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Even though cancer patients are generally considered more susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the mechanisms driving their predisposition to severe forms of coronavirus disease 2019 (COVID-19) have not yet been deciphered. Since metabolic disorders are associated with homeostatic frailty, which increases the risk of infection and cancer, we asked whether we could identify immunometabolic pathways intersecting with cancer and SARS-CoV-2 infection. Thanks to a combined flow cytometry and multiomics approach, here we show that the immunometabolic traits of COVID-19 cancer patients encompass alterations in the frequency and activation status of circulating myeloid and lymphoid subsets, and that these changes are associated with i) depletion of tryptophan and its related neuromediator tryptamine, ii) accumulation of immunosuppressive tryptophan metabolites (i.e., kynurenines), and iii) low nicotinamide adenine dinucleotide (NAD+) availability. This metabolic imbalance is accompanied by altered expression of inflammatory cytokines in peripheral blood mononuclear cells (PBMCs), with a distinctive downregulation of IL-6 and upregulation of IFNγ mRNA expression levels. Altogether, our findings indicate that cancer not only attenuates the inflammatory state in COVID-19 patients but also contributes to weakening their precarious metabolic state by interfering with NAD+-dependent immune homeostasis.