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‐γ‐ 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. The abnormal tumor vasculature and dense tumor stroma constitute a formidable physical barrier that strikingly limits the infiltration of cytotoxic T lymphocytes (CTLs) in tumors. Herein, a stromal‐cell‐accessible bioinspired lipoprotein system loading a reduction‐sensitive nitric oxide donor conjugate of furoxans–oxaliplatin is designed, which profoundly paves the way for CTL infiltration in tumors and synergizes immune‐checkpoint‐inhibitor‐mediated anticancer immunotherapy.