Abstract: Disclosed herein are systems, methods, and compositions for treating a subject diagnosed with, or suffering from cancer. In some embodiments, the method comprises determining whether a tumor sample from the subject includes a cytotoxic gene signature, and treating the subject based on the determination. In some embodiments, the subject has or is suspected of having a loss of heterozygosity in human leukocyte antigen (HLA) class I genes. In some embodiments, the therapy comprises one or more checkpoint inhibitors. In some embodiments, the cancer is colorectal, uterine, stomach, lung, skin, head or neck, or non-small cell lung carcinoma.