A Phase III Randomized Trial of Radiation +/- Pembrolizumab (MK-3475) for Newly Diagnosed Early Stage High Intermediate Risk Mismatch Repair Deficient (dMMR) Endometrioid Endometrial Cancer

• Patients must have:

‣ Stage I endometrioid endometrial cancer and a combination of age and risk factors as listed below:

• Age \>= 70 and 1 or more risk factors

∙ Age \< 50 and 3 risk factors

⁃ Risk factors:

∙ Myometrial invasion \>= 50%

‣ Lymphovascular space invasion

‣ Grade 2 or 3 OR

⁃ Stage II endometrioid endometrial cancer

• Note: Patients with isolated tumor cells in sentinel lymph nodes are eligible (considered N0i) as long as there is no evidence of micro- or macro-metastases in any lymph nodes

• CT or MRI abdomen or pelvis and either chest X-ray or CT chest demonstrating no evidence of disease outside of the uterus. Imaging can be performed pre-operatively or post-operatively. CT with contrast is the preferred modality. Positron emission tomography (PET)/CT is NOT to be used for any disease assessment or reassessment unless there is documentation that PET/CT is of diagnostic quality equal to CT with contrast

• Patients must have deficient mismatch repair as demonstrated by lack of expression of at least one mismatch repair protein by immunohistochemistry (IHC) and/or evidence of microsatellite instability (MSI) high. The institutional pathology report documenting MMR deficiency must be submitted

• Patients must have undergone surgical staging with at least hysterectomy, removal of cervix, bilateral (if both are present) salpingo-oophorectomy, and either sentinel lymph node assessment or complete pelvic +/- aortic lymphadenectomy. Secondary staging is allowed to determine stage. Patients with isolated tumor cells in sentinel lymph nodes are eligible (considered N0i) as long as there is no evidence of micro- or macro-metastases in any lymph nodes

• Patients must have received no prior therapy for endometrial cancer, including hormonal therapy, chemotherapy, targeted therapy, immunotherapy or radiation therapy

• Age \>= 18

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

• Platelets \>= 100,000/mcl (within 14 days prior to registration)

• Absolute neutrophil count (ANC) \>= 1,500/mcl (within 14 days prior to registration)

• Creatinine =\< 1.5 x laboratory upper limit of normal (ULN) (within 14 days prior to registration)

• Bilirubin =\< 1.5 x ULN (within 14 days prior to registration) (patients with known Gilbert's disease who have bilirubin level =\< 3 x ULN may be enrolled)

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 3 x ULN (within 14 days prior to registration)

• Thyroid stimulating hormone (TSH) within normal limits (TSH \< ULN allowed in euthyroid patients on thyroid replacement therapy)

• Patients must be registered between 1 and 8 weeks after initial (staging) surgery performed for the combined purpose of diagnosis and staging

• Human immunodeficiency virus (HIV) testing is not required by protocol unless clinically indicated. Known HIV positive patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial

• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information