"Dominolike" Barriers Elimination with an Intratumoral Adenosine-Triphosphate-Supersensitive Nanogel to Enhance Cancer Chemoimmunotherapy.

Abstract

Pathophysiological barriers in "cold" tumors seriously limit the clinical outcomes of chemoimmunotherapy. These barriers distribute in a spatial order in tumors, including immunosuppressive microenvironment, overexpressed chemokine receptors, and dense tumor mesenchyme, which require a sequential elimination in therapeutics. Herein, we reported a "dominolike" barriers elimination strategy by an intratumoral ATP supersensitive nanogel (denoted as B^BLZ-945@PAC-PTX) for enhanced chemoimmunotherapy. Once it has reached the tumor site, B^BLZ-945@PAC-PTX nanogel undergoes supersensitive collapse triggered by adenosine triphosphate (ATP) in perivascular regions and releases BLZ-945 conjugated albumin (B^BLZ-945) to deplete tumor-associated macrophages (TAMs). Deeper spatial penetration of shrunk nanogel (PAC-PTX) could not only block CXCR4 on the cell membrane to decrease immunosuppressive cell recruitment but also internalize into tumor cells for tumor-killing and T cell priming. The strategy of "dominolike" barriers elimination in tumors enables immune cell infiltration for a potentiated immune response and offers a high-responsive treatment opinion for chemoimmunotherapy.