Abstract DNA polymerase theta (POLQ) mediates microhomology-mediated end joining and represents a synthetic lethal target for homologous recombination deficient cancers, yet its pan-cancer clinical, immunoregulatory and predictive functions are poorly defined. Multi-omics data from TCGA, GTEx, cBioPortal, TIMER2.0 and GSCA were used for pan-cancer profiling of POLQ expression, mutations, prognosis, immune signatures. Drug sensitivity correlation analysis together with in silico molecular docking simulations were applied to predict potential binding between POLQ and candidate therapeutic agents. Differential gene expression analysis and functional enrichment were further investigated in uterine corpus endometrial carcinoma (UCEC). POLQ was overexpressed in most malignancies, associated with advanced stages and poor survival. Gene amplification drove its upregulation. POLQ expression showed significant correlations with immune cell infiltration, tumor mutation burden, and microsatellite instability. The strong negative correlations between POLQ expression and responses to multiple chemotherapeutic agents, with molecular docking predicted potential direct interactions between vincristine, paclitaxel, docetaxel and the POLQ protein. In UCEC, high POLQ activated DNA replication, cell cycle and ATR-dependent DNA damage pathways. POLQ is a pan-cancer prognostic and therapeutic biomarker. In UCEC, it accelerates tumor progression via DNA damage and cell cycle dysregulation and reshapes immune microenvironment, supporting POLQ-targeted precision immunotherapy especially for endometrial cancer.