Immune checkpoint inhibitors in <i>POLE/POLD1</i> proofreading-deficient CRC: from molecular basis to clinical practice and future directions

deficiency, emphasizing a "threshold effect" where extreme neoantigen density triggers a self-reinforcing inflammatory loop, fundamentally reshaping the tumor immune microenvironment (TIME). To ensure a robust synthesis of the field, a systematic literature search was conducted using the PubMed and Web of Science databases until December 2025, with additional manual screening of reference lists from key studies. Our analysis underscores superior, often durable, responses in this subgroup, while addressing a formidable obstacle: the interpretation of Variants of Uncertain Significance (VUS). We highlight the critical need to distinguish passenger mutations from true proofreading defects, as therapeutic benefit is strictly tethered to functional pathogenicity. Finally, we propose an integrated biomarker framework that moves beyond binary genomic screening toward a functional hierarchy of polymerase variants, providing a definitive roadmap for the next generation of precision immunotherapy in colorectal cancer.