bims-instec 2026-07-05 papers

bims-instec

Biomed News

on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration

Issue of 2026–07–05
27 papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Steatosis shapes prognosis-defining liver metastasis heterogeneity in CRC.
Colorectal Cancer Liver Metastasis-Associated Ferroptosis-Related Genes Modulate Lipid Peroxidation in Colorectal Cancer Cells.
TROP2 targeting reveals therapy-driven cell state dynamics in colorectal cancer.
EphA2 sustains the adaptive response of colorectal organoids to chemotherapy.
Lipid droplets as stress-buffering organelles in cancer cell homeostasis.
Multiscale integration of tissue and chromatin context converts cell heterogeneity into stable intestinal patterning.
Liver fat steers the outcome of advanced colorectal cancer.
α-ketoglutarate accumulation orchestrates immunosuppressive metabolic remodeling to drive cetuximab resistance in metastatic colorectal cancer.
Mutational scanning reveals substrate-assisted autoregulation of the WNT destruction complex.
Divergent roles of SPOP and CHD1 in ACSL4 regulation reveal context-dependent vulnerabilities for targeting ferroptosis.
Integrated Spatial and Bulk Untargeted Metabolomics Characterize Location- and Histology-Associated Metabolic Heterogeneity in Colorectal Cancer.
Co-clinical CT radiomics pipeline to establish candidate imaging biomarkers for colorectal cancer.
Inhibition of cyclin-dependent kinases 12/13 using CT7439 as a treatment for colorectal cancer with CDK12 upregulation.
Assessment of mitochondrial lipid peroxidation in cells and zebrafish using a targeted mass spectrometry probe.
Nuclear-specific reductive carboxylation of alpha-ketoglutarate fuels histone acetylation to induce chromatin accessibility and gene activation.
Mapping the anatomical landscape of colorectal tumours: Location-specific efficacy of anti-epidermal growth factor receptor antibodies: Pooled analysis of randomised trials.
Multi-omics and metabolic flux modeling reveal that macrophage CYP27A1-derived 26-hydroxycholesterol drives immunosuppression and cancer malignancy.
MYO5B Deficiency Is Associated with Altered MUC13 Localization and DMBT1 Accumulation in Intestinal Epithelial Cells.
Yap mediates hippo signaling to balance proliferation and differentiation in the developing glandular stomach epithelium.
Mechanisms and advances of drug resistance in colorectal cancer: A systematic overview of multi-layered regulatory networks.
Lipid metabolism of hepatocyte-like cells supports intestinal tumor growth in Drosophila.
Cell engulfment defines spatially distinct competitive metabolic niches associated with clinical outcomes in colorectal cancer.
Pan-cancer analysis reveals Rho kinase addiction as a vulnerability of de-differentiated cancer cells.
Lipid Metabolic Labeling to Study Site- and Lipid-Specific Long-Chain S-Acylation Dynamics.
A targetable FTO/SLC7A11/CBS/CTH axis controls cysteine metabolism, growth and survival in NSCLC.
Imaging the hallmarks of cancer.
SIRT7-mediated ACSL3 delactylation suppresses colorectal cancer progression by orchestrating tumor-associated macrophage ferroptosis and polarization.

Nature. 2026 Jul 01.

Steatosis shapes prognosis-defining liver metastasis heterogeneity in CRC.

Yiming Peng-Winkler, Xiao-Zheng Liu, Sanne M L Verheul, Charlotte Girondel, Sebastian Igelmann, Sara Marie Rotter, Michail Doukas, Ming Liu, Anke Vandekeere, Mélanie Planque, Juan Fernández-García, Sébastien Tabariès, Marta Buetas-Arcas, Sandra Martínez-Martín, Florian Döbbe, Margherita Demicco, Ines Vermeire, Janine Theile, Johannes Ceuppens, Jonas Haesevoets, Emma Tobarra-López, Dorien Broekaert, Johannes Georg Bode, Tom Luedde, Peter Vermeulen, Daniele V F Tauriello, Raquel Perez-Lopez, Steve Stegen, Laura Soucek, Tiago De Oliveira, Lena-Christin Conradi, Peter M Siegel, Cornelis Verhoef, Sarah-Maria Fendt.

Patients with colorectal cancer (CRC) frequently develop liver metastases1-3. The prognosis of these patients is skewed by the histopathological heterogeneity of their liver metastases4,5. Patients with 'replacement' metastases have a 5-year overall survival of less than 44.2%, compared with 73.4% in patients with 'encapsulated' (previously known as desmoplastic) metastases5; yet there are currently no approved therapies targeting replacement liver metastases. Here we show that treatment-naive patients with CRC with liver steatosis have an increased occurrence of replacement metastases compared with patients without steatosis. Mechanistically, we find that steatosis-promoted fatty acid oxidation increases formation of replacement metastases by increasing MYC stability through acetylation. In turn, MYC activates proline synthesis, fuelling collagen production, enabling growth of replacement metastases. Targeting MYC, P5CS or COL1A1 suppresses the occurrence and growth of replacement metastases in patient-derived organoids, mouse or patient-derived xenograft models. Spatial metabolite and protein analyses of liver metastases from patients with CRC further support this mechanism. In conclusion, we provide a mechanistic understanding of the emergence of liver metastases with poor prognosis in treatment-naive patients with CRC, identifying potential targets for therapeutic intervention.

DOI: https://doi.org/10.1038/s41586-026-10686-2
Mol Carcinog. 2026 Jun 30.

Colorectal Cancer Liver Metastasis-Associated Ferroptosis-Related Genes Modulate Lipid Peroxidation in Colorectal Cancer Cells.

Zheng Ge, Wei Guo, Jingxin Li, Yanqing Wang, Kexin Wang.

Distant metastasis, predominantly to the liver, remains the leading cause of death in colorectal cancer (CRC), yet biomarkers that capture metastatic competence remain limited. Ferroptosis is an iron-dependent, lipid peroxidation-driven form of regulated cell death that can restrain tumor progression, but whether primary CRC from patients with liver metastasis shows ferroptosis-resistance-related features remains incompletely understood. In a small exploratory set of T-stage-matched primary CRC tumors with or without liver metastasis, we quantified glutathione redox and lipid peroxidation-related readouts and assessed SLC7A11 and GPX4 expression. We integrated GSE62321 transcriptomic profiles with a FerrDb ferroptosis gene set, evaluated prognosis in TCGA-COAD/READ, and performed genetic knockdown, MDA assays, C11-BODIPY lipid ROS staining, ferrostatin-1 rescue assays, and Transwell assays in CRC cell models. Primary tumors from patients with liver metastasis showed a more reduced redox profile and increased expression of core ferroptosis-suppressive proteins, consistent with enhanced ferroptosis resistance potential but not direct evidence of lower in vivo ferroptotic cell death. Integrative discovery highlighted fatty acid binding protein 4 (FABP4), α-synuclein (SNCA), and discoidin domain receptor 2 (DDR2) as CRC-LM-associated ferroptosis-related candidates. High expression of each gene was associated with unfavorable disease-free survival. In CRC cell models, including the lymph-node-metastasis-derived SW620 line and additional validation lines, silencing FABP4, SNCA, or DDR2 increased bulk MDA and/or C11-BODIPY-detected lipid ROS, altered ferroptosis susceptibility, and suppressed migratory and/or invasive phenotypes. Ferrostatin-1 partially rescued knockdown-induced viability loss, lipid ROS accumulation, and migratory/invasive defects, supporting involvement of ferroptosis-associated lipid peroxidation while not excluding broader stress-response mechanisms. FABP4, SNCA, and DDR2 are CRC-LM-associated ferroptosis-related candidates that modulate lipid peroxidation, ferroptosis susceptibility, and migratory/invasive phenotypes in CRC cell models, warranting further validation in viability-controlled and liver metastasis-specific models.

DOI: https://doi.org/10.1002/mc.70143
Nature. 2026 Jul 01.

TROP2 targeting reveals therapy-driven cell state dynamics in colorectal cancer.

Nuria Vaquero-Siguero, Nikolaos Georgakopoulos, Maria C Puschhof, Ioannis Chiotakakos, Jasmin Meier, Sigrid K Fey, Gabriele Diamante, Manuel Mastel, Aitana Guiseris-Martinez, Guillaume Belthier, Nikolai Schleußner, Julia Volk, Carolin Artmann, Bryce Lim, Ronald Koschny, Cyrill Wehling, Kyanna S Ouyang, Michael Günther, Solveig Kuss, Paula Hoffmeister, Moritz Mall, Jens Neumann, Steffen Ormanns, Martin Schneider, Thomas Schmidt, Jens Puschhof, Andreas Trumpp, Jacco van Rheenen, Julio Saez-Rodriguez, Bruno C Köhler, Rene Jackstadt.

Metastasis remains the leading cause of cancer-related mortality and is driven by pronounced tumour cell plasticity1. Here we identify the transmembrane glycoprotein trophoblast cell-surface antigen 2 (TROP2) as a marker of poor-prognosis colorectal cancer (CRC) associated with WNTlow, fetal-like tumour cell states that are linked to metastasis and therapy resistance. Functional analyses demonstrate that TROP2+ cells exhibit context-dependent stem-like capacity and the ability to initiate metastatic outgrowth. Given that these detrimental tumour states converge on the cell-surface antigen TROP2, we explored therapeutic targeting of this cell population using clinically relevant TROP2-directed antibody-drug conjugates. Time-resolved analyses reveal therapy-associated dynamics in tumour cell state composition between WNThi LGR5+ states and WNTlowTROP2+ fetal-like states. Conventional chemotherapy promotes the induction of TROP2-expressing cells, whereas TROP2 antibody-drug conjugates selectively target these populations and remodel the tumour cell state landscape. Exploiting this plasticity, combined chemotherapy and TROP2 targeting enhances anti-tumour efficacy in patient-derived models. Together, our findings identify TROP2 as a therapeutic vulnerability of CRC and highlight the importance of targeting tumour cell states to improve therapeutic efficacy and overcome resistance in advanced disease.

DOI: https://doi.org/10.1038/s41586-026-10705-2
Front Cell Dev Biol. 2026 ;14 1833389

EphA2 sustains the adaptive response of colorectal organoids to chemotherapy.

Veronica Gatti, Gabriella Teresa Capolupo, Chiara Taffon, Andrea Marra, Giuseppe Perrone, Gianluca Masciana', Marco Caricato, Mario Cioce, Vito Michele Fazio.

   Introduction: EphA2 is highly expressed in colorectal cancer (CRC), and high EphA2 expression indicates a worse prognosis. We investigated EphA2 dynamics in a clinically relevant model: CRC patient-derived organoids (PDOs) treated with chemotherapy.
Methods: We evaluated the number of EphA2-expressing cells and the Aldehyde dehydrogenase activity by flow cytometry, and analyzed EphA2 protein levels and phosphorylation status using Zn-Phos-tag gels and indirect ELISA. We employed siRNA to deplete the PDO cells of EphA2.
Results: EphA2-positive cells form a stable subpopulation in organoid cultures that persists after oxaliplatin treatment. Phosphorylation of EphA2 at Ser897 increases with treatment and correlates with higher EphA2 levels. Silencing EphA2 or reducing Ser897 phosphorylation decreases organoid formation, suggesting chemosensitization. Some EphA2-positive cells show increased ALDH activity after chemotherapy, and EphA2-ALDH1A3 interaction has prognostic value in CRC.
Discussion: Here, we discovered that EphA2-positive cells constitute a persistent, ALDH-positive cell subpopulation in CRC-PDOs that withstood exposure to oxaliplatin (OXA) and 5-fluorouracil (5-FU). The enforced suppression of EphA2 or diminished Ser897 stress results in a chemosensitization effect. This sheds further light on the role of EphA2 in the adaptive stress response of CRC.

Keywords:  ALDH; CRC; DTP; EphA2; chemoresistance; patient-derived-organoids

DOI:  https://doi.org/10.3389/fcell.2026.1833389
Commun Biol. 2026 Jun 29. pii: 868. [Epub ahead of print]9(1):

Lipid droplets as stress-buffering organelles in cancer cell homeostasis.

Ruolun Wei, Claudia K Petritsch.

Lipid droplets (LDs) are dynamic organelles that support homeostasis and shield cancer cells from stress to promote cancer cell survival, progression, and therapy escape. Here, we summarize recent findings demonstrating LD crosstalk with other organelles and the immune/stromal compartments aimed at buffering metabolic, oxidative, proteotoxic, and lipotoxic stress and stress from cancer treatment and the anti-tumor immune response. We briefly summarize current experimental approaches, including imaging, biochemical, and functional approaches, used to study LD biology. Together, these findings place LDs at the center of cancer cell homeostasis and highlight their emerging potential as translational targets in cancer therapy.

DOI: https://doi.org/10.1038/s42003-026-10566-5
Cell. 2026 Jun 30. pii: S0092-8674(26)00696-3. [Epub ahead of print]

Multiscale integration of tissue and chromatin context converts cell heterogeneity into stable intestinal patterning.

Cornelia Schwayer, Silvia Barbiero, David B Brückner, Koen C Oost, Clara Baader, Nicole A Repina, Jinse Kim, Oscar E Diaz, Isa Uccelli, Laura Capolupo, Ludivine Challet Meylan, Veronique Kalck, Franziska Moos, Simon Suppinger, Qiutan Yang, Jakob Schnabl, Umut Kilik, Matthieu Bourdon, J Gray Camp, Brigitta Stockinger, Alessandra Ferrari, Marc Bühler, Michael B Stadler, Edouard Hannezo, Prisca Liberali.

  Tissue regeneration requires de novo patterning, which has been proposed to be facilitated by cellular heterogeneity. Yet how such heterogeneities are integrated with the mechanochemical state of the tissue and stabilized at the chromatin level into stable, spatially organized fates remains poorly understood. Using in vivo mouse intestinal regeneration models and organoids, we identify a critical density regime that produces a permissive window for heterogeneity in the mechanosensor Yes-associated protein 1 (YAP1). We show that YAP1 heterogeneity is coupled to lineage-biased chromatin accessibility and is decoded through FOXA1, which integrates the permissive chromatin state to Delta-Notch supracellular feedback and lineage commitment. This circuit generates fate bistability and preserves a memory of transient YAP1 activity, thereby maintaining spatial patterning as tissues return to homeostasis after injury. Together, our findings establish a multiscale framework in which tissue-scale mechanics tune single-cell competence and, through FOXA1-mediated bistability, convert transient heterogeneity into stable and self-organized tissue architecture.

Keywords:  Yap1; epigenetic competence; heterogeneity; image-based phenotyping; intestinal regeneration; mechanics; modeling; multiscale integration; organoids; tissue patterning

DOI:  https://doi.org/10.1016/j.cell.2026.06.009
Nature. 2026 Jul 01.

Liver fat steers the outcome of advanced colorectal cancer.



Keywords:  Cancer; Metabolism

DOI:  https://doi.org/10.1038/d41586-026-01747-7
Cell Death Dis. 2026 Jun 30.

α-ketoglutarate accumulation orchestrates immunosuppressive metabolic remodeling to drive cetuximab resistance in metastatic colorectal cancer.

Yingwei Zhu, Kuijie Liu, Ling Chang, Jian Lu, Hong Tang, Zhenxin Zhu, Zhiru Chen, Xiongjun Wang, Jing Xiao.

Cetuximab resistance remains a major obstacle in the treatment of metastatic colorectal cancer (mCRC), highlighting the urgent need to identify synthetic lethal partners of EGFR. In this study, we observed glutamate dehydrogenase 1 (GDH1) accumulation in cetuximab-treated CRC samples. GDH1 depletion sensitized CRC cells to cetuximab and suppressed remodeling of the tumor immune microenvironment (TIME), as revealed by single-cell RNA sequencing. Mechanistically, cetuximab treatment induced substantial cytosolic accumulation of GDH1. Under normal conditions, EGFR directly phosphorylates cytosolic GDH1 at Y451, leading to HIP1R-mediated lysosomal degradation. Cetuximab, however, blocks GDH1-Y451 phosphorylation, thereby stabilizing GDH1 and increasing α-ketoglutarate (αKG) production. Elevated αKG enhances ALKBH5 activity to demethylate m6A modifications in the 3'UTR of NDUFA2, CXCL3, and SOS1 pre-mRNAs. This cascade coordinately rewires tumor cell metabolism and reprograms the TIME, while also amplifying KRAS-driven signaling to promote CRC liver metastasis. Importantly, combining cetuximab with the GDH1 activity inhibitor R162 curbed tumor metabolic adaptation, reversed TIME remodeling, and suppressed KRAS activation, thereby preventing immune escape and metastatic progression. Our findings unveil the EGFR/GDH1/αKG/ALKBH5 axis as a key modulator of cetuximab response and suggest that post-treatment monitoring of blood αKG may help identify patients who could benefit from GDH1 inhibition to augment immunotherapy and KRAS-targeted strategies.

DOI: https://doi.org/10.1038/s41419-026-09001-8
Nat Genet. 2026 Jul 02.

Mutational scanning reveals substrate-assisted autoregulation of the WNT destruction complex.

Murugesh Padmanarayana, Saira Sakalas, Parijat Sarkar, Mengxiao Ma, Ethan R Garvin, Ethan Lee, Steven M Corsello, Sebastian Guettler, Ganesh V Pusapati, Rajat Rohatgi.

The β-catenin destruction complex (BDC) regulates WNT-β-catenin signaling and is a prime therapeutic target in colorectal cancer, yet its biochemical complexity has hindered mechanistic understanding. We mapped the sequence-function landscape of the BDC using tiled base editor screens across its components CTNNB1, AXIN1, APC and GSK3B. Amongst ~150 previously unreported mutations that affected WNT signaling, we discovered gain-of-function and separation-of-function alleles that reveal mechanisms of complex assembly, including a β-catenin region regulating TCF/LEF transcription factor binding. Critically, we found that the AXIN1-β-catenin interface controls signaling flux through the oncogenic BDC found in APC-mutant cancers. In cells expressing truncated APC, β-catenin itself scaffolds BDC assembly, establishing a substrate-assisted autoregulatory mechanism. This architecture represents an unexploited therapeutic vulnerability: strengthening the AXIN1-β-catenin interaction restores destruction complex function and impairs the growth of colorectal cancer cells. Our mutational resource provides a foundation for mechanistic understanding and therapeutic targeting of the WNT pathway.

DOI: https://doi.org/10.1038/s41588-026-02662-3
Nat Commun. 2026 Jun 30.

Divergent roles of SPOP and CHD1 in ACSL4 regulation reveal context-dependent vulnerabilities for targeting ferroptosis.

Feiyu Chen, Qidong Li, Qianlin Gu, Javier Leo, Xin Liang, Naayaa Mehta, Estefania Labanca, Peter Shepherd, Iqbal Mahmud, Yin Wang, Francisco R Saenz, Maya M Phillips, Wei Shi, Chenling Meng, Jie Zhang, Daniel E Frigo, Yue Lu, Boyi Gan, Di Zhao.

Genetic heterogeneity contributes to the variable therapeutic responses in cancers. Frequent SPOP mutations and recurrent CHD1 deletions define distinct molecular subtypes of prostate cancer (PCa) with differential responses to anti-androgen therapy. Ferroptosis, an iron-dependent cell death mechanism driven by lipid peroxidation, has emerged as a promising anticancer strategy. Here, we identify SPOP mutations and CHD1 deletion as key genetic determinants of ferroptosis susceptibility in PCa. Using genetically engineered human and murine models, we show that SPOP mutations enhance, whereas CHD1 deletion impairs, the efficacy of ferroptosis inducers targeting GPX4. Mechanistically, SPOP and CHD1 exert opposing effects on ferroptosis by antagonistically regulating the MYC-ACSL4 axis. Furthermore, we demonstrate that targeting cholesterol metabolism with cholesterol-lowering agents restores ACSL4 expression and re-sensitizes SPOP/CHD1 co-deficient tumors to ferroptosis-inducing therapy. Our findings establish SPOP/CHD1 as upstream genetic regulators of ferroptosis and provide biomarker-driven combinatorial strategies to enhance ferroptosis-based therapy in men with advanced PCa.

DOI: https://doi.org/10.1038/s41467-026-75010-y
J Proteome Res. 2026 Jun 28.

Integrated Spatial and Bulk Untargeted Metabolomics Characterize Location- and Histology-Associated Metabolic Heterogeneity in Colorectal Cancer.

Junfeng Wang, Jinjin Gao, Jia Liu, Dongzhi Hu, Yang Zhan.

  Colorectal cancer (CRC) exhibits profound molecular heterogeneity according to primary tumor location, but spatially resolved assessment is limited by interindividual variability. Here, to minimize interindividual genetic confounding, we performed an exploratory single-case spatial metabolomics study (MALDI-MSI) on a rare case of synchronous bilateral tumors from one patient. This was complemented by untargeted metabolomics (UHPLC-HRMS/MS) on tumor and matched normal tissues from a cohort of 30 CRC patients with different anatomical sites and histologies. As an observational finding in this single case, the left-sided colon cancer (LCC) showed distinct metabolite distribution features from the tumor core to the invasive margin, whereas in right-sided colon cancer (RCC), metabolic differences were more closely associated with a histological subtype. UHPLC-HRMS/MS showed that, among tubular adenocarcinomas, LCC exhibited enrichments in ether lipid and phosphatidylcholine metabolism, whereas RCC preferred nucleotide and fatty acid metabolism. Furthermore, right-sided mucinous adenocarcinomas displayed unique sphingolipid alterations, consistent with a possible desaturase-associated shift from apoptosis-promoting pathways toward structural functions compared with the tubular subtype. Collectively, these findings underscore the potential influence of primary tumor location and histology on a microenvironmental metabolic architecture, offering exploratory insights for future hypothesis testing on location- and histology-dependent tumor adaptation.

Keywords:  left-sided colon cancer; mucinous carcinomas; right-sided colon cancer; spatial metabolomics; tubular adenocarcinomas; untargeted metabolomics

DOI:  https://doi.org/10.1021/acs.jproteome.5c01260
Eur J Radiol. 2026 Jun 28. pii: S0720-048X(26)00386-4. [Epub ahead of print]203 113038

Co-clinical CT radiomics pipeline to establish candidate imaging biomarkers for colorectal cancer.

Kate Connor, Olivia Prior, Liam P Shiels, Colum Connolly, Ian S Miller, Rory Crean, Suzanne Murphy, Gerard McGuinness, Camilo Monreal, Garazi Serna, Ehita Idemudia, Gregory Eriksen, Evin Haworth, Jochen H M Prehn, J Tabernero, Elena Elez, Alice C O'Farrell, David O'Brien, Rodrigo Toledo, Paolo Nuciforo, Karl T Butterworth, Rodrigo Dienstmann, Raquel Perez-Lopez, Annette T Byrne.

  Here, we establish a co-clinical computed tomography (CT) radiomics pipeline for the identification of candidate imaging biomarkers in RAS-mutant metastatic colorectal cancer (mCRC). Orthotopic KRAS-mutant xenograft models (LOVO-Luc2 (N = 52) and SW480-Luc2 (N = 52)) were treated with standard-of-care regimens (FOLFOX, bevacizumab, or combination) and longitudinally imaged by CT (N = 104 tumour scans, N = 156 liver scans collected over 4 timepoints). Radiomic features derived from primary tumour and liver parenchyma were assessed as biomarkers of treatment sensitivity and early metastatic disease. Pre-treatment CT-radiomics identified baseline radiomic correlates of treatment sensitivity in the LOVO-Luc2 model (0.716), with first-order statistical features (Median, 10percentile) significantly associated with therapy outcome. Texture-based liver radiomic features enabled prediction of metastases earlier than visual CT assessment (AUROC = 0.871). The most predictive features, GLSZM Gray Level Non-Uniformity, GLRLM Run Length Non-Uniformity Normalized, and GLDM Small Dependence Emphasis, were significantly associated with metastatic burden and survival in a clinical CRC cohort (N = 41), indicating species conservation and translational relevance. Collectively, these data demonstrate that preclinical CT radiomics can identify quantitative imaging features associated with treatment sensitivity and early metastatic progression, supporting translational potential.

Keywords:  Colorectal cancer; Computed tomography; Liver metastasis; Precision medicine; Radiomics

DOI:  https://doi.org/10.1016/j.ejrad.2026.113038
Mol Oncol. 2026 Jun 30.

Inhibition of cyclin-dependent kinases 12/13 using CT7439 as a treatment for colorectal cancer with CDK12 upregulation.

Wylie K Watlington, Divya L Dayanidhi, Mohammad Zokaasadi, John B Mantyh, Pelumi D Olawuni, Gabrielle Rupprecht, Jeremy M Force, Shannon McCall, Ashwani K Bahl, David S Hsu, Jason A Somarelli.

  Cyclin-dependent kinase (CDK) 12 and its paralog, CDK13, phosphorylate RNA polymerase II, enabling transcriptional elongation. In solid tumors, CDK12 loss promotes progression by inducing replication-transcription conflict and fueling genomic instability. However, we have uncovered upregulation of CDK12 and CDK13 in ~5% of colorectal cancer (CRC) specimens, suggesting a role in cancer cell survival. Based on this, we postulated that CDK12/13 inhibition in CRC may represent a useful therapeutic strategy. To test this, we screened CDK12 and CDK12/13 inhibitors across multiple cancer cell lines and patient-derived organoids (PDO) from a range of solid tumors, demonstrating potent activity in CRC PDO. Using siRNA-mediated knockdown, we identified CDK13 as a potential mechanism of resistance to CDK12-specific inhibition. Mechanistically, CDK12/13 inhibition led to a decreased abundance of BRCA1 long transcripts, rendering cells susceptible to combination therapy with PARP inhibitors. To further assess the clinical utility of CDK12/13 inhibition, we focused on CRC, for which there is an urgent need for additional therapies. We tested the efficacy of CT7439, a novel CDK12/13 inhibitor and cyclin K degrader, which showed cytotoxicity in the low nanomolar range, reduced BRCA1 expression, and concomitant DNA damage. Together, our data support further clinical development of CDK12/13 inhibition in CRC.

Keywords:  CDK12; CDK12/13 inhibition; CDK13; colorectal cancer; patient‐derived organoids

DOI:  https://doi.org/10.1002/1878-0261.70290
Cell Chem Biol. 2026 Jun 30. pii: S2451-9456(26)00194-7. [Epub ahead of print]

Assessment of mitochondrial lipid peroxidation in cells and zebrafish using a targeted mass spectrometry probe.

Shinpei Uno, Stuart T Caldwell, Hiran A Prag, Chak Shun Yu, Lucie J Lamačová, María Torres-López, Andrew M James, Ana Lopez, Taylor A Woetzel, Angeleen Fleming, David C Rubinsztein, Richard C Hartley, Michael P Murphy.

  Mitochondrial lipid peroxidation is a major component of oxidative damage and is also thought to contribute to ferroptosis. Lipid peroxidation is generally assessed from the accumulation of oxidized end products, such as 4-hydroxynonenal (HNE). However, these report on damage throughout the cell and are affected by changes in how oxidized phospholipids are turned over. To overcome these constraints, we developed MitoLiPOX, a mitochondria-targeted mass spectrometry probe. Mitochondria targeting and detection sensitivity were achieved by incorporating a lipophilic triphenylphosphonium cation. Responsiveness to lipid peroxidation was brought about by building in a bis-allylic carbon-hydrogen bond mimic that, upon oxidation and processing, generated a single product, MitoLiPOX-OH. LC-MS/MS quantification of MitoLiPOX-OH followed by normalization to the amount of MitoLiPOX present enabled ratiometric quantification of mitochondrial lipid peroxidation. We then used MitoLiPOX to assess mitochondrial lipid peroxidation during ferroptosis in vitro and in zebrafish in vivo.

Keywords:  exomarker; lipid peroxidation, ferroptosis; mitochondria; oxidative stress

DOI:  https://doi.org/10.1016/j.chembiol.2026.05.015
Nat Commun. 2026 Jul 01.

Nuclear-specific reductive carboxylation of alpha-ketoglutarate fuels histone acetylation to induce chromatin accessibility and gene activation.

Abhisha Sawant Dessai, Nadya A Elhalawany, Tao Dai, Justine J Jacobi, Christian Prechtl, Alphonse N Dimeck, Sierra R Morton, Mark D Long, Prashant K Singh, Nagireddy Putluri, Mariana Lopes, Song Liu, Dominic J Smiraglia, Katerina V Gurova, Peder J Lund, Leah A Gates, Sung Yun Jung, Subhamoy Dasgupta.

Mitochondria remain at the core of cell metabolism, whereas the nucleus integrates cellular and environmental signals to activate genes. However, the mechanisms that directly link cellular metabolism to gene regulation are not well understood. Here we show, a metabolic pathway in the nucleus controls acetylation of histones by nuclear localization of mitochondrial enzymes aconitase (ACO2) and isocitrate dehydrogenase (IDH2). Metabolic tracing studies show that IDH2 and ACO2 catalyze reductive carboxylation of α-ketoglutarate to rapidly synthesize citrate to increase nuclear acetyl-CoA pool. Genetic and proteomic analyses reveal nuclear IDH2 and ACO2 form a complex with KAT2A/GCN5 for acetylation of histones to increase chromatin accessibility and activation of proliferative genes. Robust nuclear expressions of ACO2 and IDH2 drive aggressive tumors indicating the tumorigenic potential of IDH2-ACO2-KAT2A axis. Altogether, our work reveals a paradigm coupling a nuclear metabolic pathway with histone acetylation to control of gene expression that accentuates hyperproliferative phenotype in tumors.

DOI: https://doi.org/10.1038/s41467-026-74786-3
Eur J Cancer. 2026 Jun 12. pii: S0959-8049(26)00667-2. [Epub ahead of print]244 116886

Mapping the anatomical landscape of colorectal tumours: Location-specific efficacy of anti-epidermal growth factor receptor antibodies: Pooled analysis of randomised trials.

Kenta Iguchi, Kentaro Yamazaki, Toshihiro Misumi, Hideaki Bando, Yuka Nishimura, Tomomi Nishikawa, Eiji Oki, Jean-Yves Douillard, Miriam Koopman, Eric Van Cutsem, Carsten Bokemeyer, Alan P Venook, Yoshihiko Maehara, Volker Heinemann, Chiara Cremolini, Goro Nakayama, Thierry André, Qian Shi, Aimery de Gramont, Takayuki Yoshino.

   BACKGROUND: The selection of biologic therapies in metastatic colorectal cancer (mCRC) is traditionally guided by right-left classification; however, this binary classification may not fully capture heterogeneity in responsiveness to anti-epidermal growth factor receptor (EGFR) therapy. We evaluated whether treatment efficacy varies across detailed anatomical tumour segments.
METHODS: Individual patient-level data from 12 randomised controlled trials in the ARCAD database were analysed. Patients with RAS wild-type (RAS-WT) mCRC receiving first-line doublet chemotherapy plus anti-EGFR therapy or bevacizumab were included. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS) and objective response rate (ORR).
RESULTS: A total of 2867 patients were included (815 right-sided colon cancer [RSC]; 2052 left-sided colorectal cancer [LSC]). In RAS-WT RSCs, anti-EGFR therapy was not associated with improved OS or PFS versus bevacizumab. In RAS/BRAF-WT RSCs, anti-EGFR therapy was associated with inferior PFS. In contrast, in RAS-WT LSCs, anti-EGFR therapy significantly improved OS and ORR, without a significant difference in PFS. Segment-level analyses (N = 1491) showed no significant heterogeneity within RSCs, although median OS numerically varied across subsites. Within LSCs, the OS benefit was most pronounced in the rectum.
CONCLUSIONS: The efficacy of anti-EGFR therapy in mCRC appears to exhibit additional intraregional heterogeneity beyond the conventional right-left classification. These findings suggest that anatomical tumour location may reflect underlying biological differences not fully captured by this binary classification.

Keywords:  Anti-epidermal growth factor receptor antibodies; Metastatic colorectal cancer; Pooled analysis; RAS wild-type; Tumour location

DOI:  https://doi.org/10.1016/j.ejca.2026.116886
Discov Oncol. 2026 Jul 03.

Multi-omics and metabolic flux modeling reveal that macrophage CYP27A1-derived 26-hydroxycholesterol drives immunosuppression and cancer malignancy.

Jinfen Wei, Bin Yu, Na Wang, Xinyao Huang, Shuna Su, Zixi Chen, Meiling Hu, Xiaoling Wen, Jiangying Liang, Lingbo Shao, Hongjiu Wang, Hongli Du, Zhenzhen Wang.

  Emerging evidence indicates that aberrant cholesterol metabolism in macrophages plays a role in tumorigenesis, however, how specific metabolites released by macrophages influence immunosurveillance and along with their potential as therapeutic targets and prognostic biomarkers, remain unclear. We integrated 465 single-cell multi-omics and 1,318 bulk RNA-seq samples of colorectal cancer (CRC) using bioinformatics, single-cell metabolic flux modeling and machine learning to decipher cholesterol metabolic rewiring specific to tumor-associated macrophages (TAM), along with associated druggable targets and prognostic potential. We uncover that CYP27A1-mediated 26-hydroxycholesterol metabolism drives the formation of immunosuppressive SPP1 + APOE + TAM in CRC. Multi-omics and analysis (scATAC-seq, gene regulatory network, and spatial transcriptomics data) reveals that this subset activates SPI1, establishing a macrophage-Treg co-infiltration niche that inhibits CD8 + T-cell infiltration in large amounts of spatial transcriptomics data. Finally, we constructed a cholesterol metabolism-based gene signature derived from SPP1 + APOE + TAM and applied machine learning methods, achieving robust prognostic accuracy across four independent CRC cohorts. Collectively, our findings reveal CYP27A1 as a central regulator linking cholesterol metabolism to immune suppression, highlighting its therapeutic potential in tumor microenvironment-driven cancers and lipid-associated disorders.

Keywords:  25-hydroxycholesterol; 26-hydroxycholesterol; CYP27A1; Cholesterol dysregulation macrophages; Colorectal cancer; Immunosuppression; Machine learning; Multi-omics; SPI1

DOI:  https://doi.org/10.1007/s12672-026-05474-3
Am J Physiol Gastrointest Liver Physiol. 2026 Jul 01.

MYO5B Deficiency Is Associated with Altered MUC13 Localization and DMBT1 Accumulation in Intestinal Epithelial Cells.

Rachel Stubler, Charulekha Packirisamy, Jenna G Cagle, Piper McKee, Ana Pettijohn, Elena Kolobova, Sarah A Dooley, Rachel Edens, Lauren Giordano, Robin Muise-Helmericks, Kristen A Engevik, Melinda A Engevik, Amy C Engevik.

  Myosin 5b (MYO5B) is a motor protein that plays an essential role in trafficking proteins to the apical membrane. Recent studies have demonstrated that MYO5B traffics ion transporters, like NHE3, DRA, and SGLT1, water channels, like AQP7, and efflux transporters, like P-glycoprotein. However, the role of MYO5B in trafficking glycoproteins involved in mucosal defense remains unclear. Here, we investigate whether MYO5B is required for the apical localization of MUC13 and DMBT1; two glycoproteins critical for epithelial protection and wound healing. To address the requirement of MYO5B in glycoprotein trafficking, we immunostained the small intestine and colon of neonatal germline and adult inducible intestine-specific MYO5B-knockout (KO) mice and examined MUC13 and DMBT1 localization. Organoids derived from germline and inducible KO mice were analyzed to confirm findings in an epithelial-only system. Additionally, staining was performed on human organoids expressing MYO5B-Tail GFP. MYO5B loss in vivo resulted in the intracellular accumulation of MUC13 and DMBT1, reducing their colocalization with the apical marker γ-actin in both models. MUC13 colocalized with the lysosomal marker LAMP1 in adult mice after MYO5B loss, indicating that a portion of cytoplasmic MUC13 undergoes lysosomal degradation. Mislocalization of MUC13 was observed in vitro in intestinal MYO5B-deficient organoids. MYO5B-Tail GFP was associated with MUC13 in human intestinal organoids. MYO5B is required for the apical delivery of MUC13 and DMBT1 in the intestinal epithelium. Disrupting this pathway may contribute to mucosal dysfunction in MYO5B-related diseases, highlighting potential therapeutic targets for restoring epithelial barrier integrity.

Keywords:  MYO5B; cellular trafficking; colon; mucin; small intestine

DOI:  https://doi.org/10.1152/ajpgi.00131.2026
Cell Rep. 2026 Jul 03. pii: S2211-1247(26)00722-9. [Epub ahead of print]45(7): 117644

Yap mediates hippo signaling to balance proliferation and differentiation in the developing glandular stomach epithelium.

Rongzi Mu, Jiangying Liu, Dan Luo, Haidi Huang, Yu Jiang, Jianghong Yuan, Florence Wen Jing Chioh, Zhaoyu Su, Chuwen Lin, Baojie Li, Qingqiu Gong, Xinhua Lin, Zhiping Xie, Haihan Song, Jian Wan, Honggang Xiang, Yongchun Zhang.

  The glandular stomach is an important digestive organ, and its proper epithelial development is essential for its normal structure and function. However, the molecular mechanisms underlying its epithelial development remain largely unclear. Here, we employ mouse genetics to reveal that Hippo signaling regulates stomach epithelial development by balancing epithelial proliferation and differentiation. Deletion of Yap reduces epithelial growth in the developing glandular stomach, whereas overexpression of constitutively active Yap promotes its expansion. Single-cell RNA sequencing (scRNA-seq) and histological analyses further show that Yap enhances gastric epithelial proliferation while suppressing differentiation. Using 3D organoids, we find that Yap directly governs gastric epithelial proliferation and differentiation. Further genetic studies reveal that Mst1/2 deficiency regulates glandular stomach development partially through Yap. Finally, we demonstrate that Yap controls gastric epithelial proliferation and differentiation by modulating cell cycle activity. Overall, our studies demonstrate that Hippo signaling plays an important role in fine-tuning stomach development.

Keywords:  3D organoid; CP: developmental biology; CP: stem cell research; Mst1; Mst2; cell differentiation; cell proliferation; gastric epithelium; hippo; stomach development; yap

DOI:  https://doi.org/10.1016/j.celrep.2026.117644
Transl Oncol. 2026 Jun 30. pii: S1936-5233(26)00223-8. [Epub ahead of print]71 102886

Mechanisms and advances of drug resistance in colorectal cancer: A systematic overview of multi-layered regulatory networks.

Sichong Qiu, Shaocong Li, Yuzuo Chen, Xiumei Ma, Hongfang Fu, Biao Zhao.

  Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide. Although substantial advances in chemotherapy, molecular targeted therapy, and immunotherapy have improved clinical outcomes in select patient populations, therapeutic resistance remains the major obstacle to durable disease control. Accumulating evidence suggests that drug resistance in CRC does not result from isolated molecular events, but rather reflects a dynamic and adaptive process driven by coordinated tumor intrinsic programs, as well as continuous interactions between tumor cells and their surrounding microenvironment. In this Review, we present a systematic overview of the clinical manifestations and biological foundations of resistance to cytotoxic chemotherapy, targeted therapy, and immune checkpoint blockade in CRC. We summarize tumor intrinsic resistance mechanisms, including oncogenic signaling reprogramming, DNA damage response modulation, metabolic and redox adaptation, ubiquitin-regulated proteostasis, epigenetic and RNA-mediated regulation, evasion of programmed cell death, and the emergence of cancer stem cell and drug-tolerant persister states. In parallel, we examine the contribution of the tumor microenvironment, including cancer-associated fibroblasts, immunosuppressive immune networks, extracellular vesicle-mediated communication, and the gut microbiota, in establishing protective niches that promote resistance and limit therapeutic efficacy. We further discuss how emerging approaches such as single-cell and spatial multi-omics profiling, liquid biopsy, and longitudinal molecular monitoring have reshaped the understanding of drug resistance as a continuous evolutionary process under therapeutic selection pressure. Finally, we highlight therapeutic strategies inspired by systems biology and evolutionary principles, with an emphasis on rational combination and sequencing regimens, targeting adaptive vulnerabilities, and remodeling the tumor ecosystem to enable more durable and precise control of CRC.

Keywords:  CRC; Immune checkpoint blockade; Resistance mechanisms; Therapeutic implications; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.tranon.2026.102886
Nat Commun. 2026 Jul 03.

Lipid metabolism of hepatocyte-like cells supports intestinal tumor growth in Drosophila.

K Huang, T Miao, Y Chen, E Dantas, J Sanford, John M Asara, S J Moon, Y Hu, K Wang, M Han, M Goncalves, N Perrimon.

Tumors reprogram lipid metabolism in distant tissues to support their growth. In adult Drosophila, gut tumors secrete the PDGF/VEGF-like factor Pvf1, which activates the TORC1-Hnf4 pathway in hepatocyte-like oenocytes. This drives production of very long-chain fatty acids and wax esters essential for tracheal growth around the tumor. Blocking Hnf4 or the elongase mElo in oenocytes strongly suppresses tracheogenesis, tumor progression, and cachexia-like organ wasting, while extending host lifespan. The same pathway also controls tracheal development in healthy flies. Lipoprotein receptor LpR2 depletion in oenocytes rescues the observed tumor induced tracheal tracheal remodeling. This tumor-host interaction is conserved: VEGF-A induces lipid metabolism genes in human hepatocytes, and lung tumor-bearing mice show elevated hepatic Hnf4 and Elovl7. Altogether, this study reveals a non-autonomous role of the TORC1-Hnf4 axis in lipid-mediated tumor progression and identifies potential therapeutic targets for cancer-associated metabolic dysfunction.

DOI: https://doi.org/10.1038/s41467-026-75074-w
Cell Death Differ. 2026 Jun 30.

Cell engulfment defines spatially distinct competitive metabolic niches associated with clinical outcomes in colorectal cancer.

Emir Bozkurt, Batuhan Kisakol, Heiko Dussmann, Federico Lucantoni, Anna Sturrock, Mohammadreza Azimi, Sanghee Cho, Elizabeth McDonough, Joana Fay, Tony O'Grady, John P Burke, Niamh McCawley, Deborah A McNamara, Daniel B Longley, Fiona Ginty, Jochen H M Prehn.

Cell competition is an emerging mechanism in which mammalian tissues maintain homeostasis by eliminating less fit (loser) cells through direct interactions with fitter (winner) neighbouring cells. In cancer, these competitive interactions may drive tumour evolution; however, spatial organisation and clinical relevance of these events remain poorly understood. One mechanism by which winner cells eliminate loser cells is engulfment, resulting in cell-in-cell (CIC) formation. Although CICs have been observed in many tumour types for over a century, their cellular composition, spatial context, interactions with the tumour microenvironment, and biological significance in human cancers remain unclear. Here, we systematically characterised the cellular identity and functional states of CICs in situ, examined their spatial interactions within the tumour microenvironment, and assessed their clinical relevance using spatially resolved single-cell data from a large cohort of colorectal cancer patients. We demonstrated that CICs occurred predominantly between cancer cells but also involved cancer stem cell (CSC)-like populations and cytotoxic T cells. Engulfed (inner) cancer and CSC-like cells displayed molecular features consistent with a loser-cell phenotype, including increased apoptosis and reduced proliferation, whereas outer cancer cells exhibited winner-cell features such as upregulated glycolysis. Live-cell time-lapse experiments demonstrated that glucose accumulated in inner cells during lysosomal degradation following cell engulfment. Spatial analysis further revealed distinct CIC neighbourhoods, which we defined based on proximity to engulfment events. Cells within these regions, particularly CSC-like cells and cytotoxic T cells, exhibited increased metabolic stress, suggesting local competition for nutrients. Importantly, the presence of cytotoxic T cells within CIC neighbourhoods and spatial co-occurrence between cancer cells and CSC-like populations were associated with improved patient outcomes. Together, our findings demonstrate that cell engulfment defines spatially organised competitive niches and may reflect cell competition within complex tumour microenvironments.

DOI: https://doi.org/10.1038/s41418-026-01801-x
iScience. 2026 Jun 19. 29(6): 116031

Pan-cancer analysis reveals Rho kinase addiction as a vulnerability of de-differentiated cancer cells.

Jaume Barcelo, Yumiko Teigen, Joshua Alexander James Martin, Samantha George, Dipanwita Das, Joanne Sewell, Anna Perdrix-Rosell, Findlay Bewicke-Copley, Ritobrata Ghose, William Yang, Rachel Brough, Andrew Clear, Wencke Walter, Torsten Haferlach, Ilaria Malanchi, John G Gribben, Louie N van de Lagemaat, Kamil R Kranc, Christopher J Lord, Ana Rio-Machin, Oscar Maiques, Jude Fitzgibbon, Victoria Sanz-Moreno.

  Although Rho kinase (ROCK) has been studied in tumor progression, the reliance of some cancer cells on ROCK-Myosin II for survival remains poorly understood. Using systematic analysis of ROCK inhibitor sensitivity in hundreds of cancer cell lines, we find that ROCK inhibition reduces survival of highly de-differentiated, invasive cancer cells from solid tumors. Transcriptomic analysis reveals enrichment in epithelial-to-mesenchymal transition, migration, proliferation, and inflammation genes, with reduced expression of differentiation and cell-cell junction genes like E-cadherin (CDH1). Acute myeloid leukemia (AML) shows high ROCK inhibitor response among hematological malignancies. Using in vitro and in vivo approaches, we validate biomarkers of ROCK inhibitor sensitivity in breast cancer, melanoma, and AML, demonstrating their unique addiction to Rho-ROCK-myosin II signaling for survival. Our work has important pre-clinical implications while cautions against wider use of ROCK inhibitors in patient-derived organoid cultures, where they may deplete important cancer cell populations.

Keywords:  cancer; therapeutics; transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2026.116031
ACS Chem Biol. 2026 Jul 03.

Lipid Metabolic Labeling to Study Site- and Lipid-Specific Long-Chain S-Acylation Dynamics.

Samiksha Sardana, Carla Busquets-Hernández, Andrea Trezza, Alexandra Tsiotsia, Francine Rodrigues Ianiski, Peter Uljee, Anneroos E Nederstigt, Gemma Triola, Marc P Baggelaar.

Long-chain S-acylation is a post-translational modification that regulates key cellular processes, including signal transduction and metabolic regulation. However, the dynamic nature and site- and lipid-specific patterns of long-chain protein acylation remain poorly understood. Site- and lipid-specific metabolic labeling with various ω-alkynyl fatty acids uncovered the site-specific heterogeneity of long-chain protein S-acylation. Cells use various fatty acids for long-chain S-acylation, including C16:0, C18:0, and C18:1 on cysteines, while N-myristoylation preferentially incorporates C14:0 on N-terminal glycine residues. Our results demonstrate that long-chain S-acylation sites can exhibit both lipid heterogeneity and specificity and reveal that both enzymatic specificity and metabolic context can influence fatty acid incorporation. Exploration of dynamic protein long-chain S-acylation uncovered that acyl-protein thioesterases targeted by Palmostatin B regulate long-chain S-acylation involving various lipids, including C16:0, C18:0, and C18:1. Moreover, the site- and lipid-specific strategy uncovered dynamic long-chain S-acylation in a hydrophobic loop of ABHD17B that requires insertion into the lipid bilayer for efficient catalytic activity, suggesting tunability of ABHD17B enzyme activity through long-chain S-acylation. Our approach represents a significant advancement in lipid metabolic labeling methodologies, offering enhanced efficiency and sensitivity for studying S-acylation dynamics with lipid and site specificity.

DOI: https://doi.org/10.1021/acschembio.6c00517
Sci Adv. 2026 Jul 03. 12(27): eaed6463

A targetable FTO/SLC7A11/CBS/CTH axis controls cysteine metabolism, growth and survival in NSCLC.

Nishanth Kuganesan, Margaret Pan, Haowen Jiang, Stavros Melemenidis, Jiangbin Ye, Sara Richter, Maximillian Diehn, Kerriann M Casey, Edward E Graves, Quynh Thu Le, Erinn B Rankin.

Cysteine metabolism plays a crucial role in the growth and survival of non-small cell lung cancer (NSCLC), although the mechanisms governing its regulation are not fully understood. Here, we demonstrate that the RNA demethylase FTO is a therapeutic target that drives cysteine metabolism in NSCLC cells. Genetic or pharmacologic inhibition of FTO reduced cystine uptake and transsulfuration activity, leading to depleted intracellular glutathione, elevated reactive oxygen species (ROS), and ROS-mediated DNA damage and cell death. Mechanistically, FTO promotes the expression of the cystine uptake transporter SLC7A11 and the transsulfuration enzymes cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH) to promote NSCLC cystine uptake, transsulfuration activity, and survival. FTO inhibition increased lipid peroxidation, reduced tumor growth, and resulted in additive therapeutic benefit in combination with radiotherapy in multiple NSCLC xenograft models. Collectively, our study reveals a role for FTO in cysteine metabolism and highlights the therapeutic potential of targeting cancer epitranscriptomics and cysteine metabolism for NSCLC therapy.

DOI: https://doi.org/10.1126/sciadv.aed6463
Nat Rev Cancer. 2026 Jun 29.

Imaging the hallmarks of cancer.

Jan Grimm, Fabian Kiessling, Kevin M Brindle, Douglas Hanahan, Sanjay K Jain, Philippe Lambin, Twan Lammers, King C Li, I Jolanda M de Vries, Wolfgang A Weber, Bettina Weigelin, Bernd J Pichler.

The hallmarks of cancer were introduced by Hanahan and Weinberg as a conceptual organizing framework to distil the complexity of tumours. This concept of cancer hallmarks has become an enduring theme in cancer research. Moreover, an increasing number of therapeutic strategies are being aimed at targeting these hallmarks. However, translating them into the clinic requires technologies to monitor their effectiveness and biomarkers that can stratify patients for the choice of specific therapies. Tumour heterogeneity and the ability of tumour cells to rapidly mutate and develop evasion strategies makes the development of non-invasive imaging capabilities to interrogate these hallmarks as biomarkers and monitor them longitudinally and quantitatively particularly important. This Review presents a holistic discussion of non-invasive diagnostic imaging capabilities related to the hallmarks of cancer; some hallmarks can be assessed with imaging probes that directly target biomolecules, whereas others can be interrogated indirectly by imaging pathophysiological processes. Additionally, visualizing the hallmarks of cancer can be addressed with artificial intelligence-assisted, multiparametric image analysis (for example, radiomics, radiogenomics and deep learning). The approaches discussed have been evaluated in a translational context, and some of them already have a substantial role in clinical practice, for example, to guide treatment strategies, including surgical resections, radiotherapy and molecularly targeted chemo-, immuno- and radiopharmaceutical therapies.

DOI: https://doi.org/10.1038/s41568-026-00950-y
Cell Death Dis. 2026 Jun 30.

SIRT7-mediated ACSL3 delactylation suppresses colorectal cancer progression by orchestrating tumor-associated macrophage ferroptosis and polarization.

Lingzhen Jiang, Chaoqun Li, Peng Teng, Yan Qin, Junhui Tang, Xiaohui Hu, Yuna Li, Feiyu Qin, Surui Yao, Xiaowei Qi, Zhaohui Huang, Yuan Yin.

Dysregulated metabolism and functions of immune cells in the tumor microenvironment (TME) are key factors contributing to cancer progression. As the core immune cells in TME, tumor-associated macrophages (TAMs) have become a central focus in metabolic research of TME, though underlying mechanisms are not fully elucidated. Here, we found that long-chain acyl-coenzyme A synthetase-3 (ACSL3) is highly expressed in TAMs and correlates with poor prognosis in colorectal cancer (CRC). ACSL3 depletion induces TAM ferroptosis and reprograms them toward an M1-like phenotype. We further revealed that ACSL3 undergoes lactylation in TAMs, and identified Sirtuin 7 (SIRT7) as its delactylase. Mechanistically, SIRT7 delactylates ACSL3 at lysine 679, restores its enzymatic function and reprograms lipid metabolism in TAMs. Importantly, lactylated and activated ACSL3 significantly protects TAMs from ferroptotic stress and sustains their immunosuppressive phenotype. On the contrary, inhibiting ACSL3 lactylation reprograms TAMs toward an M1-like phenotype, further restores T cell cytotoxicity and suppresses CRC progression. Collectively, these findings establish ACSL3 lactylation in TAMs as a crucial signaling event that enables ferroptosis resistance and maintains M2 polarization, thereby promoting CRC progression. This study provides the therapeutic potential of targeting SIRT7-mediated delactylation of ACSL3 in TAMs, offering a promising strategy for CRC therapy.

DOI: https://doi.org/10.1038/s41419-026-09007-2