Multiple studies have reported a doubling in risk of Coronavirus Disease-2019 (COVID-19) among cancer patients. Here, we examine the potential biological rationale behind this recurrent epidemiological observation. By leveraging large-scale genome-wide transcriptional data of normal and malignant tissues from adults and children, we found evidence of increased expression of SARS-CoV-2 viral entry genes in the cancer state, particularly in respiratory, gastrointestinal, and genitourinary tract tissues, with decreased expression in pediatric vs. adult samples. Additionally, by interrogating the temporal effects of radiotherapy on human peripheral blood mononuclear and mucosal cells, we observed important treatment-related alterations in host innate immunity, specifically type I interferon responses. Overall, cancers enhance expression of critical viral entry genes, and innate viral defenses can be dysregulated transiently during radiation treatments. These factors may contribute to the observed increased susceptibility to SARS-CoV-2 entry and severity of COVID-19 in cancer patients.