Engineering tumor hypersusceptibility to checkpoint immunotherapy

Abstract

The immune checkpoint blockerpembrolizumab(Keytruda)hasproven successful in treating solidtumors harboring a DNA mismatchrepair (MMR) deficiency. We showthat it is possible to generate adrug-promoted phenotype mim-icking the MMR deficiency in solidtumors, and thereby to engineer ageneric hypersusceptibility to Key-truda through drug-induced meta-bolic stress on DNA synthesis. Thepotential of such drug–Keytrudacombinations as universal treat-ments for solid tumors deserves clinical evaluation.