The immune checkpoint blocker pembrolizumab (Keytruda) has proven successful in treating solid tumors harboring a DNA mismatch repair (MMR) deficiency. We show that it is possible to generate a drug-promoted phenotype mimicking the MMR deficiency in solid tumors, and thereby to engineer a generic hypersusceptibility to Keytruda through drug-induced metabolic stress on DNA synthesis. The potential of such drug-Keytruda combinations as universal treatments for solid tumors deserves clinical evaluation.