Reprogramming the microenvironment with tumor-selective angiotensin blockers enhances cancer immunotherapy

Proc Natl Acad Sci U S A. 2019 May 28;116(22):10674-10680. doi: 10.1073/pnas.1819889116. Epub 2019 Apr 30.


Cancer-associated fibroblasts (CAFs) can either suppress or support T lymphocyte activity, suggesting that CAFs may be reprogrammable to an immunosupportive state. Angiotensin receptor blockers (ARBs) convert myofibroblast CAFs to a quiescent state, but whether ARBs can reprogram CAFs to promote T lymphocyte activity and enhance immunotherapy is unknown. Moreover, ARB doses are limited by systemic adverse effects such as hypotension due to the importance of angiotensin signaling outside tumors. To enhance the efficacy and specificity of ARBs in cancer with the goal of revealing their effects on antitumor immunity, we developed ARB nanoconjugates that preferentially accumulate and act in tumors. We created a diverse library of hundreds of acid-degradable polymers and chemically linked ARBs to the polymer most sensitive to tumor pH. These tumor microenvironment-activated ARBs (TMA-ARBs) remain intact and inactive in circulation while achieving high concentrations in tumors, wherein they break down to active ARBs. This tumor-preferential activity enhances the CAF-reprogramming effects of ARBs while eliminating blood pressure-lowering effects. Notably, TMA-ARBs alleviate immunosuppression and improve T lymphocyte activity, enabling dramatically improved responses to immune-checkpoint blockers in mice with primary as well as metastatic breast cancer.

Keywords: cancer immunotherapy; drug delivery; tumor microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Angiotensin Receptor Antagonists / therapeutic use*
  • Animals
  • Cell Line, Tumor
  • Drug Delivery Systems
  • Female
  • Hydrogen-Ion Concentration
  • Immunotherapy / methods*
  • Male
  • Mice
  • Neoplasms* / physiopathology
  • Neoplasms* / therapy
  • Polymers / chemistry
  • Tumor Microenvironment / drug effects*


  • Angiotensin Receptor Antagonists
  • Polymers