bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2026–08–16
fifteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Dietary vitamin A restricts intestinal tuft cell differentiation.
  2. Stearoyl-CoA desaturases regulate intestinal stem and progenitor cell metabolism and function in response to nutrient abundance.
  3. Absence of EGFR signalling in granulocytic cells relieves immunosuppression sensitising CRC metastases to immune checkpoint therapy.
  4. Protocol for surgical stress-promoted colorectal cancer liver metastasis in mice.
  5. A mitochondrial antioxidant axis fuels iron addiction in colorectal cancer.
  6. TNFR1 signaling connects inflammation to impaired fatty acid oxidation to drive intestinal stem cell aging.
  7. Inhibiting menin attenuates high-fat diet-induced weight gain by limiting intestinal lipid absorption in mice.
  8. An iron logic unites bacterial and cancer persister cells.
  9. TNF Receptor 1 regulates colonic mesenchymal cell diversity and the epithelial stem cell niche.
  10. Molecular basis of HACD-TECR complex mediated very-long-chain fatty acid elongation reveal a potential target in colorectal cancer.
  11. Polyunsaturated fatty acid sequestration protects against mitochondrial dysfunction-induced ferroptosis.
  12. The sex and reproductive plasticity of intestinal muscles instruct gut size.
  13. The past, present, and future treatment of BRAFV600-mutant metastatic colorectal cancer: A comprehensive review.
  14. Polyamines buffer labile iron to suppress ferroptosis.
  15. Targeting peripheral 5-HT2AR enhances antitumor immunity in colorectal cancer.
  1. Cell Rep. 2026 Aug 12. pii: S2211-1247(26)00880-6. [Epub ahead of print]45(8): 117802
    Dietary vitamin A restricts intestinal tuft cell differentiation.
    Bailey J Didriksen, Emily M Eshleman, Taylor Rice, Amanda Waddell, Shikha Negi, Laura Engleman, Seika Hashimoto-Hill, Rebekah Karns, Mark R Frey, Theresa Alenghat.
      Despite evidence highlighting immunoregulatory roles of tuft cells, it is not known whether vitamin A or retinoic acid affects tuft cell homeostasis. Here, we find that epithelial-intrinsic retinoic acid receptor regulates tuft cell numbers in mice. However, loss of retinoic acid signaling in tuft cells does not replicate this effect, suggesting altered differentiation. Consistent with this, retinoic acid administration to stem cell-derived organoids reduces tuft cell numbers, and epithelial-intrinsic retinoic acid is sufficient to alter tuft cell responses. In addition, dietary vitamin A dynamically alters tuft cells in vivo and regulates anti-helminth immunity in a tuft cell-dependent manner. Mechanistically, epithelial retinoic acid signaling promotes expression of Sprouty2, a negative regulator of tuft cell differentiation. Furthermore, stem cell-specific Sprouty2 disruption abrogates vitamin A regulation of tuft cells. Collectively, these data indicate that retinoic acid restricts tuft cell differentiation and carries important implications for how vitamin A affects intestinal health and immunity.
    Keywords:  CP: metabolism; CP: stem cell research; Diet; Differentiation; Epithelial; ILC; Intestine; Retinoic acid; Stem cell; Tuft cell; Vitamin A
    DOI:  https://doi.org/10.1016/j.celrep.2026.117802
  2. Cell Rep. 2026 Aug 10. pii: S2211-1247(26)00809-0. [Epub ahead of print]45(8): 117731
    Stearoyl-CoA desaturases regulate intestinal stem and progenitor cell metabolism and function in response to nutrient abundance.
    Kübra B Akkaya-Colak, Andrea R Keller, Maria H Festing, Khushboo Gupta, James Sledziona, Ayobami Adeniyi, Omar West, Patrick Stevens, Maciej Pietrzak, Sue E Knoblaugh, Helaina Walesewicz, Dominique A Baldwin, Nicholas C Denko, Judith A Simcox, James M Ntambi, Steven K Clinton, Maria M Mihaylova.
      Diet composition and nutrient availability play critical roles in intestinal stem and progenitor cell function and proliferation. Here, we show that stearoyl-CoA desaturases (SCDs) are regulated by nutrient abundance and link intracellular lipid metabolism to intestinal homeostasis. Pharmacological inhibition or genetic deletion of Scd1 and Scd2 in intestinal mouse organoids disrupted lipid desaturation, induced endoplasmic reticulum (ER) stress, and impaired stem and progenitor cell proliferation, effects largely mitigated by oleic acid supplementation. Intestine-specific deletion of Scd1 and Scd2 reduced the number of LGR5+ stem cells in vivo and was accompanied by metabolic rewiring and expansion of transient amplifying cells. Loss of Scd1 and Scd2 also reduced epithelial regeneration capacity following irradiation and exacerbated tissue damage and inflammation in a DSS-induced colitis model. Together, these findings reveal important SCD dependencies and metabolic adaptations in intestinal stem and progenitor cells that are necessary for epithelial regeneration and repair following injury.
    Keywords:  CP: metabolism; CP: stem cell research; ER stress; colitis; intestinal injury; intestinal regeneration; lipid desaturation; metabolic adaptation; nutrient sensing; stearoyl-CoA desaturase; stem cell metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2026.117731
  3. Cell Death Differ. 2026 Aug 11.
    Absence of EGFR signalling in granulocytic cells relieves immunosuppression sensitising CRC metastases to immune checkpoint therapy.
    Veronica Moreno-Viedma, Emi Adachi-Fernandez, Dana Krauss, Thomas Mohr, Bernadette Blauensteiner, Jorun Buresch, Lilyana Mireva, Eleftherios Kokkinogenis, Martin Filipits, Martin Holcmann, Daniele V F Tauriello, Eduard Batlle, Maria Sibilia.
      Metastatic colorectal cancer (mCRC) is one of the deadliest cancers with very poor response to immune checkpoint blockade (ICB). Standard therapies employ chemotherapy combined with epidermal growth factor receptor (EGFR) blocking antibodies, which are only effective in a fraction of patients with RAS/RAF wild-type tumours. We have previously shown that EGFR deletion in myeloid cells of CRC, rather than in the cancer cells themselves, reduces tumour growth. Here, we investigate to which extent EGFR blockade in myeloid cells increases anti-tumour immunity, thus sensitising CRC to ICB. Using a syngeneic preclinical CRC liver metastasis model based on the transplantation of murine RAS mutant CRC organoids into mice lacking EGFR in myeloid cells, we observe a reduction in metastasis development accompanied by increased intratumoural T-cell infiltration. Importantly, we demonstrate that EGFR deletion reduces the capacity of granulocytic myeloid-derived suppressor cells (G-MDSCs) to suppress CD4+ T-cell proliferation. RNA-seq analysis of sorted MDSCs and T-cells uncovered an EGFR-dependent signature involved in immunosuppression, which in proficient-mismatch-repair (pMMR) CRC patients is associated with worse overall survival. Therapeutically, lifting immunosuppression by EGFR deletion in myeloid cells sensitised tumours to anti-PD-L1 treatment, thus preventing liver metastasis development. These results imply that anti-EGFR therapies combined with ICB might be successful in preventing metastasis of RAS mutated CRC with high infiltration of suppressive EGFR+ myeloid cells.
    DOI:  https://doi.org/10.1038/s41418-026-01828-0
  4. STAR Protoc. 2026 Aug 08. pii: S2666-1667(26)00423-5. [Epub ahead of print]7(3): 104770
    Protocol for surgical stress-promoted colorectal cancer liver metastasis in mice.
    Jian Han, Peter Tsung, Natalie Blatz, Tongyu Shen, Yunwei Zhang, Hongji Zhang.
      Although hepatectomy can be therapeutic, ischemia-reperfusion (I/R) caused by temporary interruption of blood flow creates an inflammatory microenvironment that facilitates tumor-cell seeding and postoperative metastasis. Here, we present a protocol for combining hepatic I/R in mice with portal vein injection of syngeneic colorectal cancer cells. We describe steps for injecting tumor cells under anesthesia, transiently occluding hepatic blood flow, and monitoring liver metastasis. This model recapitulates tumor-host interactions and enables investigation of surgical stress-promoted colorectal cancer liver metastasis (CRLM). For complete details on the use and execution of this protocol, please refer to Zhang Y et al.1.
    Keywords:  Cancer; Immunology; Model Organisms
    DOI:  https://doi.org/10.1016/j.xpro.2026.104770
  5. Cell Metab. 2026 Aug 04. pii: S1550-4131(26)00237-8. [Epub ahead of print]38(8): 1521-1523
    A mitochondrial antioxidant axis fuels iron addiction in colorectal cancer.
    Le Jin Sun, Gina M DeNicola.
      Colorectal cancer (CRC) cells accumulate iron to fuel proliferation yet paradoxically resist its toxicity. Jain et al. reveal that heme stabilizes succinate dehydrogenase subunit C, sustaining complex II-dependent coenzyme Q reduction and its redistribution to the plasma membrane, enabling CRC cells to buffer oxidative stress and iron-induced cell death.
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.011
  6. Nat Aging. 2026 Aug;6(8): 1631-1646
    TNFR1 signaling connects inflammation to impaired fatty acid oxidation to drive intestinal stem cell aging.
    Ruixuan Wang, Tahmineh Tabrizian, Donghai Wang, Jeb English, Anita Ayer, Maya Gal, Weng-Lang Yang, Zhiping Wu, Kai Mao, Ardijana Novaj, Xusheng Zhang, Indranil Basu, Nils P Brodin, Wade Koba, Deepak Saxena, Jiahn Choi, Leonard H Augenlicht, Aaron Ericsson, Evripidis Gavathiotis, Chandan Guha, Derek M Huffman.
      Aging is characterized by a decline in function of intestinal stem cells (ISCs), but the extent to which this is shaped by systemic factors is unclear. Here we show that the ISC aging phenotype can be propagated from old to young mice utilizing heterochronic parabiosis, and implicate a role for inflammation in these effects, as anti-inflammatory drugs, including TNF antibodies, restored function. Parabiotic rescue experiments demonstrate that TNFR1 knockout protected young ISCs from the old environment. In young organoids, TNF downregulated crypt budding, while impairing mitochondrial pathways and fatty acid oxidation (FAO). However, aged ISC function was enhanced by boosting mitochondrial fusion, whereas FAO in aged crypts was improved by countering inflammation with salicylate treatment. Thus, these data identify the old environment through the progeronic factor TNF, as a driver of ISC aging phenotypes through intestinal epithelial cell TNF receptor 1 signaling to downregulate FAO, proliferation and regenerative capacity in these cells.
    DOI:  https://doi.org/10.1038/s43587-026-01170-7
  7. J Clin Invest. 2026 Aug 11. pii: e202709. [Epub ahead of print]
    Inhibiting menin attenuates high-fat diet-induced weight gain by limiting intestinal lipid absorption in mice.
    Xiaoru Cao, Pingping Zhou, Haiyue Meng, Zhitao Guo, Yan Cao, Chenghao Wang, Lulu Liu, Yinghao Guo, Yue Wang, Guoshun Xin, Dabin Liu, Feng Geng, Jian Ma.
      Intestinal lipid metabolism is essential for systemic energy homeostasis, and its modulation is emerging as a therapeutic strategy for obesity. Menin, a scaffold protein that regulates chromatin remodeling and gene expression, is abundantly expressed in intestinal epithelial cells (IECs), but its metabolic role remains underexplored. Here, we generated IEC-specific Men1 knockout mouse and found that Men1 deficiency protected against high-fat diet-induced obesity, accompanied by elevated carboxylesterase 1 (CES1) expression in IECs. Increased CES1 promoted triglyceride (TG) hydrolysis and reduced intracellular TG storage, thereby limiting the lipid substrate pool required for ApoB48-dependent chylomicron assembly. Although lipid hydrolysis was enhanced, steady-state free fatty acid levels were not increased; instead, Men1 deficiency activated fatty acid β-oxidation programs and increased etomoxir-sensitive fatty acid-dependent mitochondrial respiration, supporting enhanced fatty acid catabolism. Mechanistically, menin recruited histone deacetylase 1 and interacted with the nuclear receptor LXRβ to suppress Ces1g transcription, thereby sustaining efficient intestinal lipid absorption. Pharmacological inhibition of menin with MI-463 recapitulated the metabolic effects of inducible Men1 deletion. In a human gut organoid-on-chip system, MI-463 dose-dependently increased CES1 expression and markedly reduced lipid accumulation. Collectively, our findings identify menin as a regulator of intestinal lipid metabolism and suggest menin inhibition as a potential therapeutic strategy for obesity-related metabolic disorders.
    Keywords:  Gastroenterology; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/JCI202709
  8. Nat Rev Mol Cell Biol. 2026 Aug 11.
    An iron logic unites bacterial and cancer persister cells.
    Raphaël Rodriguez, Patrizia Agostinis.
      
    DOI:  https://doi.org/10.1038/s41580-026-01010-x
  9. Cell Mol Gastroenterol Hepatol. 2026 Aug 10. pii: S2352-345X(26)00134-7. [Epub ahead of print] 101856
    TNF Receptor 1 regulates colonic mesenchymal cell diversity and the epithelial stem cell niche.
    Safina Gadeock, Nandini Girish, Cambrian Y Liu, Ying Huang, Barun Das, Tracy C Grikscheit, D Brent Polk.
       BACKGROUND & AIMS: Tumor necrosis factor receptor 1 (TNFR1) regulates intestinal epithelial survival and repair, yet its role in the colonic mesenchyme remains unclear. We investigated how mesenchymal TNFR1 signaling controls stromal cell identity, stem cell niche function, and epithelial homeostasis.
    METHODS: Colonic mesenchymal populations from germline TNFR1-deficient (TNFR1-/-) and mesenchymal-specific Pdgfra-Cre;TNFR1fl/fl mice were analyzed using immunostaining, western blotting, bulk and single-cell RNA sequencing, and organoid-mesenchymal co-culture systems. Functional studies included wound healing assays, recombinant RSPO3 rescue, and ITGA6 blockade.
    RESULTS: TNFR1 deletion altered mesenchymal composition, reducing PDGFRα expression while increasing αSMA expression in vivo and in vitro. Single-cell RNA sequencing demonstrated loss of mesenchymal heterogeneity following TNFR1 deletion, including depletion of a distinct TNF and interferon responsive mesenchymal subpopulation enriched for Mmp9, Cd200, Traf1, and Tnfrsf9. Transcriptomic profiling revealed downregulation of stem cell niche factors including Rspo3, Wnt2b, and Fgf2, alongside increased extracellular matrix and proliferative signaling pathways, particularly Itga6, PI3K, MAPK, and RAP1 signaling. Mesenchymal TNFR1 deletion impaired epithelial proliferation and reduced Lgr5+ and Ephb3+ intestinal stem cell expression in vivo. In organoid co-culture systems, TNFR1-deficient mesenchymal cells suppressed epithelial stem cell marker expression and altered colonoid morphology, effects which were rescued by recombinant RSPO3. ITGA6 blockade restored PDGFRα and RSPO3 expression and normalized proliferative signaling and migration in TNFR1-deficient myofibroblasts. Similarly, TNFR1-dependent regulation of ITGA6, PDGFRA, and RSPO3 was observed in human colonic myofibroblasts.
    CONCLUSIONS: Mesenchymal TNFR1 preserves colonic mesenchymal diversity, sustains RSPO3-dependent stem cell niche signaling, and maintains intestinal stem cell homeostasis.
    Keywords:  IBD organoids; Stem cell niche; TNF; mesenchyme
    DOI:  https://doi.org/10.1016/j.jcmgh.2026.101856
  10. Sci Adv. 2026 Aug 14. 12(33): eaeh5593
    Molecular basis of HACD-TECR complex mediated very-long-chain fatty acid elongation reveal a potential target in colorectal cancer.
    Rui Lv, Leiye Yu, Jingyi Liu, Youli Zhou, Ruiping He, Chen Wang, Bing Gan, Rujuan Ti, Haizhan Jiao, Baohui Song, Yiqi Chen, Feifei Lin, Mei Gao, Hongli Hu, Shankai Yin, Pinghong Zhou, Lizhe Zhu, Mingyan Cai, Tian Xie, Jia Liu, Li Chen, Yunshi Zhong, Ruobing Ren.
      Remodeling of fatty acid metabolism is increasingly recognized as a critical feature of tumor progression, yet the contribution of very long-chain fatty acid (VLCFA) remains incompletely understood. The elongation of VLCFAs, which is mediated by four consecutive enzymes in the endoplasmic reticulum (ER), has been implicated in tumor progression. However, the molecular mechanisms underlying VLCFA elongation enzymes and their specific contributions to tumorigenesis remain largely elusive. Here, we demonstrate that trans-2-enoyl-CoA reductase (TECR) is upregulated in colorectal cancer (CRC). Structural and biochemical analyses revealed a conserved catalytic mechanism for TECR-mediated trans-2-enoyl-CoA reduction. Moreover, we show that TECR forms a stable complex with 3-hydroxyacyl-CoA dehydratase (HACD), to cooperatively drive VLCFA elongation. A unique U-shaped loop in HACD is critical for recognizing TECR. Disruption of the HACD-TECR interaction interface significantly suppresses CRC cell growth. Collectively, these findings elucidate the molecular mechanism of HACD-TECR-mediated VLCFA elongation and suggest a potential therapeutic strategy for CRC treatment by modulating VLCFA metabolism.
    DOI:  https://doi.org/10.1126/sciadv.aeh5593
  11. EMBO Rep. 2026 Aug 14.
    Polyunsaturated fatty acid sequestration protects against mitochondrial dysfunction-induced ferroptosis.
    Guillermo Puertas-Frías, María José Saucedo-Rodríguez, Kristýna Čunátová, Lukáš Alán, Patrik Hrbáč, Michal Knězů, Soňa Koníčková, Jakub Schimmer, Monika Krakovková, Marek Vrbacký, Tomáš Čajka, Ondřej Kuda, Erika Fernández-Vizarra, Massimo Zeviani, Hana Hansíková, Tomáš Honzík, Josef Houštěk, Petr Pecina, Tomáš Mráček, Alena Pecinová.
      Impaired energy production is a hallmark of mitochondrial oxidative phosphorylation (OXPHOS) defects. However, secondary metabolic disturbances also represent an important trigger for pathologies originating from OXPHOS aberrations. Here we show that cells with OXPHOS deficiencies accumulate triacylglycerols enriched in polyunsaturated fatty acids (PUFAs), which are stored in lipid droplets. Sequestration of PUFAs is a critical component of a broader stress response, which also includes downregulation of cellular desaturases and upregulation of glutathione peroxidase 4 (GPX4). We demonstrate that this mechanism represents a physiologically relevant protective strategy, manifesting in cells under hypoxia and in immortalised fibroblasts derived from patients with primary mitochondrial complex IV deficiency. As a proof of principle, we observe elevated PUFA-enriched triacylglycerols in the plasma of patients with Myoclonic Epilepsy with Ragged Red Fibres (MERRF). Our findings reveal a novel protective mechanism against ferroptosis, which preserves membrane integrity when mitochondrial respiration is compromised.
    DOI:  https://doi.org/10.1038/s44319-026-00898-y
  12. Cell. 2026 Aug 11. pii: S0092-8674(26)00822-6. [Epub ahead of print]
    The sex and reproductive plasticity of intestinal muscles instruct gut size.
    Alessandro Mineo, Laura Blackie, Alexandra Milona, Emily Strachan, Pedro Gaspar, Nuno Miguel Luis, Alvaro Castano-Medina, Tomotsune Ameku, Bryon Silva, Anadika Prasad, Clara L Essmann, Jake Jacobson, Todd Fallesen, Vanessa Dao, Sanjay Khadayate, George Young, Filipe Cabreiro, Frank Schnorrer, Irene Miguel-Aliaga.
      Adult organs enlarge or regress in response to functional demands: changes commonly attributed to the dynamics of their resident stem cells. A striking example is the intestine, whose length varies with diet and reproductive status. We find that the size of the adult gut is extrinsically controlled by its surrounding muscles. In Drosophila, intestinal muscle differs in size and structure between sexes and grow in females during reproduction. By altering the sex or reproductive status of gut muscle cells, we establish that muscle-intrinsic sex determinants determine baseline sex differences in muscle myofibril width and organ size. Female muscles integrate hormonal and nutritional inputs during reproduction to elongate their sarcomeres; this reduces intestinal transit and further increases organ size. Such remodeling is adaptive and also occurs in mice. Our findings redefine the intestinal muscle as a responder to specific signals that adjust adult organ-level features and sustain reproductive demands.
    Keywords:  Drosophila; Mus musculus; intestinal visceral muscles; intestine; juvenile hormone; organ remodeling; peristalsis; plasticity; reproduction; sex differences
    DOI:  https://doi.org/10.1016/j.cell.2026.07.024
  13. Cancer. 2026 Aug 15. 132(16): e70569
    The past, present, and future treatment of BRAFV600-mutant metastatic colorectal cancer: A comprehensive review.
    Iris Dirven, Celina Ang, Cleo Bertels, Koen Kortbeek, Amy de Haar-Holleman, Marieke Vollebergh, Poulikos Poulikakos, Bart Neyns.
      BRAFV600-mutant metastatic colorectal cancer comprises a biologically distinct and clinically aggressive subset of metastatic colorectal cancer. Early attempts to apply single-agent BRAFV600 inhibition failed because of rapid acquired resistance and reactivation of mitogen-activated protein kinase signaling. Over the last decade, rational combinations (BRAF inhibitors and epidermal growth factor receptor inhibitors with or without mitogen-activated protein kinase kinase inhibitors) have become the standard of care in the refractory setting and are now being evaluated upfront, whereas a wave of next-generation approaches (extracellular signal-regulated kinase and SHP2 inhibitors, receptor tyrosine kinase-targeted agents, and immunotherapy combinations) aims to prevent or overcome resistance. The objective of this comprehensive review was to summarize historic therapeutic approaches, current standards, and the mechanistic rationale and clinical development of next-generation strategies to combat resistance in BRAFV600-mutant metastatic colorectal cancer.
    Keywords:  BRAF inhibition; BRAFV600‐mutant; adaptive resistance; comprehensive review; metastatic colorectal cancer; targeted therapy
    DOI:  https://doi.org/10.1002/cncr.70569
  14. Cell. 2026 Aug 14. pii: S0092-8674(26)00872-X. [Epub ahead of print]
    Polyamines buffer labile iron to suppress ferroptosis.
    Pushkal Sharma, Heather R Keys, Ryan P Mansell, Jillian Stark, Louisa Girard, Christalyn Ausler, Rachel Anderson, Sebastian Müller, Shinya Imada, Ivan S Pires, Tenzin Kunchok, Millenia Waite, Bingbing Yuan, Amy Deik, Luke Ferro, Paula T Hammond, Raphaël Rodriguez, Maria-Eirini Pandelia, Whitney S Henry, Ankur Jain.
      Polyamines are essential and evolutionarily conserved metabolites present at millimolar concentrations in mammalian cells. Cells tightly regulate polyamine homeostasis through complex feedback mechanisms, yet the precise role necessitating this regulation remains unclear. Here, we show that polyamines contribute to endogenous buffering of redox-active iron, providing a molecular link between polyamine metabolism and ferroptosis. Using a genome-wide CRISPR screen, we identified a synthetic lethal dependency between polyamine depletion and the key ferroptosis suppressor, glutathione peroxidase 4 (GPX4). Mechanistically, we show that polyamine deficiency triggers a redistribution of cellular iron, increasing the labile iron pool and upregulating ferritin. To directly visualize this iron buffering in living cells, we developed a genetically encoded fluorescent reporter for redox-active iron. Live-cell analysis revealed a striking inverse correlation between intracellular polyamine levels and redox-active iron at single-cell resolution. These findings reposition polyamines as key regulators of iron homeostasis, with implications for ferroptosis-linked disease states and cellular redox balance.
    Keywords:  GPX4; ferroptosis; genetically encoded iron sensor; iron homeostasis; labile iron pool; polyamines; redox-active iron; spermidine; spermine
    DOI:  https://doi.org/10.1016/j.cell.2026.07.040
  15. Cell. 2026 Aug 04. pii: S0092-8674(26)00826-3. [Epub ahead of print]
    Targeting peripheral 5-HT2AR enhances antitumor immunity in colorectal cancer.
    YaTing Wen, LingJie Tang, WenWen Duan, QingFei Ren, YangYue Ni, ShiYang Chen, Jun Chen, Lei Yang, Huan Wang, Yuan Chen, YunZhe Zheng, XingChao Pan, Hui Du, MengWen Huang, An Zeng, Zhaocai Zhou, ZhiGang Zhang, HongBin Ji, GaoXiang Ge, Yi Arial Zeng, Wei Zhang, ShiHui Wang, JianJun Cheng, Sheng Wang, JianFeng Chen.
      Cancer remains a leading cause of morbidity and mortality worldwide. While classical psychedelics have been used clinically to treat cancer-associated psychiatric disorders, their impact on tumor progression is unclear. Here, we show that by targeting the serotonin receptor 5-HT2AR, lysergic acid diethylamide (LSD) enhances CD8+ T cell-mediated antitumor immunity and suppresses colorectal cancer (CRC) growth. To harness this activity while avoiding psychedelic effects, we developed IHCH-8110, a non-brain-penetrant 5-HT2AR agonist that selectively targets peripheral 5-HT2AR. We show that IHCH-8110 inhibits CRC progression by activating 5-HT2AR on enteric glial cells, thereby inducing CXCL10 and interleukin (IL)-18 expression to promote CD8+ T cell recruitment and effector polarization within the tumor microenvironment. By converting immune-cold CRC into a more immunologically responsive state, IHCH-8110 enhances the efficacy of PD-1 blockade. Together, our findings identify enteric 5-HT2AR signaling as a regulator of antitumor immunity and support peripheral 5-HT2AR agonists as a therapeutic strategy for CRC immunotherapy.
    Keywords:  5-HT(2A)R agonist; colorectal cancer; cytotoxic CD8(+) T cell; enteric glial cell
    DOI:  https://doi.org/10.1016/j.cell.2026.07.028
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