Bioinspired Lipoproteins of Furoxans-Oxaliplatin Remodel Physical Barriers in Tumor to Potentiate T-Cell Infiltration

The infiltration of cytotoxic T lymphocytes (CTLs) in tumors is critically challenged by the intricate intratumor physical barriers, which is emerging as an important issue of anticancer immunotherapy. Herein, a reduction-sensitive nitric oxide donor conjugate of furoxans-oxaliplatin is synthesized and a stroma-cell-accessible bioinspired lipoprotein system (S-LFO) is designed, aiming to facilitate CTL infiltration in tumors for anticancer immunotherapy. S-LFO treatment significantly promotes tumor vessel normalization and eliminates multiple components of tumor stroma, ultimately producing a 2.96-fold, 5.02-fold, and 8.65-fold increase of CD3(+)CD8(+) T cells, their interferon-gamma- and granzyme B-expressing subtypes when comparing to the negative control, and considerably facilitating their trafficking to the cancer cell regions in tumors. Moreover, the combination of S-LFO with an antiprogrammed death ligand-1 produces notable therapeutic benefits of retarded tumor growth and extends survivals in three murine tumor models. Therefore, this study provides an encouraging strategy of remodeling the intratumor physical barriers to potentiate CTL infiltration for anticancer immunotherapy.

Automated summary

In this study, a reduction-sensitive nitric oxide donor conjugate of furoxans-oxaliplatin was synthesized and a stroma-cell-accessible bioinspired lipoprotein system (S-LFO) was designed to facilitate CTL infiltration in tumors for anticancer immunotherapy. The S-LFO treatment promoted tumor vessel normalization, eliminated components of tumor stroma, increased the number of CD3(+)CD8(+) T cells, and facilitated their trafficking to cancer cell regions in tumors. Additionally, the combination of S-LFO with an antiprogrammed death ligand-1 showed therapeutic benefits of retarded tumor growth and extended survivals in three murine tumor models.