Background: A potential limitation to the use of immune checkpoint inhibitors in younger patients with immune-resistant histologies is related to low tumor associated antigen expression and an immunosuppressive microenvironment. Low dose decitabine, as an inhibitor of DNA methyltransferase, can unrepress immunogenic cancer testes antigen expression, while hypofractionated radiation promotes infiltration of immune effector cells, stimulation of toll-like receptors on dendritic cells, and induction of type I interferons and other cytokines. As induced PD-L1 expression may also result, we hypothesize that decitabine, radiation, and the PD-1 inhibitor, pembrolizumab, will be synergistic. Here, we aim to verify the safety and preliminary activity of the combination. Correlative studies include an investigation of changes in antigen expression, the kinetics of immune effector and regulatory cell phenotype and function, and microbiome. Methods: Treatment program: Every 28 day cycle, patients receive 10 mg/m² IV decitabine on days 1-5 and 2 mg/m² (max dose 200 mg) IV pembrolizumab on day 8. Hypofractionated radiation (8 Gy x 3) to one or more lesion(s) is given on days 5-7 of the second cycle only. Adult patients may consent to optional biopsy of an irradiated lesion. Beyond cycle 3, patients may undergo elective surgery of one or more lesions. Patients remain on therapy for 27 cycles, absent progression by irRECIST or unacceptable toxicity. Patient eligibility: Patients 12 months to 40 years with available archived tissue may be considered, and must have adequate organ function including an absolute neutrophil count ≥ 750/mm³ and platelet count ≥ 75,000/mm³. Patients may have stable central nervous system metastases. Patients previously treated with radiotherapy may be eligible. Patients previously treated with PD-1 inhibitor therapy may be eligible, unless treated for an immune related adverse event. Current enrollment: This trial has been open to enrollment since February of 2018. No dose limiting toxicities have been observed in 2 patients evaluable for toxicity. Clinical trial information: NCT03445858