Engineering CAR-T cells to remodel the mucin-rich cancer cell glycocalyx.

Authors

Sangwoo Park, Cassidy Ho, Alexandra N Wolff, Yueyang Fan, Amanda A Bouffard, Justin Paek, Adele Mucci, Trisha R Berger, Matthew J Paszek, Marcela V Maus

Published in

bioRxiv : the preprint server for biology. Sep 27, 2026. Epub Sep 27, 2026.

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.

PMID:
42818058
Bibliographic data and abstract were imported from PubMed on 01 Oct 2026.

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