Colorectal cancer (CRC) is the third most common malignancy worldwide and the second leading cause of cancer-related mortality in the United States. The incidence of early-onset colorectal cancer (EOCRC) has been increasing over the past several decades. While the etiologies for this rising incidence remain unclear, genetic factors likely play an important role. DNA polymerase epsilon (POLE) mutations occur at a higher rate than average-onset colorectal cancer (AOCRC). DNA polymerase epsilon (Pol ε) is a high-fidelity, processive polymerase that is a promising target for immune checkpoint inhibitors due to its association with various human malignancies, including colorectal cancer. EOCRC remains a major area of focus, and POLE mutations leading to the high-TMB subtype constitute a potential therapeutic target.