Dysregulated inflammation in solid tumor malignancy patients shapes polyfunctional antibody responses to COVID-19...

Solid tumor malignancy (STM) patients experience increased risk of breakthrough SARS-CoV-2 infection owing to reduced COVID-19 vaccine immunogenicity. However, the underlying immunological causes of impaired neutralization remain poorly characterized. Furthermore, non-neutralizing antibody functions can contribute to reduced disease severity but remain understudied within high-risk populations. We dissected polyfunctional antibody responses in STM patients and age-matched controls who received adenoviral vector- or mRNA-based COVID-19 vaccine regimens. Elevated inflammatory biomarkers, including agalactosylated IgG, interleukin (IL)-6, IL-18, and an expanded population of CD11c^-CD21^- double negative 3 (DN3) B cells were observed in STM patients and were associated with impaired neutralization. In contrast, mRNA vaccination induced Fc effector functions that were comparable in patients and controls and were cross-reactive against SARS-CoV-2 variants. These data highlight the resilience of Fc functional antibodies and identify systemic inflammatory biomarkers that may underpin impaired neutralizing antibody responses, suggesting potential avenues for immunomodulation via rational vaccine design.