---
title: "CAR T Cells Targeting O-Glycosylated Fibronectin (Tn-FN) Show Potent Cytotoxicity and Synergy with"
id: "pubmed-42397032"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42397032"
content_type: "clinical_feed_article"
specialty: "Pharmacology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42397032/"
doi: "10.1158/2326-6066.CIR-26-0009"
published_at: "2026-09-02T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# CAR T Cells Targeting O-Glycosylated Fibronectin (Tn-FN) Show Potent Cytotoxicity and Synergy with
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42397032
- **Specialty:** [Pharmacology](https://medichelpline.com/clinical-feed/pharmacology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42397032/)
- **DOI:** [10.1158/2326-6066.CIR-26-0009](https://doi.org/10.1158%2F2326-6066.CIR-26-0009)
- **Published At:** 2026-09-02T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- Tumors remodel the extracellular matrix and glycosylation, creating epitopes with restricted detectability in normal adult tissues; the study evaluated the **O-glycosylated fibronectin (Tn-FN)** IIICS domain as a CAR target. - Researchers built an FDC6-based CAR (FDC6-BBζ) that recognizes the Tn-glycosylated IIICS region and compared it to **L19-BBζ** (EDB-FN target) and **5E5-BBζ** (Tn-MUC1 target). - In vitro and in NOD/SCID gamma prostate cancer xenografts, **FDC6-BBζ** mediated robust, antigen-dependent activation and cytotoxicity, outperforming L19-BBζ and matching 5E5-BBζ. - FDC6-BBζ and 5E5-BBζ CAR T cells produced durable tumor control, increased intratumoral **CD3+** T-cell infiltration, and reduced tumor–collagen overlap in treated tumors. - Effective cytotoxicity by CARs required intact tumor **IFNγ receptor 1 (IFNγR1)**; L19-BBζ additionally depended on **Fas**, while FDC6-BBζ and 5E5-BBζ were less Fas-dependent. - Agonism of tumoral **Toll-like receptors (TLR)** — specifically **TLR2/6** or **TLR4** — restored FDC6-BBζ killing against IFNγR1-deficient tumor targets and induced broad inflammatory and stress-response transcriptional programs. - Pharmacologic perturbation implicated **caspase-dependent** mechanisms and contributions from inflammasome-linked signaling in restored killing; blockade of **ferroptosis** did not abrogate the restored cytotoxicity. - The findings establish **Tn-FN** as a glycoform-restricted, extracellular-matrix–derived CAR target and demonstrate that innate agonists can reprogram tumor state to overcome resistance linked to impaired IFNγ signaling. - Conflict of interest: Two authors (T.R.K-P. and A.D.P.) are inventors on patents related to CAR T therapies targeting Tn-FN; other authors declared no potential conflicts. - Details on experimental numbers, dosing, specific agonists used, and full methodological parameters were not reported in the PubMed abstract and require consultation of the full text for complete methods and quantitative results.
## Clinical Analysis & Structured Key Points
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more resources ](https://pubmed.ncbi.nlm.nih.gov/42397032/#linkout) Title & authors Abstract Conflict of interest statement Figures Similar articles References MeSH terms Substances Related information Grants and funding LinkOut - more resources Cancer Immunol Res Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Cancer+Immunol+Res%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Cancer+Immunol+Res%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42397032/) . 2026 Sep 2;14(9):1400-1415. doi: 10.1158/2326-6066.CIR-26-0009. # CAR T Cells Targeting O-Glycosylated Fibronectin Exhibit Potent Cytolytic Activity and Combine with Tumoral Toll-Like Receptor Agonism to Overcome Tumor Resistance [Tiffany R King-Peoples](https://pubmed.ncbi.nlm.nih.gov/?term=King-Peoples+TR&cauthor_id=42397032)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#full-view-affiliation-1 "Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania."), [John T Keane](https://pubmed.ncbi.nlm.nih.gov/?term=Keane+JT&cauthor_id=42397032)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#full-view-affiliation-1 "Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania."), [Hyeon-Gyu S Lewis](https://pubmed.ncbi.nlm.nih.gov/?term=Lewis+HS&cauthor_id=42397032)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#full-view-affiliation-1 "Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania."), [Fang Liu](https://pubmed.ncbi.nlm.nih.gov/?term=Liu+F&cauthor_id=42397032)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#full-view-affiliation-1 "Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania."), [Shawna K Brookens](https://pubmed.ncbi.nlm.nih.gov/?term=Brookens+SK&cauthor_id=42397032)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#full-view-affiliation-1 "Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania."), [Oula K Dagher](https://pubmed.ncbi.nlm.nih.gov/?term=Dagher+OK&cauthor_id=42397032)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#full-view-affiliation-1 "Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania."), [Kalpana Parvathaneni](https://pubmed.ncbi.nlm.nih.gov/?term=Parvathaneni+K&cauthor_id=42397032)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#full-view-affiliation-2 "Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania."), [Brittany L Gardner](https://pubmed.ncbi.nlm.nih.gov/?term=Gardner+BL&cauthor_id=42397032)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#full-view-affiliation-1 "Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania."), [Amal Ahmed](https://pubmed.ncbi.nlm.nih.gov/?term=Ahmed+A&cauthor_id=42397032)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#full-view-affiliation-1 "Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania."), [Emma E Furth](https://pubmed.ncbi.nlm.nih.gov/?term=Furth+EE&cauthor_id=42397032)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#full-view-affiliation-2 "Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania."), [Priti Lal](https://pubmed.ncbi.nlm.nih.gov/?term=Lal+P&cauthor_id=42397032)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#full-view-affiliation-2 "Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania."), [Avery D Posey Jr](https://pubmed.ncbi.nlm.nih.gov/?term=Posey+AD+Jr&cauthor_id=42397032)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#full-view-affiliation-1 "Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#full-view-affiliation-3 "Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania.") Affiliations Expand ### Affiliations * 1 Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. * 2 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. * 3 Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania. * PMID: **42397032** * PMCID: [ PMC13488855 ](https://pmc.ncbi.nlm.nih.gov/articles/PMC13488855/) * DOI: [ 10.1158/2326-6066.CIR-26-0009 ](https://doi.org/10.1158/2326-6066.cir-26-0009) Item in Clipboard # CAR T Cells Targeting O-Glycosylated Fibronectin Exhibit Potent Cytolytic Activity and Combine with Tumoral Toll-Like Receptor Agonism to Overcome Tumor Resistance Tiffany R King-Peoples et al. Cancer Immunol Res. 2026. Show details Display options Display options Format Abstract PubMed PMID Cancer Immunol Res Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Cancer+Immunol+Res%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Cancer+Immunol+Res%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42397032/) . 2026 Sep 2;14(9):1400-1415. doi: 10.1158/2326-6066.CIR-26-0009. ### Authors [Tiffany R King-Peoples](https://pubmed.ncbi.nlm.nih.gov/?term=King-Peoples+TR&cauthor_id=42397032)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#short-view-affiliation-1 "Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania."), [John T Keane](https://pubmed.ncbi.nlm.nih.gov/?term=Keane+JT&cauthor_id=42397032)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#short-view-affiliation-1 "Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania."), [Hyeon-Gyu S Lewis](https://pubmed.ncbi.nlm.nih.gov/?term=Lewis+HS&cauthor_id=42397032)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#short-view-affiliation-1 "Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania."), [Fang Liu](https://pubmed.ncbi.nlm.nih.gov/?term=Liu+F&cauthor_id=42397032)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#short-view-affiliation-1 "Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania."), [Shawna K Brookens](https://pubmed.ncbi.nlm.nih.gov/?term=Brookens+SK&cauthor_id=42397032)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#short-view-affiliation-1 "Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania."), [Oula K Dagher](https://pubmed.ncbi.nlm.nih.gov/?term=Dagher+OK&cauthor_id=42397032)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#short-view-affiliation-1 "Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania."), [Kalpana Parvathaneni](https://pubmed.ncbi.nlm.nih.gov/?term=Parvathaneni+K&cauthor_id=42397032)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#short-view-affiliation-2 "Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania."), [Brittany L Gardner](https://pubmed.ncbi.nlm.nih.gov/?term=Gardner+BL&cauthor_id=42397032)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#short-view-affiliation-1 "Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania."), [Amal Ahmed](https://pubmed.ncbi.nlm.nih.gov/?term=Ahmed+A&cauthor_id=42397032)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#short-view-affiliation-1 "Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania."), [Emma E Furth](https://pubmed.ncbi.nlm.nih.gov/?term=Furth+EE&cauthor_id=42397032)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#short-view-affiliation-2 "Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania."), [Priti Lal](https://pubmed.ncbi.nlm.nih.gov/?term=Lal+P&cauthor_id=42397032)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#short-view-affiliation-2 "Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania."), [Avery D Posey Jr](https://pubmed.ncbi.nlm.nih.gov/?term=Posey+AD+Jr&cauthor_id=42397032)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#short-view-affiliation-1 "Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42397032/#short-view-affiliation-3 "Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania.") ### Affiliations * 1 Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. * 2 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. * 3 Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania. * PMID: **42397032** * PMCID: [ PMC13488855 ](https://pmc.ncbi.nlm.nih.gov/articles/PMC13488855/) * DOI: [ 10.1158/2326-6066.CIR-26-0009 ](https://doi.org/10.1158/2326-6066.cir-26-0009) Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID ## Abstract Tumors remodel the extracellular matrix (ECM) and glycosylation, yielding epitopes with restricted or limited detectability in normal adult tissues. In this study, we evaluated the O-glycosylated type III connecting segment domain of fibronectin (Tn-FN) as a chimeric antigen receptor (CAR) T-cell target. FDC6-BBζ CAR T cells recognizing Tn-FN were benchmarked against extra domain B-FN-targeted L19-BBζ and Tn-MUC1-targeted 5E5-BBζ. FDC6-BBζ mediated robust, antigen-dependent activation and cytotoxicity, outperforming L19-BBζ and matching 5E5-BBζ in vitro and in NOD/SCID gamma xenografts of prostate cancer. FDC6-BBζ and 5E5-BBζ CAR T cells achieved durable tumor control with increased intratumoral CD3+ infiltration and reduced tumor-collagen overlap. Cytotoxicity required an intact tumor IFNγ receptor 1 (IFNγR1); L19-BBζ further depended on Fas, whereas FDC6-BBζ and 5E5-BBζ were less Fas-dependent. Tumoral Toll-like receptor (TLR) 2/6 or TLR4 agonism restored FDC6-BBζ killing of IFNγR1-deficient targets and induced broad inflammatory and stress-response programs. Pharmacologic perturbation implicated caspase-dependent mechanisms and a contribution from inflammasome-linked signaling, whereas ferroptosis blockade did not abrogate restored killing. These findings establish Tn-FN as a glycoform-restricted, ECM-derived CAR target and show that innate agonists can reprogram tumor state to overcome resistance from impaired IFNγ signaling. ©2026 American Association for Cancer Research. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement Conflict of Interest Statement T.R.K-P. and A.D.P. are inventors on patents held by the Trustees of the University of Pennsylvania related to chimeric antigen receptor T cell therapies targeting Tn-FN. All other authors declare no potential conflicts of interest. ## Figures [ ![Figure 1.](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4da4/13488855/d749daf192cf/nihms-2194620-f0001.gif) ](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4da4/13488855/7543ad6511da/nihms-2194620-f0001.webp) ** Figure 1.. FDC-6 recognizes the tumor-specific Tn-glycosylated… ** ** Figure 1.. FDC-6 recognizes the tumor-specific Tn-glycosylated IIICS domain of fibronectin. ** **(A)** Schematic of fibronectin… **Figure 1.. FDC-6 recognizes the tumor-specific Tn-glycosylated IIICS domain of fibronectin.** **(A)** Schematic of fibronectin (FN1) highlighting the alternatively spliced EDA, EDB, and IIICS regions; the FDC-6 epitope maps to the IIICS domain and requires Tn O-glycosylation. **(B)** Human prostate tumor tissue microarray (TMA) cores immunostained with FDC-6 mAb. FDC-6 staining was evaluated in 76 evaluable prostate adenocarcinoma cases after exclusion of missing or non-evaluable cores, and representative staining patterns are shown. Staining was classified by compartmental localization of staining within each tissue core. “Tumor only” indicates staining predominantly within malignant epitheli
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