Immune checkpoint blockade therapy targeting the T cell immune inhibitory receptors (e.g. PD1 and CTLA4) has reinvigorated the field of cancer immunotherapy and demonstrated the power of harnessing the adaptive immune system to fight cancers. However, fundamental challenges and questions remain. Endometrial cancers specifically, are largely resistant to immune checkpoint blockade, while the underlying mechanisms of why T cell-mediated tumor elimination largely fails in EC are not well understood. Endometrial cancer encompasses a number of genetically-distinct diseases characterized by recurrent molecular alterations driving each disease subtype. Specifically, four major molecular subtypes have been identified, including POLE-ultramutated, MSI-high, and microsatellite stable copy-number high (serous-like) and copy number-low (endometrioid) cancers. In MSI-H endometrial cancers specifically, response rates of over 50% to single agent PD-1/PD-L1 blockade have been reported across a number of studies. Unfortunately, in non-MSI-H tumors, responses to immune checkpoint inhibitors have been rather limited, calling for novel combinations. Importantly, a trial of combination of multi-targeted tyrosine kinase inhibitor (TKI) lenvatinib with pembrolizumab (anti-PD1) demonstrated response rates of close to 40% irrespective of MMR status, which established this combination as a new standard of care treatment in metastatic endometrial cancer. Nevertheless, even with these promising findings: 1) A large proportion of patients does not benefit; 2) Predictive biomarkers and mechanisms defining immunotherapy response or resistance remain unknown; and 3) Insights into the mechanistic basis underlying the TKI/anti-PD-1 synergy are desperately needed. There is a growing appreciation that intrinsic tumor genomic features are critical in shaping the composition and phenotype of the immune microenvironment, including the recruitment, infiltration, phenotypes and functional states of tumor infiltrating lymphocytes. Understanding how these features predict response to immune checkpoint blockade will be key to development of novel biomarkers and therapeutic combinations. Citation Format: Dmitriy Zamarin. Immunology of endometrial cancers: Tumor genetics, immune recognition, and immunotherapy response [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA010.