Immune checkpoint inhibitors in proofreading-deficient CRC: from molecular basis to clinical practice and future directions.

Immune checkpoint inhibitors (ICIs) have fundamentally reshaped the therapeutic paradigm for metastatic colorectal cancer (mCRC). Beyond the established dMMR/MSI-H population, a molecularly distinct, hyper-immunogenic subset-governed by pathogenic aberrations in the exonuclease domains of -has emerged as a pivotal clinical entity. Characterized by an ultra-hypermutated phenotype, these tumors harbor a mutational load that typically dwarfs the benchmarks established by dMMR/MSI-H malignancies. In this review, we synthesize the molecular underpinnings of 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.