Tumor microenvironment-activated angiotensin blockers enhance cancer immunotherapy

Cancer-associated fibroblasts (CAFs) suppress anti-tumor immunity mediated by T-lymphocytes – making CAFs tempting targets for enhancing cancer immunotherapy. Unfortunately, the signaling mechanisms driving CAF activity in tumors have crucial functions outside tumors. Consequently, agents like angiotensin receptor blockers (ARBs) that inhibit CAF activity are limited by systemic adverse effects such as hypotension. To address this challenge, we developed tumor microenvironment-activated ARBs (TMA-ARBs) by chemically linking ARBs to novel polymeric materials that selectively degrade in the tumor microenvironment. TMA-ARBs remain in an inactive, material-bound state until they reach tumors, wherein the ARBs become active as the materials break apart. This tumor-selective activity enhances the CAF-inhibiting effects of ARBs while eliminating blood pressure-lowering effects. By reducing CAF activity, TMA-ARBs induce a comprehensive immunostimulatory shift in the tumor microenvironment with improved T-lymphocyte activity and distribution. Accordingly, TMA-ARBs dramatically increase animal survival when combined with immunotherapy in mice with metastatic breast cancer. 5 control samples, 5 TMA-ARB treated samples