Engineering CAR-T cells to remodel the mucin-rich cancer cell glycocalyx
- 1Massachusetts General Hospital and Harvard Medical School
Abstract
The dense glycocalyx of cancer cells can restrict immune-cell access to surface antigens and limit CAR-T cell activity. Here, we show that mucin density and epitope position determine how glycocalyx remodeling affects CAR-T cell recognition and killing. We identify KLK5 as a human protease that cleaves tumor-associated mucins, increases access to membrane-proximal antigens, and enhances CAR-T cell function. We then engineer CAR-T cells to display or secrete KLK5, enabling remodeling of the tumor glycocalyx during antigen recognition. KLK5-engineered CAR-T cells improved tumor control across multiple xenograft models, and KLK5-secreting MUC17 CAR-T cells produced the strongest in vivo benefit, prolonging survival compared with conventional MUC17 CAR-T cells. These findings show that CAR-T cells can be engineered to breach the mucin-rich glycocalyx while preserving accessible target epitopes.
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BibTeX
@misc{park2026engineering,
title = {{Engineering CAR-T cells to remodel the mucin-rich cancer cell glycocalyx}},
author = {S. Park and C. Ho and A. N. Wolff and Y. Fan and A. A. Bouffard and J. Paek and A. Mucci and T. R. Berger and M. J. Paszek and M. V. Maus},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.25.754490},
url = {https://www.biorxiv.org/content/10.64898/2026.09.25.754490v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Engineering CAR-T cells to remodel the mucin-rich cancer cell glycocalyx
AU - S. Park
AU - C. Ho
AU - A. N. Wolff
AU - Y. Fan
AU - A. A. Bouffard
AU - J. Paek
AU - A. Mucci
AU - T. R. Berger
AU - M. J. Paszek
AU - M. V. Maus
PY - 2026
DA - 2026/09/25
PB - bioRxiv
DO - 10.64898/2026.09.25.754490
UR - https://www.biorxiv.org/content/10.64898/2026.09.25.754490v1
AB - The dense glycocalyx of cancer cells can restrict immune-cell access to surface antigens and limit CAR-T cell activity. Here, we show that mucin density and epitope position determine how glycocalyx remodeling affects CAR-T cell recognition and killing. We identify KLK5 as a human protease that cleaves tumor-associated mucins, increases access to membrane-proximal antigens, and enhances CAR-T cell function. We then engineer CAR-T cells to display or secrete KLK5, enabling remodeling of the tumor glycocalyx during antigen recognition. KLK5-engineered CAR-T cells improved tumor control across multiple xenograft models, and KLK5-secreting MUC17 CAR-T cells produced the strongest in vivo benefit, prolonging survival compared with conventional MUC17 CAR-T cells. These findings show that CAR-T cells can be engineered to breach the mucin-rich glycocalyx while preserving accessible target epitopes.
ER -