{"title":"Microbiota-regulated TCDCA associates with Parkinson's disease severity and promotes BBB dysfunction through VSMC TGR5 signaling in mice.","authors":"Zhe Zhao, Yixuan Liu, Wen Ma, Gaofei Hu, Jincen Hao, Chaobo Bai, Jing Chen, Qi Zhang, Huanhuan Cao, Xiaoyi Liu, Yujie Zhu, Manyuan Dong, Zheng Zhang, Shenge Su, Rui Zhan, Huibo Li, Rongsheng Zhao, Junliang Yuan","doi":"10.1016/j.xcrm.2026.103098","DOIUrl":"10.1016/j.xcrm.2026.103098","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a systemic disorder linked to gut dysbiosis, yet key microbiota-regulated metabolites remain unclear. Here, we observe elevated taurochenodeoxycholic acid (TCDCA) in patients with PD that correlates with disease severity. Reduced bile salt hydrolase (BSH) gene abundance correlates inversely with circulating TCDCA, consistent with altered bile acid deconjugation. Exogenous TCDCA correlates with aggravated motor and gastrointestinal deficits, impaired blood-brain barrier (BBB) integrity, and accelerated dopaminergic neurodegeneration in a PD mouse model. Mechanistically, TCDCA links to TGR5 signaling activation in vascular smooth muscle cells (VSMCs), alongside PKCα-dependent mitochondrial apoptosis and BBB disruption. VSMC-specific Tgr5 deletion coincides with neurovascular protection. Supplementation with a BSH-high Lactobacillus reuteri strain reduces TCDCA concentrations, improves gut and BBB integrity, mitigates inflammation, and alleviates PD-like phenotypes in a BSH-dependent manner. These data support a gut-BBB-brain axis linked to PD, identifying TCDCA as a candidate pathological marker.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103098"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The next click in antibody drug conjugate development.","authors":"Avantika Gupta, Sarat Chandarlapaty","doi":"10.1016/j.xcrm.2026.103099","DOIUrl":"https://doi.org/10.1016/j.xcrm.2026.103099","url":null,"abstract":"<p><p>The clinical success of antibody drug conjugates has been shaped by the promise of delivering cytotoxic payloads precisely to tumors while minimizing systemic exposure. Simó and colleagues aim to improve on conventional ADC delivery by decoupling tumor localization from payload delivery to enhance pharmacokinetics and addressing antigen heterogeneity by enabling dual targeting.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"7 10","pages":"103099"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2026-10-20Epub Date: 2026-09-11DOI: 10.1016/j.xcrm.2026.103047
Federica Esposito, Arjun Padmanabhan, Manuel Rhiel, Mariangela Lupo, Elena Marrocco, Stefano Auricchio, Xabier Bujanda Cundin, Simona Pellecchia, Tatjana I Cornu, Geoffroy Andrieux, Manel Llado-Santaeularia, Enrico Maria Surace, Ivana Trapani, Pasqualina Colella, Gennaro Gambardella, Toni Cathomen, Alberto Auricchio
{"title":"Targeted insertion of an optimized donor DNA is effective in a humanized mouse model of dominant retinitis pigmentosa.","authors":"Federica Esposito, Arjun Padmanabhan, Manuel Rhiel, Mariangela Lupo, Elena Marrocco, Stefano Auricchio, Xabier Bujanda Cundin, Simona Pellecchia, Tatjana I Cornu, Geoffroy Andrieux, Manel Llado-Santaeularia, Enrico Maria Surace, Ivana Trapani, Pasqualina Colella, Gennaro Gambardella, Toni Cathomen, Alberto Auricchio","doi":"10.1016/j.xcrm.2026.103047","DOIUrl":"10.1016/j.xcrm.2026.103047","url":null,"abstract":"<p><p>Retinitis pigmentosa (RP) affects 1 in 3,000 individuals worldwide, with 30%-40% of cases inherited as autosomal dominant (AD). Mutations in RHO (RP4) are the most common cause of ADRP. Because most RHO mutations exert gain-of-function or dominant-negative effects, conventional gene supplementation is insufficient, requiring mutant allele inactivation. Allele-specific editing is impractical, as each mutation requires a unique therapeutic strategy. We present a mutation-agnostic, RHO-specific approach using adeno-associated viral vector-mediated homology-independent targeted integration (AAV-HITI). Optimized donor DNA design enables targeted integration and efficient transgene expression from the endogenous RHO locus. In a humanized RP4 mouse model harboring the RHO P23H mutant allele alongside an endogenous wild-type mouse Rho allele, AAV-HITI significantly improves retinal structure, function, and visual acuity up to 1 year post-treatment. Comprehensive molecular analyses characterize on-target editing in mouse retina and off-target editing in a human cell line. These findings establish an effective, human-centric AAV-HITI platform for RP4 and support its evaluation in this and other dominant genetic conditions.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103047"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Punicalin targets RSV glycoprotein and fusion protein at non-overlapping sites to prevent viral escape.","authors":"Yingcai Xiong, Jingyi Ming, Zhaowei Zhang, Jiru Zhang, Xiaoqing Zhou, Biyu Cao, Guang Li, Yuqing Zhu, Zepeng Yang, Junxi Song, Zhao Wang, Mei Chen, Keyu Tao, Yue Kang, Jianjian Ji","doi":"10.1016/j.xcrm.2026.103078","DOIUrl":"10.1016/j.xcrm.2026.103078","url":null,"abstract":"<p><p>Respiratory syncytial virus (RSV) causes substantial respiratory disease, while treatment is limited by drug resistance. Molecular docking of a 3,880-compound natural-product library identifies punicalin (PUN) as a dual-target RSV entry inhibitor. PUN inhibits the evaluated RSV-A and RSV-B strains, including a clinical isolate, and retains activity against strains resistant to ziresovir, ribavirin, nirsevimab, and palivizumab. After 20 passages under PUN selection, the half-maximal inhibitory concentration (IC<sub>50</sub>) increases 3.88-fold, remaining below the predefined >10-fold resistance threshold. Mechanistic analyses suggest that PUN interacts with the G protein cystine-noose region involving N178, N179, and W183 to inhibit attachment and with an F protein region involving V243, T245, and P246 to stabilize prefusion F and inhibit membrane fusion. These regions do not overlap known resistance hotspots. In RSV-infected mice, nebulized PUN provides sustained respiratory exposure, reduces lung viral loads and pathology, and attenuates inflammatory responses.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103078"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2026-10-20Epub Date: 2026-09-15DOI: 10.1016/j.xcrm.2026.103051
Michael T Sandholzer, Clara Serger, Alessia G Liner, Sarp Uzun, David König, Helen Thut, Reto Ritschard, Jonas D Fürst, Andreas Zingg, Natalia Rodrigues Mantuano, Benjamin Kasenda, Katharina Glatz, Elisabeth A Kappos, Matthias Matter, Andreas Holbro, Frank Stenner, Jakob Passweg, Nina Khanna, Lukas Jeker, Mascha Binder, Alfred Zippelius, Heinz Läubli
{"title":"Single-cell tracking reveals tumor-reactive T cell plasticity during melanoma TIL therapy.","authors":"Michael T Sandholzer, Clara Serger, Alessia G Liner, Sarp Uzun, David König, Helen Thut, Reto Ritschard, Jonas D Fürst, Andreas Zingg, Natalia Rodrigues Mantuano, Benjamin Kasenda, Katharina Glatz, Elisabeth A Kappos, Matthias Matter, Andreas Holbro, Frank Stenner, Jakob Passweg, Nina Khanna, Lukas Jeker, Mascha Binder, Alfred Zippelius, Heinz Läubli","doi":"10.1016/j.xcrm.2026.103051","DOIUrl":"10.1016/j.xcrm.2026.103051","url":null,"abstract":"<p><p>Adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) induces durable responses in metastatic melanoma, yet the clonal and transcriptional dynamics governing tumor-reactive T cell fate during ex vivo expansion and after transfer remain poorly understood. Here, we perform longitudinal single-cell RNA and T cell receptor sequencing across five time points, from baseline tumors through two-phase ex vivo expansion to post-infusion blood and tumor biopsies, in seven melanoma patients, resolving both the CD8<sup>+</sup> and CD4<sup>+</sup> compartments. Tumor-reactive CD8<sup>+</sup> T cells are reinvigorated from exhaustion and acquire HLA-II-high or KLF2-high profiles. We further dissect the tumor-responsive CD4<sup>+</sup> compartment in depth, revealing lineage-dependent reinvigoration in which follicular helper T cells adopt an effector state while exhausted CD4<sup>+</sup> T cells retain dysfunction. In non-responders, across three cohorts, co-transferred type 17 T cells and de novo regulatory T cell expansion after transfer associate with treatment failure. These data define subtype-specific signatures across both lineages to guide TIL expansion.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103051"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148975759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2026-10-20Epub Date: 2026-09-29DOI: 10.1016/j.xcrm.2026.103082
Meng Guan, Xiao-Ting Xie, Bin Zhang, Zi-Hui Yan, Xin-Yue Xu, Jia-Hua Zou, Yuan-Di Zhao, Kai Cheng, Jin-Xuan Fan
{"title":"Reversal of the neutrophil barrier for potentiating immune-engineered bacteria therapy in pancreatic cancer.","authors":"Meng Guan, Xiao-Ting Xie, Bin Zhang, Zi-Hui Yan, Xin-Yue Xu, Jia-Hua Zou, Yuan-Di Zhao, Kai Cheng, Jin-Xuan Fan","doi":"10.1016/j.xcrm.2026.103082","DOIUrl":"10.1016/j.xcrm.2026.103082","url":null,"abstract":"<p><p>Engineered bacterial therapy holds the potential to overcome drug delivery barriers; remodel the immunosuppressive tumor microenvironment; and enable precise, sustained drug release within tumors. However, after infiltrating the tumor, engineered bacteria extensively recruit neutrophils, which directly phagocytose and eliminate the bacteria, confining them to the necrotic core and impeding their migration toward proliferative tumor regions, thereby limiting therapeutic efficacy. In this study, we introduce indole-3-acetic acid as an adjuvant to bacterial therapy. Note that, indole-3-acetic acid directly suppresses neutrophil recruitment. Simultaneously, it synergizes with gemcitabine to eliminate existing neutrophils. Experiments demonstrate that this method promotes intratumoral colonization, enhances immune activation efficiency, and can significantly reduce the clearance of therapeutic bacteria in pancreatic cancer mouse models. Taking PD-L1 antibody-expressing engineered bacteria as an example, the combination further strengthens T-cell-mediated antitumor immune responses through synergistic immune checkpoint blockade, ultimately achieving remarkable tumor growth suppression.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103082"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Microbiota-mediated naringenin release limits postoperative acute gastrointestinal injury by suppressing ferroptosis.","authors":"Fan Deng, Jingjuan Hu, Yue Min, Sun Xie, Zebin Lin, Qishun Sun, Huamin Liu, Shiying He, Siyuan Feng, Ling Wu, Xiaofeng Chen, Linghong Xu, Zheang Zhang, Wenqi Tang, Zhuang Li, Hongwei Zhou, Kexuan Liu","doi":"10.1016/j.xcrm.2026.103101","DOIUrl":"10.1016/j.xcrm.2026.103101","url":null,"abstract":"<p><p>Acute gastrointestinal injury (AGI) remains a major complication after cardiopulmonary bypass, yet its microbiome-related determinants are unclear. We identify microbiota-mediated naringenin (NAR) release as a candidate modulator of AGI susceptibility. Patients who subsequently develop AGI have lower preoperative fecal NAR levels and β-glucuronidase (GUS) activity, accompanied by reduced abundance of Bacteroides vulgatus (B. vulgatus). In germ-free and conventional mice, B. vulgatus alleviates intestinal ischemia-reperfusion injury through GUS-dependent release of NAR from its glucuronide conjugate. Mechanistically, NAR engages the TLR4/MyD88-SPRR2A axis to suppress CHAC1-driven ferroptosis, thereby maintaining epithelial integrity and promoting mucosal repair in vivo and in organoids. Clinically, preoperative fecal NAR concentration and GUS activity show exploratory value as noninvasive markers for postoperative AGI risk stratification. Collectively, these findings support a microbiota-host metabolic model in which microbial NAR release may mitigate postoperative gastrointestinal injury by restricting ferroptosis, with potential implications for risk assessment and therapeutic modulation.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103101"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2026-10-20Epub Date: 2026-07-02DOI: 10.1016/j.xcrm.2026.102888
Tobias Deuse, Sonja Schrepfer
{"title":"Transplantation tolerance versus immune evasion: Mechanistic divergences and therapeutic frontiers for islet cell replacement.","authors":"Tobias Deuse, Sonja Schrepfer","doi":"10.1016/j.xcrm.2026.102888","DOIUrl":"10.1016/j.xcrm.2026.102888","url":null,"abstract":"<p><p>Allogeneic transplantation is encumbered by the toxicities of chronic immunosuppression, driving innovations for lifelong graft acceptance without ongoing therapy. Transplantation tolerance, a recipient-centric strategy, utilizes central deletional processes through mixed hematopoietic chimerism and thymic repertoire sculpting, complemented by peripheral mechanisms such as T cell anergy, exhaustion, apoptotic deletion, and regulatory T cell dominance. Adjunctive costimulatory blockade enhances the latter pathways, yet tolerance remains precarious, susceptible to destabilization by infections or inflammatory perturbations via heterologous immunity. Conversely, immune evasion adopts a product-centric approach, engineering grafts to intrinsically circumvent adaptive allorejection, innate cytotoxicity, and autoimmune recognition and responses. These mechanistic contrasts-dynamic recipient modulation versus robust graft stealth-underscore immune evasion's transformative promise and resilience, with empirical validation for cell and organoid transplantation. This review focusses on islet cell replacement therapy, wherein cadaveric allogeneic islet allografts have been clinically available for over four decades, complemented by recent advancements in stem cell-derived islet products.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102888"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2026-10-20Epub Date: 2026-09-25DOI: 10.1016/j.xcrm.2026.103053
Akiko Maeda, Xiaoxu Han, Michiko Mandai
{"title":"iPSC-derived retinal organoids: Biological insights and progress toward photoreceptor replacement therapy.","authors":"Akiko Maeda, Xiaoxu Han, Michiko Mandai","doi":"10.1016/j.xcrm.2026.103053","DOIUrl":"10.1016/j.xcrm.2026.103053","url":null,"abstract":"<p><p>Induced pluripotent stem cell (iPSC)-derived retinal organoids (ROs) have emerged as a platform for photoreceptor replacement therapy, supported by two complementary approaches: cone precursor cell transplantation and RO transplantation. Both have demonstrated proof of concept for functional synaptic integration with the host retinal network, with the first clinical application of iPSC-derived RO transplantation conducted in 2020. Key mechanistic insights include the role of the host environment in cone integration, genome editing-based enhancement of host-graft synaptogenesis recapitulating developmental synaptic assembly, and synaptic rewiring capacity in the adult primate retina. Beyond biology, successful clinical translation requires establishing meaningful endpoints that reflect stepwise therapeutic improvement, scalable good manufacturing practice (GMP)-compliant manufacturing including validated preservation protocols, and regulatory frameworks accommodating progenitor-stage cell therapies. Together, these advances offer a realistic path toward vision restoration in patients with currently untreatable retinal degenerative diseases.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103053"},"PeriodicalIF":14.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}