Ancestrally Diverse Autologous Patient-Derived Organoid–Immune Cell Coculture Platform for Addressing Immunotherapeutic Outcome Disparities in High-Grade Endometrial Cancer

High-grade endometrial cancers (HGEC) disproportionately affect women of African ancestry and often resist currently available immunotherapies. Defining the mechanisms driving this resistance is impeded by a lack of preclinical models that preserve ancestral diversity and patient-matched tumor–immune interactions without confounding alloreactivity. To address this gap, we established a biobank of 85 endometrial cancer patient-derived organoids (PDO) from a diverse cohort, enriched for HGEC PDOs from African American patients, and paired these with autologous immune cells to develop a patient-specific PDO–immune cell coculture platform with real-time live-imaging readouts. Using this system, we found that HGECs evade immune surveillance through pronounced suppression of major histocompatibility complex (MHC) class I and II antigen presentation pathways relative to their matched normal counterparts. Restoring antigen presentation, either by IFNγ stimulation or epigenetic reprogramming via enhancer of zeste homolog 2 inhibition, rescued MHC expression and sensitized HGEC PDOs to autologous T cell–mediated cytotoxicity. Extending the platform to NK cells revealed heightened killing of low–MHC-I PDOs. Consistent with clinical observations, mismatch repair (MMR)-deficient HGEC PDOs exhibited stronger immune engagement than their MMR-proficient counterparts. Finally, this platform enabled evaluation of the safety and efficacy of emerging immunotherapies, including protease-activatable bispecific T-cell engagers and EGFR-targeted chimeric antigen receptor T cells. Together, this sustainable, scalable, ancestrally diverse autologous PDO–immune cell coculture platform offers a robust resource for dissecting immune evasion mechanisms and accelerating the development of new immunotherapies to address disparities in endometrial cancer outcomes.