Frontline immunotherapy and immune cold reprogramming across molecular subtypes of advanced endometrial cancer

The management of endometrial cancer (EC) has transitioned from a histopathological model to a framework based on molecular precision. This change is centered on the integration of immune checkpoint inhibitors, which has altered clinical standards for different genomic subsets. For patients with mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumors, PD-1 and PD-L1 blockade has moved from late-line therapy to a frontline standard. Results from the RUBY and NRG-GY018 trials show that combining dostarlimab or pembrolizumab with platinum-based chemotherapy improves survival in patients with untreated advanced disease. Mismatch repair proficient (pMMR) tumors, which make up the majority of cases, remain difficult to treat due to an immune-cold microenvironment. Overcoming this resistance requires combination strategies, such as using anti-angiogenic agents like lenvatinib with immune checkpoint inhibitors, as shown in the KEYNOTE-775 trial. Data from the DUO-E study also suggest that including DNA damage response inhibitors may improve results in pMMR populations. As molecular monitoring via liquid biopsy and the use of antibody-drug conjugates (ADCs) evolve, the personalization of immunotherapy continues to progress. This review examines current clinical evidence and the mechanisms of resistance to define the future of precision medicine in endometrial cancer.