Innate immune cells constitute the majority of the tumor microenvironment (TME) and mediate anti-tumor immunity and immunotherapy responses. While single-cell T and B cell receptor sequencing have revealed insights into the clonal dynamics of adaptive immunity, the lack of analogous tools has precluded similar analysis of innate immune cells. Here, we describe a method leveraging somatic mitochondrial DNA (mtDNA) mutations to reconstruct clonal lineage relationships between cells in native human tissues. By jointly profiling single-cell chromatin accessibility and mtDNA variants, we resolve clonal dynamics of 218,715 cells from matched tumors, tissues, and blood from patients with lung and ovarian cancers. Clonal tracing reveals that TME-resident myeloid subsets, including macrophages and type 3 dendritic cells (DC3), are clonally related to circulating and tissue-infiltrating monocytes. We further identify distinct DC-biased and macrophage-biased clones, whose circulating monocyte precursors exhibit distinct epigenetic profiles, suggesting intratumoral myeloid differentiation fate may be peripherally programmed before TME infiltration.
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