Abstract Adoptive T-cell transfer has transformed the treatment landscape for hematological cancers, yet its efficacy against solid tumors remains limited—largely due to inadequate infiltration of vascularly administered T cells into tumor tissue. Since shear-resistant interaction between endothelial E-selectin and its cognate ligand expressed on leukocytes, sialyl Lewis X (sLeX), is an essential prerequisite for extravasation of circulating leukocytes, enhancing this interaction may improve therapeutic delivery. Here, we demonstrate that enforced sLeX display on T cells via surface “exofucosylation” using α1-3-fucosyltransferase (FUT6) significantly boosts their E-selectin binding and homing to tumor microenvironment with detectable E-selectin expression. This enhanced homing translates into potent antitumor activity across diverse murine models of solid tumors and metastatic disease, and restores sensitivity of galectin-3-rich tumors that are otherwise refractory to PD-1 checkpoint blockade. Mechanistically, exofucosylation enables CAR-T cells to overcome anti-PD-1 resistance by preventing galectin-3-mediated disruption of PD-1 antibody engagement. Furthermore, combining adoptive transfer of exofucosylated peripheral CD8⁺ T cells with bispecific T cell engager (BiTE) molecules produces strong synergistic therapeutic effects. Together, these findings establish exofucosylation as a clinically actionable strategy to overcome trafficking bottlenecks and unlock the full potential of adoptive T-cell and BiTE immunotherapies against solid and metastatic cancers. Citation Format: Yingqin Hou, Peng Wu. E-selectin ligand engineering overcomes trafficking barriers to potentiate adoptive T-cell and BiTE therapies abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB137.
Hou et al. (Fri,) studied this question.