Natural killer cells at the interface of tumor immune escape and immunotherapy resistance in endometrial cancer

Abstract

Endometrial cancer (EC) is characterized by significant molecular and immunological heterogeneity, which influences both disease progression and response to therapy. Although immune checkpoint blockade has improved the clinical management of selected EC subtypes, durable responses remain limited in many patients, particularly in tumors with poorly inflamed or mismatch repair-proficient/microsatellite-stable profiles. In this context, natural killer (NK) cells represent an important but still insufficiently explored component of anti-tumor immunity. NK cells can recognize transformed or stressed cells independently of antigen-specific priming, which may be relevant in EC tumors characterized by altered antigen presentation, immune exclusion, or limited T-cell responsiveness. Within the EC tumor microenvironment, NK-cell dysfunction is likely shaped by a complex interplay between defective recruitment, altered receptor–ligand interactions, suppressive cytokine networks, and tumor-driven immune remodeling. These mechanisms may reduce NK-cell cytotoxicity and favor immunoregulatory or tolerance-like phenotypes, some of which resemble programs involved in maternal–fetal immune tolerance. Here, we examine how EC may reshape NK-cell recruitment, phenotype, and function, and discuss how these alterations intersect with molecular tumor heterogeneity, immune escape, and emerging NK-directed therapeutic strategies. Particular attention is given to how NK-directed and NK-complementary approaches, including cytokine-based activation, NK-cell engagers, adoptive NK-cell transfer, chimeric antigen receptor natural killer cell (CAR-NK) platforms, and their integration with immune checkpoint blockade, may help address resistance in EC.