<p>Lead exposure is of high prevalence, and over a billion people are chronically exposed to alarming level of lead. Human immune system is highly vulnerable to lead, but the underlying mechanism remains unknown. Using single-cell mass cytometry and mass spectrometry-based proteomics, we performed a panoramic survey of lead targets at both cellular and molecular levels in murine immune system upon chronic lead exposure. We produced a single-cell landscape of lead, thiol metabolism and lead-induced toxicity across all immune cell types. We found that immune cells with extreme thiol metabolism are the most sensitive upon chronic lead exposure. It shows that CD4 + T cells and neutrophils are the most sensitive to lead, which is due respectively to a molecular mechanism rooted in their characteristic thiol metabolic capacity. Meanwhile, we found that lead accumulation by RBC further inflicted secondary toxicity to RBC phagocytes in spleen, e.g. macrophages and neutrophils. Unlike CD4 + T cells, which can be rescued by supplementation with thiol chelator, lead toxicity in these phagocytes cannot be effectively mitigated by thiol chelators. Overall, it forms a multiscale panoramic lead-immune system interactome upon chronic lead exposure, which provides valuable information for proactive prevention, therapy formulation and public health evaluation.</p> Graphical abstract <p>Graphical headlights<UnorderedList Mark="Bullet"> <ItemContent> <p>Established a lead-immune system interactome across cellular and molecular level.</p> </ItemContent> <ItemContent> <p>Thiol metabolic heterogeneity leads to diversified molecular mechanisms of toxicity in different immune cells.</p> </ItemContent> <ItemContent> <p>Thiol chelator can only mitigate lead toxicity in CD4 + T cells but not splenic RBC phagocytes.</p> </ItemContent> <ItemContent> <p>PKC-like, PE/DAG-binding proteins are potential targets of immune activation retardation upon lead exposure.</p> </ItemContent> </UnorderedList></p> <p></p>