DNA polymerase epsilon catalytic subunit (POLE) in cancer: Implications for tumor biology and therapeutic strategies - A comprehensive review.

POLE, the catalytic subunit of DNA polymerase epsilon, is essential for accurate DNA replication and proofreading. While rare, pathogenic POLE variants in the exonuclease domain -both germline and somatic-define ultramutated tumors with high mutational burden and distinctive molecular features. Beyond mutation status, altered POLE expression may independently influence tumor aggressiveness, remodeling of the tumor-immune microenvironment, and prognosis. Germline POLE variants underlie rare hereditary cancer syndromes with early-onset colorectal and extracolonic malignancies, although precise cancer risk estimates and surveillance strategies remain challenging. Clinically, POLE-mutated tumors often show relative resistance to conventional chemotherapy but marked sensitivity to immune checkpoint inhibitors, highlighting opportunities for molecularly guided therapy. Detection of POLE alterations remains challenging due to low mutation frequency, limited coverage of targeted sequencing panels, variants of uncertain significance, and inconsistent testing standards across institutions. Recognizing POLE as a multidimensional biomarker supports integrated molecular-immune stratification, informs potential therapeutic de-escalation, and guides prioritization of immunotherapy. Prospective studies and registry-based analyses are needed to refine risk assessment, optimize management, and maximize the clinical utility of POLE profiling. This review provides a comprehensive and integrative overview of POLE alterations across human cancers, integrating molecular, clinicopathological, and immunological insights with therapeutic implications.