Enzyme-activated orthogonal proteolysis chimeras for tumor microenvironment-responsive immunomodulation

Abstract

We present a novel tumor microenvironment (TME)-responsive enzyme-activated clickable PROTACs, enabling the in situ formation of heterobifunctional degraders to disrupt epigenetic BRD4 proteins in the tumor only. Such clickable-PROTACs exhibit promising selectivity and superior penetration in tumors, effectively downregulating PD−L1 expression both in vitro and in vivo, offering potential for immunotherapy against tumor growth. Graphical abstract: [Figure not available: see fulltext.]