Single-Cell Phylogenetic Tracing Maps the Landscape of Human Tumor Immune Cell Plasticity Driven by Microenvironment Factors-Mediated Epigenetic Reprogramming

Abstract

The tumor microenvironment harbors a complex ecosystem of immune cells, the heterogeneity of which has been extensively characterized, yet the developmental trajectories and plasticity of these populations remain poorly understood. Here, by integrating mitochondrial DNA mutations and chromosomal single-nucleotide polymorphisms inferred from single-cell RNA sequencing data, we established a robust lineage tracing framework to precisely reconstruct phylogenetic relationships among immune cells at single-cell resolution across multiple human cancers. This approach enabled us to systematically map the dynamics within the tumor immune landscape, revealing extensive plasticity including transitions between immune cell subtypes, transdifferentiation across lineages, and dedifferentiation toward progenitor states--all occurring with cancer-type specificity. Tumor microenvironment extrinsic factors were identified as key drivers of this plasticity, directing both the acquisition of transitional states and the orientation of fate changes. Mechanistically, these plasticity events were governed by profound epigenetic reprogramming, with global remodeling of chromatin accessibility and DNA methylation patterns underlying identity shifts. Our study provides a comprehensive atlas of immune cell plasticity in human tumors, establishes the molecular principles governing these dynamic processes, and reveals new opportunities for therapeutic intervention through manipulation of immune cell state or fate decisions.