Immunotherapy response and resistance in endometrial cancer: Integrating molecular subtype, spatial immune states,...

Immunotherapy has reshaped the treatment landscape of endometrial cancer (EC), yet durable benefit remains heterogeneous, particularly outside mismatch repair-deficient disease. Current patient-selection strategies still rely heavily on static baseline biomarkers and often fail to explain non-response at the tissue level.

This review synthesizes current evidence on immunotherapy response and resistance in EC and discusses a constraint-based framework linking TCGA/ProMisE molecular classes to recurring spatial immune states, including inflamed, immune-excluded, and immune-desert phenotypes. Within this framework, resistance can be interpreted through three coupled, tissue-testable barriers: Spatial Access, Priming Competence, and Habitat Fitness. We further outline a pharmacodynamic approach in which paired baseline and early on-treatment biopsies, evaluated using fixed spatial segmentation and prespecified directional criteria, are used to determine whether a regimen has measurably relieved its intended barrier. Dynamic, compartment-aware readouts, such as increased intraepithelial CD8 + engagement, tertiary lymphoid structure maturation, interferon-driven chemokine reinforcement, and vascular-normalization signatures, may help distinguish true mechanism engagement from transient clinical stability.

Together, these principles support a shift from static biomarker assignment toward a more spatially grounded and mechanism-oriented strategy for precision care, resistance interpretation, and future trial design in EC immunotherapy.