T cell-nanodrug conjugates synchronize vascular normalization and immune activation for solid tumor therapy.

Authors

Xin Yang, Ye Su, Xiaoyun Ye, Changjiang Liu, Xin Zhao, Yuyan Su, Qingyu Dong, Wenxuan Zeng, Xinghua Sui, Xiuman Zhou, Guanyu Chen, Yujia Zhang, Dalin Wu, Juan Liu

Published in

Science advances. Volume 12. Issue 32. Pages eadp2955. Aug 07, 2026. Epub Aug 07, 2026.

Abstract

Adoptive T cell therapy requires T cells to infiltrate vascular tissues and preserve immune function. In solid tumor treatment, however, the surrounding microenvironment produces abnormal vasculature that impedes T cell infiltration. An approach that enables vascular normalization and enhances adoptive T cell function in parallel is essential for effective therapy but has not been reported. Here, we report the use of lenvatinib (LEN) to induce transient vascular normalization, thereby facilitating T cell infiltration. Moreover, LEN enhances T cell persistence by promoting the differentiation of T cells toward a memory phenotype. Our results indicate that the differentiation is by suppressing the PI3K-AKT-mTOR pathway, which drives effector differentiation, and by activating FOXO1, a transcription factor that promotes memory formation. To coordinate the transient vascular normalization and T cell enhancement, we link LEN-loaded, PD-L1-blocking micelles to T cells through acid-labile click chemistry, forming pH-responsive T cell-nanodrug conjugates. The conjugates synchronize the intratumoral release of LEN and the PD-L1 antagonist peptide OPBP-1, thereby coordinating vascular normalization, T cell differentiation, and checkpoint blockade. In vivo, the conjugates increased intratumoral CD8⁺ T cells and splenic memory T cells by over sixfold in B16-OVA tumors and achieved complete regression in a subset of MC38-OVA tumors without systemic toxicity, providing a promising strategy for solid tumor immunotherapy.

PMID:
42566523
Bibliographic data and abstract were imported from PubMed on 08 Aug 2026.

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