POLE and POLD1 are genes that encode for the catalytic subunits of DNA polymerases epsilon and delta, respectively. These polymerases are involved in DNA replication and repair and possess proofreading abilities to correct errors during DNA synthesis. Mutations in these genes can lead to a proofreading deficiency, resulting in a high number of mutations within the genome, a condition referred to as ‘ultramutated’. Colorectal cancers (CRC) with POLE or POLD1 proofreading deficiencies (POLE/D1pd) are characterized by a very high mutation burden, which is much higher than typically observed in other forms of CRC. Mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancers are also characterized by a high number of mutations. Still, these arise due to defects in the mismatch repair system, which is different from the proofreading deficiencies of POLE and POLD1. The high mutation burden in both dMMR/MSI-H and POLE/D1pd tumors can lead to the production of neoantigens, which are novel protein sequences that the immune system can recognize as foreign, potentially making these tumors more responsive to immune checkpoint inhibitors (ICIs). ICIs are a class of drugs that block proteins cancer cells use to avoid being attacked by the immune system. By inhibiting these proteins, ICIs can enhance the immune response against cancer cells. The most commonly targeted proteins by ICIs are PD-1, PD-L1, and CTLA-4. While dMMR/MSI-H mCRCs have been shown to respond well to ICIs, the response of POLE/D1pd mCRCs to these therapies has been less clear due to the rarity of this condition. However, the high mutational burden suggests they may also be sensitive to ICIs. Given the rarity of these mutations, there may not be extensive data or large clinical trials that specifically address the efficacy of ICIs in POLE/D1pd mCRCs. However, ongoing research and initial studies are are exploring this topic. Picture by freepik, https://www.annalsofoncology.org/article/S0923-7534(24)00104-2/fulltext?rss=yes