Redefining the Treatment Landscape of Advanced Endometrial Cancer in the Era of Immunotherapy and Precision Oncology

The therapeutic landscape of advanced and recurrent endometrial cancer (EC) has evolved substantially in recent years due to the integration of molecular classification and novel systemic therapies. This review summarizes current treatment strategies in advanced EC, focusing on immunotherapy, targeted therapies, and molecularly guided approaches. Immune checkpoint inhibitors (ICIs) have become a cornerstone of treatment, particularly in mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) tumors, where durable clinical benefit has been observed. Recent phase III trials demonstrated that the addition of ICIs to platinum-based chemotherapy significantly improves progression-free survival in the first-line setting, especially in dMMR disease, with more modest but clinically meaningful benefit in mismatch repair-proficient (pMMR) tumors. In the post-platinum setting, combinations such as pembrolizumab plus lenvatinib have expanded treatment options for pMMR patients, despite increased toxicity. Advances in molecular profiling, including the ProMisE classification, are increasingly guiding treatment personalization. Emerging therapies, including PARP inhibitors and antibody–drug conjugates targeting HER2 and Trop-2, are showing promising activity. Despite these advances, challenges remain regarding resistance mechanisms, optimal treatment sequencing, and predictive biomarkers beyond MMR status.