08.687404. [Epub ahead of print]
    Microcompartments in archaeal ancestors of eukaryotes: a bioenergetic engine that could have fuelled eukaryogenesis.
    Huan Du, Aoxiang Xu, Xiaoyuan Feng, Wen-Cong Huang, Huayu Li, Li Liu, Yuling Li, Siyu Zhang, Ning Song, Kathryn E Appler, Brett Baker, Eugene V Koonin, Meng Li, Yang Liu.
      Eukaryotic intracellular compartmentalization is a key innovation in the evolution of complex cellular life. While microcompartments enable metabolic specialization in many bacteria, to our knowledge, no analogous systems have been identified in Archaea. Here, we report the discovery of archaeal microcompartments (AMCs) in Hodarchaeales, an order within the phylum Promethearchaeati (Asgard archaea) that includes the closest known archaeal relatives of eukaryotes. Phylogenetic and structural analyses indicate that these catabolic AMCs, which are specialized for sugar-phosphate metabolism, were acquired by horizontal gene transfer from deep-rooted bacteria of the phylum Myxococcota. The shell pentamers of AMCs are fused to lysine/arginine-rich intrinsically disordered regions that capture cytosolic DNA, facilitating nutrient scavenging. Reaction-diffusion modelling predicts that enzyme colocalization and substrate channelling within AMCs can increase the NADH flux approximately 100-fold. Thus, the AMCs substantially boost energy production in the cell and might have primed the archaeal host for eukaryogenesis.
    DOI:  https://doi.org/10.1101/2025.11.08.687404
  17. Anticancer Res. 2026 Jan;46(1): 135-141
    Methionine Restriction, Not Cysteine Restriction, Is a Cancer-specific Vulnerability.
    Yuta Miyashi, Kohei Mizuta, Yohei Asano, Byung Mo Kang, Jin Soo Kim, Qinghong Han, Shukuan Li, Michael Bouvet, Yasunori Tome, Kotaro Nishida, Robert M Hoffman.
       BACKGROUND/AIM: Recently, there have been numerous publications on the induction of ferroptosis by cysteine restriction in cancer cells. The present report aimed to determine whether cysteine restriction (CR) is a cancer-specific vulnerability in comparison with methionine restriction (MR), which is a known cancer-specific vulnerability.
    MATERIALS AND METHODS: Human cancer cell lines (HCT116 colon cancer, 143B osteosarcoma or HT1080 fibrosarcoma) and normal human fibroblasts (Hs27) were cultured in Dulbecco's modified Eagle's medium (DMEM) with dialyzed fetal bovine serum from which methionine or cysteine or both or neither had been depleted. Cancer and normal cells were co-cultured in 12-well plates under the above conditions. HCT116 cells expressing green fluorescent protein, and 143B and HT1080 cells expressing red fluorescent protein, were visualized by fluorescence microscopy. Normal fibroblasts and cancer cells were visualized by phase-contrast microscopy as well.
    RESULTS: In co-culture, of either 143B, HCT116 or HT1080 with Hs27 human fibrosarcoma, CR was toxic to Hs27 normal fibroblasts as well as to all three cancer cell lines. In contrast, MR was toxic only to the cancer cells but not normal fibroblasts. Dual CR and MR was toxic to normal and cancer cells.
    CONCLUSION: For all three cancer cell lines, HCT116 colon cancer, HT1080 fibrosarcoma and 143B osteosarcoma, both MR and CR were highly inhibitory in the co-cultures with Hs27 normal fibroblasts. In all cases MR had only a slight effect on normal fibroblasts, but CR was highly toxic to normal fibroblasts. Thus, MR is a cancer-specific vulnerability in contrast to CR which is toxic to both normal and cancer cells and is not a cancer-specificity vulnerability. Therefore, attempting to induce ferroptosis of cancer cells by CR does not appear to have potential as an effective cancer therapy.
    Keywords:  143B osteosarcoma cells; Cysteine; HCT116 colon cancer cells; HT1080 fibrosarcoma cells; Hs27 human normal fibroblasts; cancer-specific vulnerability; co-culture; dependence; methionine
    DOI:  https://doi.org/10.21873/anticanres.17929
  18. Life Sci Alliance. 2026 Mar;pii: e202503523. [Epub ahead of print]9(3):
    The Janus framework of the integrated stress response: from homeostasis to maladaptation.
    Dogus M Altintas, Marina Cerqua, Paolo M Comoglio, Cédric Chaveroux.
      Every cell must adapt to environmental changes. When nutrients decrease, oxygen levels fall, or protein synthesis outpaces resources, cells activate stress pathways to restore balance. Among these, the integrated stress response (ISR) stands out for its capability to integrate diverse stress signals into a unified translational output. By temporarily slowing global protein synthesis while maintaining the selective translation of stress-adaptive factors, the ISR saves energy, redirects metabolism, and promotes either recovery or, if challenges surpass repair capacity, cell death. In many chronic diseases-including cancer, metabolic, inflammatory, and fibrotic disorders-ISR activity persists. Is this persistence merely a prolonged defensive phase, or does it represent a rewired, self-sustaining state with its own control mechanisms actively reshaping cell fate and disease? We argue that chronic ISR cannot be defined by time alone, challenging the monolithic view. It signifies a qualitative shift in regulation-from rhythmic homeostasis to entrenched maladaptation. Understanding this Janus framework is essential for elucidating the origins of pathology and for guiding future fundamental and translational research.
    DOI:  https://doi.org/10.26508/lsa.202503523
  19. bioRxiv. 2025 Dec 18. pii: 2025.12.17.694973. [Epub ahead of print]
    Self-renewal of neuronal mitochondria through asymmetric division.
    Tejashree Pradip Waingankar, Camryn Zurita, Angelica E Lang, Cliff Vuong, Ahmad Shami, Diana Bautista, Catherine Drerup, Samantha C Lewis.
      Mitochondrial ATP production is essential for life. Mitochondrial function depends on the spatio-temporal coordination of nuclear and mitochondrial genome expression, yet how this coordination occurs in highly polarized cells such as neurons remains poorly understood. Using high-resolution imaging in mouse peripheral sensory neurons and zebrafish larvae, we identified a sub-population of mitochondria enriched in mtDNA that are positioned at the collateral branch points of long sensory neurites, both in vitro and in vivo . While the mitochondria in neurites are generally depleted of mtDNA, those at axon branch points preferentially engage in mtDNA replication and transcription, accumulate nuclear-encoded mitochondrial mRNA, and are spatially linked to nascent cytosolic peptide synthesis. The mtDNA-positive mitochondrial pool exhibits asymmetric genome partitioning at division, shedding highly motile daughters that lack mtDNA. Asymmetric division rejuvenates the membrane potential of the mtDNA-rich, biogenesis-dedicated mitochondria. We also found that, in peripheral sensory neurons, axonal mitochondria rarely fuse or share matrix contents, explaining how differentiated daughters maintain their distinct composition and fate after fission. Thus, division-coupled mitochondrial self-renewal is yoked to neurite topology in sensory neurons, patterning mitochondrial diversity and homeostasis from micron to meter scales.
    DOI:  https://doi.org/10.64898/2025.12.17.694973
  20. JCI Insight. 2026 Jan 09. pii: e191990. [Epub ahead of print]11(1):
    An integrated single-cell and spatial transcriptomic atlas of thyroid cancer progression identifies prognostic fibroblast subpopulations.
    Matthew A Loberg, George J Xu, Sheau-Chiann Chen, Hua-Chang Chen, Claudia C Wahoski, Kailey P Caroland, Megan L Tigue, Heather A Hartmann, Jean-Nicolas Gallant, Courtney J Phifer, Andres A Ocampo, Dayle K Wang, Reilly G Fankhauser, Kirti A Karunakaran, Chia-Chin Wu, Maxime Tarabichi, Sophia M Shaddy, James L Netterville, Sarah L Rohde, Carmen C Solórzano, Lindsay A Bischoff, Naira Baregamian, Barbara A Murphy, Jennifer H Choe, Jennifer R Wang, Eric C Huang, Quanhu Sheng, Luciane T Kagohara, Elizabeth M Jaffee, Ryan H Belcher, Ken S Lau, Fei Ye, Ethan Lee, Vivian L Weiss.
      Although well-differentiated thyroid carcinoma (WDTC) is characterized by a robust treatment response, aggressive subtypes, such as anaplastic thyroid carcinoma (ATC), remain highly lethal. To understand thyroid cancer evolution in both children and adults, we analyzed single-cell transcriptomes of 423,733 cells from 81 samples and spatially resolved key tumor and microenvironment populations across 28 tumors with spatial transcriptomics, including rare and unique composite WDTC/ATC tumors and pediatric diffuse sclerosing thyroid carcinomas. Additionally, we identified gene signatures of stromal cell populations in 5 large thyroid cancer bulk RNA-sequencing cohorts. Through this multi-institutional effort, we defined a population of POSTN+ myofibroblast cancer-associated fibroblasts (myCAFs) that are intimately associated with invasive tumor cells and correlate with poor prognosis, lymph node metastasis, and disease progression in thyroid carcinoma. We also revealed a population of inflammatory CAFs that are distant to tumor cells and are found in the inflammatory stromal microenvironment of autoimmune thyroiditis. Together, our study provides spatial profiling of thyroid cancer evolution in samples with mixed WDTC/ATC histopathology and identifies a prognostic myCAF subtype with potential clinical utility in predicting aggressive disease in both children and adults.
    Keywords:  Cancer; Genetics; Head and neck cancer; Oncology; Thyroid disease
    DOI:  https://doi.org/10.1172/jci.insight.191990
  21. bioRxiv. 2025 Dec 16. pii: 2025.12.15.694525. [Epub ahead of print]
    Translational Downregulation of 5' TOP mRNAs During T Cell Exhaustion.
    Erica S Pledger, Navya Ambavaram, Lucas Ferguson, Jamie H D Cate.
      T cell exhaustion is a dysfunctional state that arises during chronic infections and cancer, characterized by impaired effector functions and sustained expression of inhibitory receptors. While transcriptional, epigenetic, and metabolic rewiring have been well documented in exhausted T cells, a comprehensive understanding of how translation is regulated in this state remains incomplete. To address this gap, we performed ribosome profiling and RNA sequencing on exhausted human CD8+ T cells to globally assess translational control. Our analyses reveal a marked repression of 5' terminal oligopyrimidine (TOP) mRNAs during exhaustion. Unexpectedly, we demonstrate that this translational repression occurs despite evidence of elevated mTOR activity in exhausted T cells. These findings uncover a previously unknown layer of translational control in exhausted T cells.
    DOI:  https://doi.org/10.64898/2025.12.15.694525
  22. Angew Chem Int Ed Engl. 2025 Dec 30. e20934
    Real-Time Super-Resolution Tracking of mtDNA Remodeling and Inflammatory Release with a Selective Fluorescent Probe.
    Shixian Cao, Caixia Sun, Xin-Yue Zhang, Changyu Yoon, Zhiqiang Liu, Jiyoung Yoo, Yujin Kim, Xiaoqiang Yu, Yunjie Xu, Jong Seung Kim, Kang-Nan Wang.
      Mitochondrial DNA (mtDNA) is vital for mitochondrial function and cellular homeostasis, with its spatiotemporal dynamics are tightly linked to development, metabolism, and disease progression. However, super-resolution tracking of mtDNA in live cells remains limited by lack of selective, photostable small-molecule probes. Here, we present mtNARed, a rationally engineered, wash-free fluorescent probe featuring a large Stokes-shift, and high photostability that enables super-resolution tracking of mtDNA dynamics in live cells using stimulated emission depletion (STED) microscopy, with complementary readouts by fluorescence-lifetime imaging microscopy (FLIM). mtNARed precisely localizes to mitochondrial nucleoids and supports long-term imaging while minimizing interference from nuclear DNA. This capability generalizes across diverse mammalian cell types, including highly polarized sperm cells. Importantly, under mitochondrial stress or inflammatory stimulation, mtNARed reports in situ and at super-resolution of the progressive release of mtDNA, correlating with mitochondrial depolarization, membrane disintegration, and immune activation. This work provides a robust and versatile platform for advanced mtDNA imaging, opening opportunities to dissect mitochondrial genome dynamics, maintenance, and signaling across physiological and pathological states.
    Keywords:  STED super resolution imaging; mtDNA dynamics tracking; mtDNA remodeling & inflammatory release; mtDNA selective targeting probe
    DOI:  https://doi.org/10.1002/anie.202520934
  23. J Clin Invest. 2026 Jan 02. pii: e192599. [Epub ahead of print]136(1):
    Glioblastoma stem cells resist cuproptosis with circadian variation of copper levels.
    Fanen Yuan, Xujia Wu, Huairui Yuan, Donghai Wang, Tengfei Huang, Po Zhang, Hailong Mi, Weichi Wu, Suchet Taori, Priscilla Chan, Kenji Miki, Maged T Ghoche, Linjie Zhao, Kalil G Abdullah, Steve A Kay, Qiulian Wu, Jeremy N Rich.
      Cuproptosis involves accumulation of intracellular copper that triggers mitochondrial lipoylated protein aggregation and destabilization of iron-sulfur cluster proteins, leading to cell death. Pharmacologic induction of cuproptosis has been proposed as a cancer therapy. Here, we find that glioblastoma (GBM) stem cells (GSCs) displayed relative resistance to cuproptosis with circadian variation of intracellular copper levels. CRISPR screening of copper regulators under concurrent treatment with copper ionophore or clock disruption revealed dependency on ATPase copper transporting alpha (ATP7A). Circadian control of copper homeostasis was mediated by the core clock transcription factor, brain and muscle ARNT-like 1 (BMAL1). In turn, ATP7A promoted tumor cell growth through regulation of fatty acid desaturation. Copper levels negatively fed back into the circadian circuitry through sequestosome 1/p62-mediated lysosomal degradation of BMAL1. Targeting the circadian clock or fatty acid desaturation augmented cuproptosis antitumor effects. Crosstalk between the core circadian clock and copper sustains GSCs, reshaping fatty acid metabolism and promoting drug resistance, which may inform development of combination therapies for GBM.
    Keywords:  Brain cancer; Cell biology; Neuroscience; Oncology; Stem Cells
    DOI:  https://doi.org/10.1172/JCI192599
  24. Immunology. 2025 Dec 28.
    Regulatory T Cell Metabolism in Cancer.
    Keywan Mortezaee.
      Regulatory T cells (Tregs) display metabolic fitness to adopt tumour microenvironment (TME), characterized by hypoxia, acidity and metabolic depletion/competition, in order to impair anti-tumour immunity and allow metastasis. Tregs and other TME immune cells interact metabolically, with glycolysis supporting proliferation of Tregs along with cancer cells and CD8+ T cells and a basal oxidative phosphorylation (OXPHOS) promoting Treg and CD8+ T cell activity. Lactate is a glycolysis byproduct that its accumulation creates acidosis within TME, and its uptake provides a fuel source for Treg activity and fosters their persistence in the hypoxic TME. Itaconate and hypoxic TME increase succinate accumulation, but they take complex roles on Tregs and T cells. Hypoxia and hypoxia inducible factor-1 (HIF-1) activity induce lactate release and Treg recruitment/accumulation via stimulating glycolysis path and extracellular adenosine aggregation. Knockout of HIF-1α although reduces lactate, it secondarily induces OXPHOS to fulfil Treg immunosuppressive function. FOXP3 is stabilized by mitochondrial transcription factor A (Tfam) and induces Treg CD36 and OXPHOS, which can be disturbed by nucleus accumbens-associated protein 1 (NAC1). Liver kinase B1 (LKB1) and AMP-activated protein kinase (AMPK) although induce FOXP3 stability and OXPHOS in Tregs, their activities downregulate programmed death-1 (PD-1) in such cells. OXPHOS augmentation (by α-ketoglutarate [αKG]) or suppression (by metformin) disrupt Treg metabolism. Finally, indoleamine 2,3-dioxygenase (IDO) seems to affect Tregs and can be a promising target in advanced immunotherapy naïve cancer patients. The focus of this review is to describe Treg metabolic regulators/connectome and opportunities they bring about in cancer therapy.
    Keywords:  adenosine; aryl hydrocarbon receptor (AHR); glycolysis; hypoxia inducible factor (HIF); lactate; liver kinase B1 (LKB1); metformin; oxidative phosphorylation (OXPHOS); regulatory T cell (Treg); α‐Ketoglutarate (αKG)
    DOI:  https://doi.org/10.1111/imm.70096
  25. Cancer Cell. 2025 Dec 31. pii: S1535-6108(25)00543-4. [Epub ahead of print]
    Spatial omics at the forefront: emerging technologies, analytical innovations, and clinical applications.
    Yunhe Liu, Yibo Dai, Linghua Wang.
      Spatial omics transforms our understanding of cancer by revealing how tumor cells and the microenvironment are organized, interact, and evolve within tissues. Here, we synthesize advances in spatial technologies that map tumor ecosystems with unprecedented fidelity. We highlighted analytical breakthroughs-including multimodal integration and emerging spatial foundation models-that resolve functional niches and spatial communities, converting spatial patterns into mechanistic insights. We summarize how spatially organized features, from immune hubs to microbiota and neural interfaces, shape tumor evolution and clinical outcomes. We then outline how spatial approaches illuminate precancer biology, metastatic adaptation, and therapy response. Bridging discovery and translation, we provide a practical roadmap for incorporating spatial readouts into clinically oriented study design. We conclude by discussing persistent challenges in standardization and scalability and how high-plex spatial discoveries may be distilled into scalable, AI-enabled, clinically deployable assays, positioning spatial omics as a cornerstone of next-generation predictive and precision oncology.
    Keywords:  AI; ML; TME; artificial intelligence; cell-cell interaction; cellular neighborhood; computational pathology; machine learning; molecular imaging; multi-omics; multimodal data integration; proteomics; spatial biomarkers; spatial heterogeneity; spatial niche; spatial omics; transcriptomics; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2025.12.009
  26. Antioxidants (Basel). 2025 Dec 12. pii: 1496. [Epub ahead of print]14(12):
    Redox Modulation in Therapy of Cancer: Some Pros and Cons.
    Ljubava D Zorova, Dmitry S Semenovich, Savva D Zorov, Ilya P Oleynikov, Anastasia S Kargapoltceva, Dmitry V Prutskikh, Polina A Abramicheva, Irina B Pevzner, Gennady T Sukhikh, Dmitry B Zorov.
      Redox potential controls a vast array of biochemical reactions, and its changes influence the transition from normal to pathological states. However, cellular redox potential is primarily assessed after extraction of water-soluble components (reduced and oxidized) from biological material, particularly glutathione, which, due to its abundance, determines intracellular redox potential. This process involves mechanistic averaging of redox potential values across tissue or cell, although existing data suggest, and sometimes directly indicate, heterogeneity in redox potential both within cells and within tissue. We argue that mitochondria determine cellular redox state, in particular through changes in the state of the mitochondrial reticulum caused by various internal and external factors. We describe the possibilities for regulation of redox status of the cell and organ as a potential therapy for various pathologies, particularly cancer, and propose intensifying efforts to utilize intrinsic redox indicators. We specifically examine the possibility of changes the redox potential in cancer cells through the use of oxidative phosphorylation uncouplers and propose mechanisms by which cancer cells may be killed using uncouplers. Particular attention is paid to the mitochondrial membrane potential as a powerful regulator of cellular metabolism, possibly unrelated to the regulation of reactive oxygen species levels, with the possible existence of a membrane potential sensor in cells.
    Keywords:  NAD; NADH; cancer; fragmentation; glutathione; membrane potential; mitochondria; redox potential; reticulum; sensor; uncouplers; uncoupling
    DOI:  https://doi.org/10.3390/antiox14121496
  27. Cell Metab. 2025 Dec 29. pii: S1550-4131(25)00530-3. [Epub ahead of print]
    Uridine depletion impairs CD8⁺ T cell antitumor activity through N-glycosylation.
    Jianbiao Xiao, Zhiyang Li, Yi Ding, Kejin Zhu, Zhihao Zheng, Yaowei Zhang, Jiawen Weng, Feifei Wang, Yuqin Zhang, Sisi Zeng, Minxing Qiu, Zhaowen Zhang, Zhizhang Wang, Li Liang.
      Immune checkpoint blockade (ICB) faces limitations owing to high cost and restricted efficacy. This study identifies SNX17 as a key mediator of ICB resistance. Elevated SNX17 correlates with poor anti-PD-1 response in humans and mice. SNX17 deletion in tumor cells inhibits tumor growth via CD8+ T cell-dependent mechanisms. SNX17 reduces uridine in the tumor microenvironment (TME), suppressing IFN-γ and upregulating PD1 in CD8+ T cells. Exogenous uridine shows antitumor efficacy comparable to anti-PD-1/PD-L1 in low-SNX17 tumors and overcomes resistance in high-SNX17 models. Uridine enhances CD8+ T cell function by promoting CD45 N-glycosylation and LCK phosphorylation. Mechanistically, SNX17 stabilizes RUNX2, promoting UPP1 transcription and uridine degradation in the TME. These findings position SNX17 as an ICB response biomarker and nominate uridine as a cost-effective immunotherapeutic strategy.
    Keywords:  CD8+ T cell; N-glycosylation; SNX17; UPP1; checkpoint blockade; immunotherapy resistance; uridine
    DOI:  https://doi.org/10.1016/j.cmet.2025.11.016
  28. Cell Signal. 2025 Dec 26. pii: S0898-6568(25)00759-4. [Epub ahead of print] 112344
    Targeting USP28 inhibits clear cell renal cell carcinoma growth.
    Ying Ren, Yunfang Yang, Xiaodan Zhu, Lingyi Li, Yaoyao Pan, Hong Sun, Qian Fang, Hui Xiong, Dong Guo, Yongzhan Sun, Hailong Li, Junqi Wang.
      Clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer, remains challenging to treat due to the lack of effective targeted therapies. Although c-Myc is frequently overexpressed in ccRCC, the mechanisms governing its stability are not well understood. Here, we identify the deubiquitinating enzyme USP28 as a key regulator of c-Myc protein stability in ccRCC. USP28 interacts with c-Myc, removes K48-linked polyubiquitin chains, and thereby prevents its proteasomal degradation, leading to c-Myc stabilization in ccRCC cells. Genetic or pharmacological inhibition of USP28 significantly reduces c-Myc expression, impairs ccRCC cell proliferation in vitro, and suppresses tumor growth in vivo. Tumors with high c-Myc expression exhibit heightened sensitivity to USP28 inhibition, underscoring the therapeutic potential of targeting this axis. Collectively, our findings position USP28 as a promising therapeutic target for ccRCC.
    Keywords:  AZ1; C-Myc; USP28; Ubiquitin-proteasome system; ccRCC
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112344
  29. Cell Rep. 2025 Dec 30. pii: S2211-1247(25)01612-2. [Epub ahead of print]45(1): 116840
    Inhibition of PAK2 in endothelial cells suppresses tumor angiogenesis and promotes immune sensitization through CXCL10.
    Jeanne Corriveau, Pascale Monot, Chantal Delisle, Marie-Anne Goyette, Camille Gasse, Yassine El Bakkouri, Trang Hoang, Jean-François Côté, Jean-Philippe Gratton.
      Tumor angiogenesis is driven by pro-angiogenic factors and results in a disorganized tumor vasculature that limits effective perfusion and immune infiltration. The p21-activated kinase 2 (PAK2) regulates endothelial cell (EC) migration, an essential step in angiogenesis, yet its role in tumor angiogenesis remains ill-defined. Here, we show that endothelial-specific deletion of PAK2 in orthotopic tumor mouse models markedly reduces tumor size and angiogenesis. Additionally, loss of endothelial PAK2 normalizes the remaining tumor vasculature and promotes infiltration of dendritic and natural killer cells. Mechanistically, PAK2 regulates chemokine expression, notably CXCL10. PAK2 depletion enhances CXCL10 secretion from ECs, and CXCL10 expression is required for the inhibitory effects of PAK2 silencing on EC sprouting. Moreover, CXCL10 neutralization in mice reverses the vascular and immune changes induced by endothelial PAK2 deletion. Together, these findings identify endothelial PAK2 as a potential target to limit tumor angiogenesis and reprogram ECs to promote immune infiltration through CXCL10 signaling.
    Keywords:  CP: cancer; CXCL10; NK cells; PAK2; dendritic cells; endothelial cells; immune response; tumor angiogenesis; tumor immunity; tumor microenvironment; vascular nomalization
    DOI:  https://doi.org/10.1016/j.celrep.2025.116840
  30. Sci Adv. 2026 Jan 02. 12(1): eadu0292
    Systemically inducing trained immunity overcomes solid tumors' immunosuppressive microenvironment.
    Bram Priem, Lisa Willemsen, Tom Anbergen, Yuri van Elsas, Jeroen Deckers, David P Schrijver, Stijn R J Hofstraat, Iris V Messing, Jazz Munitz, Dionne Honing, Geoffrey Prévot, Yohana C Toner, Judit Morla, William Wang, Anna Ranzenigo, Isabella Sirchia, Tomas Post, Raphaël Duivenvoorden, Ewelina Kluza, Glenn A O Cremers, Joost H C M Kreijtz, Carlos Pérez-Medina, Mandy M T van Leent, Abraham J P Teunissen, Roy van der Meel, Yi Zhou, Chris Glass, Jordi Ochando, Leo A B Joosten, Zahi A Fayad, Romana T Netea-Maier, Mihai G Netea, Menno P J de Winther, Thijs J Beldman, Arjan W Griffioen, Willem J M Mulder.
      Hematopoietic bone marrow progenitors are increasingly implicated as an origin of immunosuppression in cancer. We have previously shown that trained immunity induction using nanomedicine potentiates checkpoint blockade therapy. Here, we studied how this approach's induction of trained immunity systemically overcomes the immunosuppressive tumor microenvironment. We found changes in the tumor microenvironment to mirror functional changes in the hematopoietic system in a melanoma mouse model. Single cell sequencing methods disclosed a shift in the tumor-associated macrophage population from immunosuppressive to antitumorigenic. Uniquely, a trained immunity and checkpoint blockade combination therapy mobilized natural killer cells which, in conjunction with the functional changes in the myeloid cell compartment, effectively activated T cells. Last, we established the effectiveness of our approach in mouse models of breast, lung, and pancreatic cancer. Collectively, our data show that the systemic induction of trained immunity rebalances the immune system for effective checkpoint blockade therapy.
    DOI:  https://doi.org/10.1126/sciadv.adu0292
  31. Cell Rep. 2025 Dec 30. pii: S2211-1247(25)01540-2. [Epub ahead of print]45(1): 116768
    Longevity of cardiac and skeletal muscle proteins is dependent on tissue and subcellular compartmentation patterns.
    Jack Gugel, Jordan Currie, Lorena Alamillo, Jason Flint, Keun-Young Kim, Marc Debliqui, Mark H Ellisman, Maggie P Y Lam, Edward Lau, Rafael Arrojo E Drigo, Leslie Leinwand.
      Myocytes are exceptionally long-lived cells that must maintain proteome integrity over decades while adjusting for changes in functional output and metabolic demand. We used in vivo stable isotope labeling combined with mass spectrometry proteomics and correlated multi-isotope imaging mass spectrometry to quantify and visualize protein turnover across cardiac, fast-twitch, and slow-twitch skeletal muscles, creating a resource of hundreds of individual protein turnover rates from each tissue. We found that cardiac muscle has the highest rate of protein turnover, followed by slow-twitch skeletal muscle and then fast-twitch skeletal muscle, and that these different rates of protein turnover are driven by different levels of muscle use, rather than myosin isoform composition. We also identified protein age heterogeneity at the myofiber and sarcomere levels. These findings uncover fundamental principles of muscle protein maintenance and have broad implications for understanding cellular aging, muscle disease, and the design of therapeutic strategies targeting muscle protein turnover.
    Keywords:  CP: Metabolism; CP: Molecular biology; actin; cardiac muscle; half-life; long-lived proteins; multi-isotope imaging; protein turnover; skeletal muscle; stable-isotope labeling
    DOI:  https://doi.org/10.1016/j.celrep.2025.116768
  32. Nat Cell Biol. 2025 Dec 29.
    T follicular helper cells transiently unlock a plasticity state in germinal centre B cells during the humoral immune response.
    Laurianne Scourzic, Franco Izzo, Matt Teater, Alexander P Polyzos, Lucretia Cucereavii, Christopher R Chin, Antonin Papin, Hugo B Pinto, Coraline Mlynarczyk, Ioanna Tsialta, Min Xia, Abigail Lidoski, Robert M Myers, Eva M Israel, Leandro Venturutti, Simon P Mackay, Kenneth B Hoehn, Arthur I Skoultchi, Wendy Béguelin, Matthias Stadtfeld, Zhengming Chen, Dan A Landau, Ari M Melnick, Effie Apostolou.
      During the germinal centre (GC) reaction, mature B cells undergo rapid and reversible phenotypic shifts that are essential for adaptive immunity. Here we report that GC B cells, unlike other mature B cells, transiently acquire a unique epigenetic plasticity, demonstrated by their enhanced capacity to reprogram to induced pluripotent stem cells. This plasticity depends on T follicular helper (TFH) cells and is not due to increased proliferation or MYC activation. Instead, it involves weakening of B-cell identity and derepression of stem and progenitor programs driven by NF-κB and other TFH-derived signals. Thus, physiological GC plasticity is tightly constrained by the affinity maturation process of positive selection. Loss of histone 1, a chromatin compaction regulator restricting the accessibility of embryonic stem cell programs, further enhances GC plasticity by bypassing this gatekeeping mechanism. Importantly, patients with B-cell lymphoma enriched for GC plasticity signatures had worse outcomes, suggesting that this mechanism may also contribute to lymphomagenesis.
    DOI:  https://doi.org/10.1038/s41556-025-01833-4
  33. Cancer Cell. 2025 Dec 31. pii: S1535-6108(25)00539-2. [Epub ahead of print]
    Cancer cell death: Cell-autonomous and immunogenic dimensions.
    Lorenzo Galluzzi, Oliver Kepp, Laurence Zitvogel, Daolin Tang, Guido Kroemer.
      Regulated cell death (RCD) shapes neoplastic transformation, tumor progression, and response to treatment. While apoptosis was long viewed as the only RCD variant, additional modalities, including necroptosis, pyroptosis, and ferroptosis, have been characterized. These interconnected pathways operate in a context-dependent manner to influence the dynamic interplay between malignant and non-malignant cells that governs disease progression or regression, both naturally and during therapy. Major advances stemmed from recognizing immunogenic cell death (ICD) as an RCD type defined by the emission of immunomodulatory damage-associated molecular patterns (DAMPs) from dying cancer cells. The balance between immunostimulatory and immunosuppressive DAMPs dictates whether neoplastic cells undergoing RCD effectively activate adaptive immunity. Thus, ICD provides mechanistic grounds for the durable efficacy of certain cancer therapeutics, and underpins their synergy with immune checkpoint inhibitors. Understanding the molecular determinants of RCD and ICD is reshaping oncology, allowing for an increasingly refined integration between cytotoxicity and durable anticancer immune responses.
    Keywords:  PD-1; STING; autophagy; cellular senescence; persister cells; type I interferon
    DOI:  https://doi.org/10.1016/j.ccell.2025.12.005
  34. Cancer Res. 2026 Jan 02. 86(1): 7-9
    Lung Metastases in Pancreatic Cancer: Timing Their First Breath.
    Gianluca Mucciolo, Giulia Biffi.
      Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor survival rate. This is largely due to patients being diagnosed when the disease has already metastasized to other organs, most commonly the liver and lungs. For these patients, no effective treatment exists, and the 5-year survival rate is less than 5%. Despite its highly metastatic nature, the timing and mechanisms of metastasis formation in PDAC remain largely unknown. In this issue of Cancer Research, Lasse Opsahl and colleagues identify a role for premalignant pancreatic intraepithelial neoplasia (PanIN) lesions in lung premetastatic niche formation. By performing histology and single-cell RNA sequencing analyses of a KRASG12D inducible mouse model of PDAC, the authors identify pSTAT3+ fibroblasts in the lungs, but not the liver, upon PanIN formation. Notably, pSTAT3+ fibroblasts in the lungs are required for metastasis formation. Mechanistically, KRAS activation in the pancreatic epithelium and consequential IL6 release activate STAT3 in lung fibroblasts. Altogether, Lasse Opsahl and colleagues demonstrate that PanIN lesions prime the lungs to favor future malignant cell outgrowth before the development of a pancreatic tumor and that blocking the formation of this lung premetastatic niche impairs metastasis in mice. See related article by Lasse Opsahl et al., p. 22.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-4465
  35. Mol Cell. 2025 Dec 30. pii: S1097-2765(25)00981-5. [Epub ahead of print]
    How does cytoplasmic crowding affect reaction rates?
    Jo-Hsi Huang, James E Ferrell.
      The cytoplasm of eukaryotic cells is crowded with macromolecules. In principle, this crowding could have either a positive or a negative effect on the rates of biochemical reactions. Here, we review two commonly invoked theories to account for these possible effects then survey recent experimental work in cells and extracts that measures the effects. The evidence so far suggests that the effective second-order rate constants (a measure of the speed of a reaction for a given concentration of reactants) for reactions in vivo generally go down when crowding increases due to the slowing of diffusion. If the evidence presented so far proves to be general, it would have important implications for how we view the trade-offs that determine the biochemical dynamics of the cytoplasm.
    Keywords:  Phillies’s law; diffusion; excluded volume; in vivo biochemistry; molecular crowding; rate constants; scaled-particle theory
    DOI:  https://doi.org/10.1016/j.molcel.2025.12.007
  36. bioRxiv. 2025 Dec 16. pii: 2025.12.12.694055. [Epub ahead of print]
    Senescent cells secrete chromatin components via senescence-associated extracellular particles.
    Sviatlana Zaretski, Jose L Nieto Torres, Xue Lei, John P Nolan, Malene Hansen, Peter D Adams.
      Senescent cells influence their surroundings through the senescence-associated secretory phenotype (SASP), an assortment of secreted molecules and macromolecular complexes. Among SASP's intracellular drivers are cytoplasmic chromatin fragments (CCFs), nuclear-derived DNA that activates the pro-inflammatory cGAS/STING pathway. While autophagy contributes to CCFs degradation, the full repertoire of CCF fates and signaling functions remains unclear. Here, we show that senescent cells release CCF components, ɣH2AX and double-stranded DNA (dsDNA), into the extracellular space via an ESCRT-independent multivesicular body pathway. Secreted CCF components localize to extracellular particles exhibiting an unusual "popcorn"-like morphology, distinct from canonical small extracellular vesicles. Notably, inhibition of autophagy enhances secretion of CCF components and particles, suggesting an inverse relationship between intracellular clearance and extracellular release. A fraction of CCF-containing extracellular particles activates cGAS-STING signaling in non-senescent proliferating cells and is enriched in the circulation of aged mice, pointing to a previously unrecognized mode of extracellular signaling by senescent cells.
    DOI:  https://doi.org/10.64898/2025.12.12.694055
  37. Nat Genet. 2025 Dec 29.
    Aneuploidy-driven vulnerabilities in breast cancer metastasis.
    Samuel F Bakhoum.
      
    DOI:  https://doi.org/10.1038/s41588-025-02444-3
  38. Elife. 2025 Dec 29. pii: RP96783. [Epub ahead of print]13
    Sex differences in bile acid homeostasis and excretion underlie the disparity in liver cancer incidence between males and females.
    Megan E Patton, Sherwin Kelekar, Lauren J Taylor, Angela E Dean, Qianying Zuo, Rhishikesh N Thakare, Sung Hwan Lee, Emily C Gentry, Morgan Panitchpakdi, Pieter Dorrestein, Yazen Alnouti, Zeynep Madak-Erdogan, Ju-Seog Lee, Milton J Finegold, Sayeepriyadarshini Anakk.
      Hepatocellular carcinoma (HCC), the common liver cancer, exhibits higher incidence in males. Here, we report that mice lacking bile acid (BA) regulators, Farnesoid X Receptor (FXR also termed NR1H4) and Small Heterodimer Partner (SHP also termed NR0B2), recapitulate the sex difference in liver cancer risk. Since few therapeutic options are available, we focused on understanding the intrinsic protection afforded to female livers. Transcriptomic analysis in control and NR1H4 and NR0B2 double knockout livers identified female-specific changes in metabolism, including amino acids, lipids, and steroids. To assess translational relevance, we examined if transcriptomic signatures obtained from this murine HCC model correlate with survival outcomes for HCC patients. Gene signatures unique to the knockout females correspond with low-grade tumors and better survival. Ovariectomy blunts the metabolic changes and promotes liver tumorigenesis in females that, intriguingly, coincides with increased serum bile acid (BA) levels. Despite similar genetics, knockout male mice displayed higher serum BA concentrations, while female knockouts excreted more BAs. Decreasing enterohepatic BA recirculation using cholestyramine, an FDA-approved resin, dramatically reduced the liver cancer burden in male mice. Overall, we reveal that sex-specific BA metabolism leading to lower circulating BA concentration protects female livers from developing cancer. Thus, targeting BA excretion may be a promising therapeutic strategy against HCC.
    Keywords:  bile acid metabolism; cancer biology; liver cancer; mouse; sex differences
    DOI:  https://doi.org/10.7554/eLife.96783
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