bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2026–05–17
fifteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. The Interaction Between Iron and Selenium Affects Ferroptosis in Colorectal Cancer.
  2. An inflammasome-driven differentiation program in intestinal stem cells protects against Salmonella infection.
  3. The emergence of metastasis in colorectal cancer.
  4. Fucosylation Dynamics as a Critical Determinant of Cancer Cell Fate in Colorectal Carcinoma: Integrating Hallmark Plasticity, Microenvironmental Remodelling, and Therapeutic Resistance.
  5. m6A modification suppresses innate anti-tumour immunity in colorectal cancer by limiting alu-derived dsRNA accumulation.
  6. QSOX1 confers ferroptosis resistance via redox modification of SLC7A11 in colorectal cancer.
  7. Single-cell transcriptomics reveals EpCAM regulates the development and morphology of intestinal epithelium via controlling the EGFR pathway.
  8. Non-canonical transcription and splicing shape the colorectal cancer immunopeptidome in MSI and MSS tumors.
  9. New developments and applications of human organoids.
  10. Arid3b suppresses CD8 + T cell infiltration and function in microsatellite-stable colorectal cancer via Runx3.
  11. Mismatch Repair-Proficient Colorectal Cancer can evade Immune Surveillance Through an Intrinsic Suppressive Program.
  12. An orthotopic organoid-based model to study early CD8⁺ T cell dysfunction and immunotherapy response in colorectal cancer.
  13. Drug-tolerant persister cells in cancer: a scoping review of definitions, models, and molecular mechanisms.
  14. Raman spectroscopic characterization of protein changes induced by 5-fluorouracil in colon cancer cells.
  15. Characterisation of tumor-infiltrating gamma-delta T cells in human colorectal cancer with MHC-I loss.
  1. Int J Mol Sci. 2026 Apr 29. pii: 3963. [Epub ahead of print]27(9):
    The Interaction Between Iron and Selenium Affects Ferroptosis in Colorectal Cancer.
    Fulin Tao, Menghui He, Yong Dai.
      Colorectal cancer (CRC) remains a major cause of cancer-related death, and resistance to chemotherapy and radiotherapy continues to limit durable disease control. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has therefore emerged as a potential therapeutic strategy. However, models focused solely on glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) do not fully explain why CRC cells differ in their sensitivity to ferroptosis. In this review, we examine how ferroptosis in CRC is shaped by iron trafficking and selenium-dependent antioxidant defense. We first discuss the poly(rC)-binding proteins 1 and 2 (PCBP1/2)-nuclear receptor coactivator 4 (NCOA4) axis, which regulates iron storage, trafficking, and ferritinophagy. We then review the AlkB homolog 8 (ALKBH8)-directed selenoprotein network, which supports the detoxification of lipid peroxides and maintenance of redox homeostasis. We next consider how these two systems intersect and how their interplay influences ferroptosis sensitivity. We also discuss why concurrent disruption of iron handling and selenium-dependent defense mechanisms may enhance therapeutic efficacy. Finally, we outline potential clinical applications, including combination strategies and biomarker development.
    Keywords:  ALKBH8; NCOA4; PCBP1/2; colorectal cancer; ferroptosis; iron homeostasis; selenium metabolism; selenoproteins
    DOI:  https://doi.org/10.3390/ijms27093963
  2. Nat Immunol. 2026 May 12.
    An inflammasome-driven differentiation program in intestinal stem cells protects against Salmonella infection.
    S Lebon, A Habshush Menachem, N Davidzohn, A Katz, N Wigoda, T Braun, D Yahalomi, R Rotkopf, V Holiar, T Dadosh, S Levin-Zaidman, N Dezorella, I Goliand, M Kupervaser, S Leebhoff, N Blumberger, D Hoffman, M Grunewald, Y Levin, Y Haberman, M Hofree, M Biton.
      Intestinal stem cells (ISCs) are essential for sustaining epithelial renewal and barrier integrity, yet their role in orchestrating defense against enteric pathogens remains unclear. Here we identify a stem cell-intrinsic immune mechanism whereby Lgr5+ ISCs detect intracellular Salmonella enterica and activate an inflammasome-dependent differentiation program. Using fluorescent-labeled S. enterica, single-cell transcriptomics, fate mapping, organoid models, and genetic perturbations, we show that invaded ISCs undergo rapid reprogramming toward antimicrobial peptide-enriched Paneth cells via apoptosis-associated Speck-like protein containing a CARD (ASC, encoded by Pycard)-mediated inflammasome signaling. This fate switch enhances epithelial antimicrobial capacity and restricts pathogen persistence in the crypt. The response is Salmonella-specific and conserved in human intestinal organoids. Moreover, the invasion-associated transcriptional signature is enriched in ISCs from patients with Crohn's disease. Our findings reveal that ISCs act as active sensors of bacterial invasion and initiate epithelial remodeling through inflammasome signaling, highlighting stem cell plasticity as a frontline innate immune strategy.
    DOI:  https://doi.org/10.1038/s41590-026-02514-6
  3. Nat Genet. 2026 May;58(5): 955
    The emergence of metastasis in colorectal cancer.
    Safia Danovi.
      
    DOI:  https://doi.org/10.1038/s41588-026-02622-x
  4. Biology (Basel). 2026 Apr 28. pii: 689. [Epub ahead of print]15(9):
    Fucosylation Dynamics as a Critical Determinant of Cancer Cell Fate in Colorectal Carcinoma: Integrating Hallmark Plasticity, Microenvironmental Remodelling, and Therapeutic Resistance.
    Abdulaziz Alfahed, Abdulrahman A Alahmari, Glowi Alasiri.
      Fucosylation, the enzymatic addition of fucose residues to glycans, modulates receptor signalling and cellular identity in the intestinal epithelium. Its role as an integrative determinant of cancer cell fate in colorectal cancer (CRC) remains undefined. Transcriptomic and clinicopathological data from 976 CRC patients across three independent cohorts (TCGA-CRC, CPTAC2-CRC, Sidra-LUMC) were analysed. A curated fucosylation gene set was used to calculate tumour fucosylation scores. Associations with histogenetic status, genomic features, microenvironmental phenotypes, drug resistance programmes, and survival were evaluated using gene set enrichment analysis, multivariable Cox regression, and integrated molecular subtyping. High-fucosylation tumours exhibited elevated epithelial differentiation, MSI-H/BRAF-mutant enrichment, oxidative phosphorylation dominance, the complete absence of EMT and invasion programmes, and favourable prognosis (HR = 0.633, 95% CI: 0.470-0.853, p = 0.003). Low-fucosylation tumours demonstrated mesenchymal phenotypes, TP53 mutations, chromosomal instability, comprehensive multi-family RTK signalling, immune-excluded microenvironments, and poor outcomes. Distinct multidrug resistance programmes emerged: drug efflux in low-fucosylation tumours versus xenobiotic sensing, target bypass, and drug sequestration in high-fucosylation tumours. Tumour fucosylation status defines two fundamentally distinct CRC cell states with mutually exclusive engagement of invasion programmes, metabolic pathways, immune phenotypes, and resistance mechanisms. Fucosylation represents an independent prognostic biomarker and integrative determinant of cancer cell fate, with significant implications for risk stratification and personalised therapeutic strategies.
    Keywords:  cell fate determination; colorectal cancer; epithelial–mesenchymal transition (EMT); fucosylation; metabolic reprogramming; microsatellite instability (MSI); multidrug resistance; prognostic biomarker; receptor tyrosine kinase (RTK) signalling; tumour microenvironment (TME)
    DOI:  https://doi.org/10.3390/biology15090689
  5. Nat Commun. 2026 May 14.
    m6A modification suppresses innate anti-tumour immunity in colorectal cancer by limiting alu-derived dsRNA accumulation.
    Yucheng Wang, Alice A Daddi, Amir Hosseini, Kazuki Kato, Ehsan Khalili, Håvard T Lindholm, Mengjie Li, Yadong Wang, David C Michael, Catherine A O'Brien, Daniel D De Carvalho, Jan Rehwinkel, Parinaz Mehdipour.
      How cancer cells evade immune detection despite expressing immunostimulatory retroelement (RE) transcripts remains unclear. In cancer, endogenous REs that escape epigenetic silencing are transcribed and can form double-stranded RNA (dsRNA), which activates innate immune responses through viral mimicry. However, RNA-level mechanisms can limit this effect. Here we show that the m6A RNA methyltransferase METTL3 acts as a key regulator of this suppression in colorectal cancer (CRC). Targeting METTL3 increases the accumulation of dsRNAs derived from both pre-existing and newly transcribed REs, amplifying immunostimulatory signalling and activating cell-intrinsic anti-tumour immunity. CRCs display variable sensitivity to METTL3 inhibition: tumours with high basal dsRNA and RNA methylation respond to METTL3 blockade alone, whereas those with low RNA methylation require combination therapy. Co-treatment with DNA methyltransferase inhibitors (DNMTis) restores immune activation in resistant tumours. Together, our findings identify METTL3 as an RNA-level immune checkpoint and suggest combined METTL3 and DNMT inhibition as a therapeutic strategy in CRC.
    DOI:  https://doi.org/10.1038/s41467-026-73211-z
  6. Cell Mol Biol Lett. 2026 May 15.
    QSOX1 confers ferroptosis resistance via redox modification of SLC7A11 in colorectal cancer.
    Mengqi Jia, Hanxiang Chen, Yulin Liu, Jianzhuang Guo, Xiaofei Wang, Qiang Liu, Zhiheng Liu, Zhaoqing Meng, Chunqing Wang, Yunqiu Wang.
       BACKGROUND: Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising therapeutic target for colorectal cancer (CRC). However, the precise mechanisms by which CRC cells evade ferroptosis remain incompletely understood. Cysteine redox modification, typically catalyzed by cysteine oxidases, is a key regulatory factor governing protein structure and function. Quiescin sulfhydryl oxidase 1 (QSOX1), a Golgi-localized sulfhydryl oxidase known to promote various physiological functions, has an uncharacterized role in ferroptosis. Therefore, this study investigated the effects of QSOX1 on ferroptosis sensitivity in colorectal cancer.
    METHODS: We utilized a comprehensive set of analytical techniques to elucidate the mechanisms of QSOX1 in CRC ferroptosis resistance. We assessed cell proliferation, colony formation, and sensitivity to ferroptosis inducers (Erastin and RSL3) in CRC cells. Levels of reactive oxygen species (ROS), intracellular Fe2+, and redox metabolites were measured by biochemical assays and flow cytometry. RNA sequencing (RNA-seq) and untargeted metabolomics were performed using QSOX1-deficient HT-29 cells. The interaction between QSOX1 and SLC7A11 was confirmed via coimmunoprecipitation, immunofluorescence, and nonreducing gel electrophoresis. Cystine uptake and glutamate release assays were used to assess SLC7A11 function. Tumor xenografts were generated to assess the in vivo sensitivity of colon cancer cells to ferroptosis inducers.
    RESULTS: QSOX1 was significantly upregulated in CRC tissues and promoted CRC cell proliferation in vitro and in vivo. Knockdown of QSOX1 sensitized CRC cells to ferroptosis inducers, whereas QSOX1 overexpression conferred resistance. Mechanistically, QSOX1 enhanced redox homeostasis and GSH metabolism in CRC cells. QSOX1 interacted with and facilitated redox modification of SLC7A11 at cysteine 158 via its thioredoxin motif (C449-C452) in the ERV/ALR domain. This oxidative regulation enhanced SLC7A11 membrane localization, cystine uptake, and glutamate release, thereby boosting intracellular GSH synthesis and suppressing ferroptosis.
    CONCLUSIONS: QSOX1 promotes ferroptosis resistance in CRC cells through redox-dependent post-translational modification of SLC7A11, enhancing its activity and promoting GSH synthesis. The QSOX1-SLC7A11 axis represents a potential therapeutic target to overcome ferroptosis resistance in CRC.
    Keywords:  Colorectal cancer; Ferroptosis; QSOX1; Redox modification; SLC7A11
    DOI:  https://doi.org/10.1186/s11658-026-00938-4
  7. Genes Dis. 2026 Sep;13(5): 102072
    Single-cell transcriptomics reveals EpCAM regulates the development and morphology of intestinal epithelium via controlling the EGFR pathway.
    Zili Lei, Ya Nie, Lulu Liu, Yanhong Yang, Xuan Liu, Guibin Chen, Yunjuan Wang, Wanwan Liu, Qing Hu, Ting Lin, Jiao Guo.
      
    DOI:  https://doi.org/10.1016/j.gendis.2026.102072
  8. Mol Cell Proteomics. 2026 May 07. pii: S1535-9476(26)00077-0. [Epub ahead of print] 101581
    Non-canonical transcription and splicing shape the colorectal cancer immunopeptidome in MSI and MSS tumors.
    Mathieu Courcelles, Marie-Pierre Hardy, Chantal Durette, Joel Lanoix, Robin Minati, Jean-Philippe Laverdure, Krystel Vincent, Claude Perreault, Pierre Thibault.
      Treatment with immune checkpoint inhibitors in colorectal cancer (CRC) has largely benefited patients with microsatellite instability-high (MSI-H) and not the larger proportion of patient with microsatellite-stable (MSS) tumors. This clinical dichotomy has fueled the view that high mutational burden is the dominant driver of tumor immunogenicity and that MSS CRC fails to respond because it is "antigen poor". To directly test this premise and define the origins of presented tumor antigens, we integrated HLA class I immunopeptidomics and matched RNA-seq from 26 primary CRC tumors spanning MSI-H and MSS subtypes. Using patient-specific canonical and cancer-specific proteogenomic databases, we identified 115,292 unique MHC-associated peptides (MAPs) across 61 HLA alleles, with a mean of 9,292 MAPs per tumor and no significant difference in MAP counts between MSI-H and MSS tumors. In toto, we identified 266 tumor antigens, all coded by unmutated genomic sequences, comprising 70 aberrantly expressed tumor-specific antigens (aeTSAs) and 196 tumor-associated antigens (TAAs). In our cohort, MSS tumors presented more TAAs and a comparable number of aeTSAs per tumor relative to MSI-H tumors. In TCGA-COAD stratified analyses (483 tumors), MSS tumors yielded more presentable aeTSAs and TAAs per patient than MSI-H tumors. Across both subtypes, aeTSAs arose predominantly from intronic translation, UTR usage, retroelement activation, and germline-like transcription, including recurrent aeTSAs from PIWIL1, L1TD1, and endogenous retroviral loci. Together, these data demonstrate that MSS CRC is not antigen poor and highlight non-canonical translation as a major, previously underappreciated contributor to the CRC immunopeptidome.
    Keywords:  cancer immunotherapy; colorectal cancer; immunopeptidomics; mass spectrometry; tumor-specific antigen
    DOI:  https://doi.org/10.1016/j.mcpro.2026.101581
  9. Nat Rev Mol Cell Biol. 2026 May 11.
    New developments and applications of human organoids.
    Amanda Andersson-Rolf, Hans Clevers.
      Organoid technology offers unique opportunities for studying human biology and disease in vitro. Organoids are self-organizing 3D structures, derived from pluripotent or tissue-resident stem cells that recapitulate key aspects of primary tissues. Compared with classical cell lines, organoids provide distinct advantages. They can be derived from both healthy tissues and diseased tissues, enabling the investigation of disease mechanisms and the development of personalized therapies, and they better recapitulate the cellular heterogeneity of the native tissue, allowing for better modelling of human (patho)physiology. Although current organoids have provided valuable insights, these insights are inherently reductionist and do not fully capture the complexity of human tissues. The research field is, therefore, moving towards next-generation models that more accurately represent the intricate cellular interactions, tissue architecture and microenvironmental cues that underlie human biology and disease. In this Review, we outline the limitations and challenges of current organoid systems, highlight recent advances aimed at increasing their complexity, and discuss innovations that support their translation into clinical applications. The focus is on human tissue stem cell-derived organoids, with comparisons to pluripotent stem cell-derived organoids where relevant. We conclude by identifying key factors and remaining challenges for developing the next generation of organoids.
    DOI:  https://doi.org/10.1038/s41580-026-00974-0
  10. Nat Commun. 2026 May 15.
    Arid3b suppresses CD8 + T cell infiltration and function in microsatellite-stable colorectal cancer via Runx3.
    Shuo Wang, Sen Hou, Ce Luo, Haorui Zhang, Yiteng Jin, Rui Zhang, Yanping Zhao, Xiaoyu Xiong, Rui Guo, Chao Wang, Yudi Bao, Liang Wen, Deng Pan, Yingjiang Ye, Zexian Zeng, Zhidong Gao.
      Microsatellite-stable/proficient mismatch repair (MSS/pMMR) colorectal cancer (CRC) is characterized by a cold tumor microenvironment, with limited CD8⁺ T cell infiltration and poor responsiveness to immune checkpoint inhibitors (ICIs). Here, using an in vivo CRISPR/Cas9 screen in a CMT93 cell-derived murine tumor model, we identify Arid3b as a key negative regulator of CD8⁺ T cell infiltration and antitumor activity. Genetic ablation of Arid3b in CD8⁺ T cells significantly enhances their intratumoral accumulation and promotes robust tumor control. Mechanistically, Arid3b deficiency upregulates Runx3, driving a tissue-resident memory-like phenotype and effector function. Notably, the benefits conferred by Arid3b deficiency are abrogated upon Runx3 deletion, indicating a RUNX3-dependent mechanism. Together, targeting ARID3B could offer a promising strategy to reshape the tumor microenvironment and sensitize MSS CRC to immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-026-73241-7
  11. Cancer Discov. 2026 May 13.
    Mismatch Repair-Proficient Colorectal Cancer can evade Immune Surveillance Through an Intrinsic Suppressive Program.
    Chiara Maria Cattaneo, Sharon Scardellato, Gianluca Mauri, Vittoria Matafora, Veera K Ojala, Costanza Cannariato, Rosaria Chila, Zulma Irene Magnani, Wouter Scheper, Luca Lazzari, Emile E Voest, Maria Chiara Bonini, Angela Bachi, Salvatore Siena, Silvia Marsoni, Giovanni Germano, Alberto Bardelli.
      While microsatellite-instable (MSI) colorectal cancers (CRC), reflecting mismatch repair deficiency, often respond to immune checkpoint inhibitors, microsatellite-stable (MSS) tumors remain largely resistant. This disparity is typically attributed to differences in neoantigen load. However, whether antigen-independent mechanisms contribute to immune evasion in MSS-CRC remains unclear. To address this, we engineered a model in which MSI- and MSS-CRC cells express identical levels of a defined antigen recognized by TCR-engineered T cells. Despite equivalent antigen presentation, MSS tumors exhibited impaired T-cell activation, reduced cytotoxicity, and resistance to killing. We linked this immune evasion to the MSS tumor secretome, which suppressed immune responses even in immunogenic MSI cells by impairing immune synapse formation. Surfaceome profiling by mass spectrometry identified glycosylation-dependent alterations that impair immune recognition. Our findings demonstrate that MSS-CRC evades immune attack via intrinsic secretome-driven mechanisms, independent of antigenicity. Targeting glycosylation-linked suppressive pathways may restore T-cell responsiveness and improve immunotherapy efficacy in MSS-CRC.
    DOI:  https://doi.org/10.1158/2159-8290.CD-26-0542
  12. Oncoimmunology. 2026 Dec 31. 15(1): 2674362
    An orthotopic organoid-based model to study early CD8⁺ T cell dysfunction and immunotherapy response in colorectal cancer.
    Lorenzo Lucantonio, Ludovica Schiano, Francesca Sozio, Andrea Kosta, Giovanna Peruzzi, Rosa Molfetta, Giuseppe Pietropaolo, Mattia Laffranchi, Antonio Francesco Campese, Giovanni Bernardini, Silvano Sozzani, Angela Gismondi, Angela Santoni, Giuseppe Sciumè, Stabile Helena, Cinzia Fionda.
      Colorectal cancer (CRC) treatment represents a major clinical challenge, with immunotherapy providing durable responses only in a minority of patients. A deeper understanding of CD8⁺ T cell exhaustion and its contribution to immune checkpoint inhibitor (ICI) responsiveness is essential for the development of more effective therapeutic strategies. Preclinical models that faithfully reproduce the immune landscape of human CRC are therefore critical to address these challenges. Here, we established a syngeneic organoid-based orthotopic CRC mouse model by transplanting quadruple mutant Apc⁻/⁻KrasG12D/+Trp53R172H/⁻Smad4⁻/⁻ (AKPS) intestinal organoids into the rectal submucosa of immunocompetent mice. Single-cell transcriptomic profiling revealed that CD8⁺ T cells represent the predominant leukocyte population within the tumor infiltrate and comprise populations transitioning toward dysfunction. Functionally, CD8⁺ T cell depletion led to increased tumor burden in orthotopic AKPS implants, underscoring their antitumor activity. Importantly, anti-PD-1 treatment increased the abundance of dysfunctional CD8⁺ T cell populations within AKPS tumors and reduced tumor growth, demonstrating the responsiveness of this model to ICIs. In contrast, subcutaneous implants of AKPS were infiltrated by mixed CD4⁺ and CD8⁺ T cell subsets, with CD8⁺ T cells exhibiting a markedly less dysfunctional profile, highlighting the limitations of heterotopic tumor models for studying antitumor immune responses. Together, our findings establish the AKPS orthotopic CRC model as a platform to dissect the molecular mechanisms of early CD8⁺ T cell dysfunction and to preclinically evaluate novel immunotherapeutic interventions in CRC.
    Keywords:  CD8+ T cell exhaustion; Colorectal cancer; immunotherapy
    DOI:  https://doi.org/10.1080/2162402X.2026.2674362
  13. Front Oncol. 2026 ;16 1771061
    Drug-tolerant persister cells in cancer: a scoping review of definitions, models, and molecular mechanisms.
    Jose S Lopez-Gonzalez, Mario Perez-Medina, Miriam Galicia-Velasco, Dolores Aguilar-Cazares.
      Drug-tolerant persistent (DTP) cells have emerged as a reversible, slow-cycling survival state that enables early therapeutic tolerance and underlies the development of stable resistance in all types of cancer. To comprehensively characterize this phenomenon, we conducted a PRISMA-ScR-guided exploratory review across four major databases (PubMed, Scopus, Web of Science, Dimensions), identifying 343 eligible records spanning 2010-2025. In all experimental systems, including 2D cell lines, spheroids, organoids, xenografts, residual disease models, and clinical samples, DTP cells consistently showed survival under high drug concentrations or prolonged exposure, depending on non-genetic adaptive programs, and recovery of proliferative potential and drug sensitivity after treatment cessation. Analysis of the molecular mechanisms revealed a convergence of reversible pathways involving apoptosis escape, quiescence, chromatin remodeling, phenotypic plasticity, metabolic rewiring, downstream survival signaling, and transient programs, such as those of stem cells. These findings support a model in which DTP cells represent an early and plastic node within a broader continuum of resistance, capable of progressing toward genetically fixed resistance through stress-induced mutagenesis. Methodological heterogeneity among studies did not diminish the reproducibility of DTP cells fundamental characteristics but underscored the need for standardized experimental criteria. Notably, the integrated evidence identifies therapeutically exploitable vulnerabilities-epigenetic, metabolic, signaling-based, and plasticity-targeted-that have shown promise in reducing DTP persistence and delaying the development of resistance. This review consolidates current knowledge and provides a mechanistic framework to guide therapeutic strategies that aim to intercept cancer resistance in the earliest and most reversible stages of its development.
    Keywords:  cancer cell plasticity; drug-tolerant persister (DTP) cells; epigenetic reprogramming; metabolic rewiring; non-genetic drug resistance; reversible drug tolerance; therapy-induced adaptation; tumor relapse
    DOI:  https://doi.org/10.3389/fonc.2026.1771061
  14. Biochim Biophys Acta Mol Basis Dis. 2026 May 08. pii: S0925-4439(26)00150-X. [Epub ahead of print] 168287
    Raman spectroscopic characterization of protein changes induced by 5-fluorouracil in colon cancer cells.
    Monika Kopeć, Karolina Beton-Mysur, Anna Sroka-Bartnicka, Beata Brożek-Płuska.
      This paper aims to evaluate the current state of knowledge on understanding the impact of cytostatic on colon cancer progression. We have compared the Raman profile of the normal colon fibroblast cell line (CCD-18Co) and two colon epithelial cancer cell lines (Caco-2 and LoVo). Our results indicate that ratios 1656/1305, 1256/1305, and 1656/1256 are the most relative Raman biomarkers for discrimination between normal fibroblast and cancer epithelial colon cells. The study results demonstrate that metabolic pathway reprogramming induced by 5-fluorouracil (5-FU) during colon cancer progression is detectable within both the whole cell and individual cell substructures, such as nucleus. These findings suggest that 5-FU-associated metabolic changes directly impact nuclear functions, which are critical for mechanisms of resistance and disease advancement. In the presented studies, the analysis of the secondary structure of proteins has also been performed. The obtained results demonstrate that CCD18-Co-CTRL and Lovo+5-FU (100 μM) cells are dominated by α-helix protein structure. Moreover, the obtained results indicate that supplementation with 5-fluorouracil (5-FU) may reduce the structural features associated with β-sheet-rich proteins.
    Keywords:  5-fluorouracil; Proteins; Raman imaging; Raman spectroscopy; colon cancer
    DOI:  https://doi.org/10.1016/j.bbadis.2026.168287
  15. Clin Transl Immunology. 2026 ;15 e70097
    Characterisation of tumor-infiltrating gamma-delta T cells in human colorectal cancer with MHC-I loss.
    Tianming A Li, Luke T Quigley, Kok Fei Chan, David S Williams, Lisa A Mielke, Andreas Behren, Jessica Da Gama Duarte.
       Objectives: Gamma-delta (γδ) T cells have been associated with favorable prognoses across several malignancies, underscoring their potential as targets for novel immunotherapies. These unconventional T lymphocytes exhibit an intrinsic tropism for the tumor microenvironment, largely driven by their capacity to recognize stress-induced antigens characteristic of metabolically dysregulated tumors. Unlike the mechanism governing conventional cytotoxic CD8+ alpha-beta (αβ) T cells, γδ T-cell receptors can engage tumor cell moieties independent of major histocompatibility complex class-I (MHC-I) and human leukocyte class-I molecules. Therefore, γδ T cells may have a pivotal role in the immune response to beta-2 microglobulin-mutated MHC-I negative (MHC-I-) colorectal cancers (CRCs) with deficient mismatch repair.
    Methods: To determine whether γδ T-cell mobilisation extends to diverse aetiologies of MHC-I loss, we used multispectral immunohistochemistry to stain 150 stage I-IV primary CRC tissues, across eight tissue microarrays.
    Results: Our investigation revealed MHC-I loss in ~30% of CRC primary tumors across all disease stages, with a notable increase in stromal γδ T-cell frequency and activation status among stage III cases. Importantly, these findings extend previous observations largely confined to mismatch repair-deficient CRC by demonstrating that stromal γδ T-cell enrichment associated with MHC-I loss also occurs in mismatch repair-proficient tumors, suggesting a broader role for γδ T cells in immune surveillance of MHC-I-deficient CRC.
    Conclusion: These data highlight the potential of γδ T cells in counteracting immune evasive MHC-I- tumors, thereby offering a robust rationale for their strategic deployment in next-generation immunotherapy regimens.
    Keywords:  MHC class I loss; colorectal cancer; multispectral immunohistochemistry; γδ T cells
    DOI:  https://doi.org/10.1002/cti2.70097
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