InVivoMAb anti-mouse IFNAR-1

The proteasome inhibitor bortezomib induces apoptosis in multiple myeloma cells and has transformed patient outcome. Using in vitro as well as in vivo immunodeficient and immunocompetent murine multiple myeloma models, we here show that bortezomib also triggers immunogenic cell death (ICD), characterized by exposure of calreticulin on dying multiple myeloma cells, phagocytosis of tumor cells by dendritic cells, and induction of multiple myeloma-specific immunity. We identify a bortezomib-triggered specific ICD gene signature associated with better outcome in two independent cohorts of patients with multiple myeloma. Importantly, bortezomib stimulates multiple myeloma cell immunogenicity via activation of the cGAS/STING pathway and production of type I IFNs, and STING agonists significantly potentiate bortezomib-induced ICD. Our study therefore delineates mechanisms whereby bortezomib exerts immunotherapeutic activity and provides the framework for clinical trials of STING agonists with bortezomib to induce potent tumor-specific immunity and improve patient outcome in multiple myeloma. SIGNIFICANCE: Our study demonstrates that cGAS/STING-dependent immunostimulatory activity mediates bortezomib anti-myeloma activity in experimental models and associates with clinical response to bortezomib in patients with multiple myeloma. These findings provide the rationale for clinical evaluation of STING agonists to further potentiate anti-multiple myeloma immune response.See related commentary by Zitvogel and Kroemer. ©2021 American Association for Cancer Research.

Zika virus (ZIKV) can traverse the placental barrier, leading to fetal microcephaly and congenital zika syndrome (CZS). The viral E protein mediates host-cell interactions and infection. Here, we demonstrated that cord blood natural killer cell-derived extracellular vesicles (CBNK-EVs) potently inhibit ZIKV infection in vitro without compromising cellular viability. Mechanistically, CBNK-EVs engage ZIKV through ITGB2, a surface-enriched integrin that interacts with the viral E protein, facilitating nanoparticle-virion contact or membrane fusion. This interaction triggers antiviral activity via perforins within extracellular vesicles (EVs), resulting in diminished viral infectivity. Notably, CBNK-EVs not only effectively crossed the placental barrier to protect fetuses from ZIKV-induced pathologies, but also reduced the ZIKV burden in IFN-deficient murine models and decreased CZS incidence and mortality. Additionally, either blockade of ITGB2 with a monoclonal antibody or chelation of Ca2+ with EGTA impaired the anti-ZIKV activity of CBNK-EVs. Collectively, our findings identified CBNK-EVs as natural antiviral nanoparticles that play a pivotal role in curbing ZIKV infection and vertical transmission, offering a promising therapeutic strategy against congenital ZIKV-related complications.

Metabolic signals critically shape innate immune responses. Through pharmacological screening of metabolic pathways, we identified aspartate metabolism as a key regulator of cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling. Genetically or aminooxyacetic acid-mediated (AOA-mediated) pharmacologically reducing aspartate levels markedly potentiated the cGAS-STING pathway, leading to stronger upregulation of type I interferons and interferon-stimulated genes. Mechanistically, disruption of de novo pyrimidine synthesis, a major downstream pathway of aspartate, induced mtDNA replication stress and increased mtDNA double-strand breaks, promoting mtDNA release into the cytosol. Cytosolic mtDNA synergized with cGAS-STING agonists to upregulate Z-DNA binding protein 1 (ZBP1), which recruits RIPK1/3 to sustain IRF3 phosphorylation, forming a positive feedback loop that amplifies innate immune signaling. In immunocompetent mouse models, AOA enhanced the antitumor efficacy of STING agonists, chemotherapy, or radiotherapy, whereas aspartate supplementation abrogated these effects. Consistently, aspartate levels negatively correlated with antitumor immunity in colorectal cancer patient samples. Together, our study identifies aspartate-pyrimidine metabolism as a critical metabolic checkpoint that licenses STING signaling by enabling mtDNA stress to cooperate with agonist stimulation, driving type I interferon-dependent ZBP1 induction and feed-forward amplification of STING signaling, thus offering a promising strategy to enhance antitumor immunity.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging bunyavirus causing severe systemic infection with high mortality rates. Previously, SFTSV RNA was reported in the semen of infected patients, but whether SFTSV infects the male reproductive tract remains unclear. Here we demonstrate that SFTSV exhibits broad tropism for male reproductive organs in mice, resulting in low sperm count and local inflammation. SFTSV infects Leydig cells in the testis, triggering apoptosis, pyroptosis and inflammation, thereby disrupting testosterone production. Single-cell RNA sequencing identified infiltration of CCR2+ and SPP1+ macrophages expressing S100A4, a key driver of epididymal hyperinflammation and fibrosis. An S100A4 inhibitor reduced pathology and mortality in infected mice. Potential male-to-female sexual transmission risk was observed in mice. In infected patients, viral shedding in semen correlated with disease severity and spermatogenic dysfunction, with viral persistence lasting nearly 3 months after symptom onset. These findings suggest a potential risk of sexual transmission and adverse effects on male reproductive health.