Abstract: Presented are methods of assessing a deficit in DNA damage repair capability in cancer cells. Cancer cells having this DNA damage repair phenotype have increased susceptibility to certain treatments, including genotoxic treatments, treatment with PARP1 inhibitors, and immunotherapies. The methods encompass the use of novel gene expression signatures that enable facile and rapid determination of the DNA damage repair phenotype in cancer cells of a sample. By these methods, subjects having cancer that is amenable to genotoxic treatment, PARP1 inhibition, or immunotherapy may be identified and administered a suitable treatment. Also disclosed is a method of inducing the DNA damage repair deficit phenotype in cancer cells to sensitize them to various treatments.