Influenza-associated pulmonary aspergillosis (IAPA) is a severe fungal superinfection affecting critically ill patients with influenza. Current treatments target the causative pathogens but do not address the dysregulated host immune responses that drive morbidity. Host-directed immunotherapies could overcome this treatment gap. Here, we studied the host-pathogen factors driving IAPA using patient samples and an IAPA mouse model. We identified interleukin-1 (IL-1)–mediated inflammation, neutrophil activation, and neutrophil extracellular trap (NET) release as crucial features in IAPA pathogenesis. This inflammation led to an immunological imbalance with defective neutrophil effector functions, including impaired reactive oxygen production (ROS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, thereby impairing the fungal host immune response toward a permissive environment for Aspergillus fumigatus . Blocking the IL-1 receptor with anakinra reduced inflammation and NET release, restored ROS production in neutrophils, and rescued influenza virus–infected mice from invasive pulmonary aspergillosis. Our findings underscore the crucial role of IL-1–driven inflammation in the immunological misfiring that drives IAPA and suggest anakinra as a promising immunomodulatory therapy for patients with IAPA.

Multiple myeloma (MM) is an incurable hematologic malignancy arising from clonal plasma cells, with poor long-term outcomes due to inevitable relapse after conventional therapies. Chimeric antigen receptor (CAR) T-cell immunotherapy targeting B-cell maturation antigen (BCMA) has shown remarkable efficacy in relapsed patients. Conventional CARs employ single-chain variable fragments (scFvs), whereas single-domain antibodies (sdAb or VHHs) offer advantages such as small size, high stability, and potentially reduced immunogenicity. We designed and evaluated a novel anti-BCMA nanoCAR-T based on the VHH Nb17, compared with the conventional scFv-based CAR-T CT103a. Nb17 demonstrated strong BCMA binding and was incorporated into a CAR construct. Both nanoCAR-T and CT103a were generated via lentiviral transduction of primary T cells. Their cytotoxicity, cytokine secretion, degranulation, memory phenotype, and gene expression were assessed in vitro, along with antitumor activity in vivo. Nb17-nanoCAR-T demonstrated specific cytotoxicity, cytokine release (IL-2, TFNa, IFNg), and CD107a degranulation comparable to CT103a. Transcriptomic analysis revealed overlapping pathways between both CARs. Upon rechallenge, both CARs showed enhanced proliferation compared with untransduced T cells. In vivo, Nb17-nanoCAR-T and CT103a eradicated tumors in NSG mice. These findings demonstrate Nb17-nanoCAR-T exhibits potent anti-myeloma efficacy comparable to scFv-based CAR-T, supporting its potential as a promising therapeutic alternative.