Clinical features and prognostic impact of POLE/POLD1 mutations in colorectal cancer treated with immunotherapy

POLE/POLD1 mutations are associated with DNA proofreading defects and immunotherapy response in colorectal cancer (CRC), but their comprehensive profile and clinical utility remain incompletely clarified. We enrolled 450 consecutive CRC patients to systematically characterize POLE/POLD1 mutational profiles, their associations with clinicopathological features, immunotherapy efficacy, and survival outcomes, and subsequently developed and validated an integrated prognostic nomogram. The overall POLE/POLD1 mutation frequency was 5.78%, with heterogeneous mutation types and no significant association with core clinical characteristics, TNM stage, or tumor features. Patients with POLE/POLD1 mutations exhibited significantly superior immunotherapy efficacy, with an objective response rate (ORR) of 72.2% versus 27.5% in wild-type patients, and a disease control rate (DCR) of 94.4% versus 71.0% in wild-type counterparts, longer median progression-free survival (16.0 vs. 9.8 months) and overall survival (77.5 vs. 22.7 months) than wild-type patients. Mutations correlated with elevated tumor mutation burden, increased PD-L1 expression, and enhanced tumor-infiltrating lymphocytes, with higher immune-related adverse event (irAE) incidence but lower severe irAE risk. The nomogram integrating POLE/POLD1 mutation and clinical factors showed moderate predictive accuracy (C-index = 0.717) for OS. POLE/POLD1 mutation is a pivotal biomarker independently predicting favorable immunotherapy response and prognosis in CRC, and the established nomogram achieves moderate discriminative capacity for OS prediction, with restricted clinical applicable threshold ranges, which offers auxiliary risk stratification reference for personalized clinical management.