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Coronavirus disease 2019 (COVID-19), which is known to be caused by the virus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is characterized by pneumonia, cytokine storms, and lymphopenia. Patients with malignant tumors may be particularly vulnerable to SARS-CoV-2 infection and possibly more susceptible to severe complications due to immunosuppression. Recent studies have found that CD209 (DC-SIGN) might be a potential binding receptor for SARS-CoV-2 in addition to the well-known receptor ACE2. However, pan-cancer studies of CD209 remain unclear. In this study, we first comprehensively investigated the expression profiles of CD209 in malignancies in both pan-carcinomas and healthy tissues based on bioinformatic techniques. The CD209 expression declined dramatically in various cancer types infected by SARS-CoV-2. Remarkably, CD209 was linked with diverse immune checkpoint genes and infiltrating immune cells. These findings indicate that the elevation of CD209 among specific cancer patients may delineate a mechanism accounting for a higher vulnerability to infection by SARS-CoV-2, as well as giving rise to cytokine storms. Taken together, CD209 plays critical roles in both immunology and metabolism in various cancer types. Pharmacological inhibition of CD209 antigen (D-mannose), together with other anti-SARS-CoV-2 strategies, might provide beneficial therapeutic effects in specific cancer patients.