Immune Checkpoint Inhibitors: Sculpting the Landscape of Endometrial Cancer Treatment

Background: Outcomes for advanced or recurrent endometrial cancer (EC) remain poor, with historically limited systemic options beyond platinum-based chemotherapy. EC is uniquely immunotherapy-amenable among solid tumors: it harbors the highest prevalence of mismatch repair deficiency (dMMR) and microsatellite instability-high (MSI-H) status of any cancer, and its molecular classification into four major molecular subtypes defines a spectrum of tumor mutational burden, neoantigen load, and immune infiltration that predicts the response to checkpoint blockade. Current Landscape: Over the past several years, multiple programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have received regulatory approval in EC, spanning monotherapy in dMMR/MSI-H disease, combination with carboplatin–paclitaxel in the first-line advanced setting, and combination with anti-angiogenic therapy in biomarker-unselected recurrent disease, fundamentally altering the standard of care. Scope and Objectives: This narrative review synthesizes the molecular rationale for checkpoint inhibition in EC, including the biological basis of its molecular subtypes and their immune microenvironments, and provides a focused overview of the trial evidence supporting each major checkpoint inhibitor class, including PD-1 inhibitors, PD-L1 inhibitors, cytotoxic T-lymphocyte-associated protein 4 inhibitors, and emerging targets. We further review the landscape of ongoing trials addressing unresolved questions, including chemotherapy-free regimens in dMMR disease, maintenance intensification for mismatch repair-proficient (pMMR) disease, neoadjuvant and fertility-sparing approaches, and novel combinations. This review aims to provide a comprehensive, up-to-date synthesis of this rapidly evolving field and to identify challenges and opportunities that will shape the next phase of immunotherapy in EC.