Remodeling of T and endothelial cells during total neoadjuvant therapy in rectal cancer

Total neoadjuvant therapy (TNT) is a standard care for locally advanced rectal cancer (LARC), yet the immune remodeling mechanisms underlying its efficacy remain unclear. Using single-cell RNA, T cell receptor, and spatial transcriptome sequencing of matched pre- and post-treatment samples, we depicted the tumor microenvironment (TME) dynamics induced by different neoadjuvant therapies. TNT is associated with reduced regulatory T cells and increased IFNG + CD8 + effector memory T cells with high IFNG expression, potentially contributing to improved complete response rates. The abundance of tumor-infiltrating CD8 + T cells is correlated with the enrichment of the ACKR1 + endothelial subset after TNT. We further validated that endothelial cells (ECs), when stimulated by IFNγ, potentially released by CD8 + T cells, acquire an enhanced ability for presenting antigens and activating CD8 + T cells. Together, our study systematically characterizes the TME dynamics and uncovers the unique interaction between activated CD8 + T cells and ECs after TNT. • Multi-omics unveil distinct tumor microenvironment shifts in neoadjuvant therapies • IFNG + CD8 + Tem cells and ACKR1 + endothelial cells increase following TNT • ACKR1 + ECs recruit and activate CD8 + T cells, and an IFNG - IFNGR loop forms post TNT • IFNG + CD8 + T cell abundance and PBL IFNG signals mark response to TNT Gao et al. characterize the tumor microenvironment dynamics following total neoadjuvant therapy (TNT) in locally advanced rectal cancer using a multi-omics approach. They uncover a unique interaction between IFNG + CD8 + T cells and ACKR1 + endothelial cells, suggesting a potential positive feedback loop mediated by the IFNG - IFNGR axis and enhanced antigen presentation by endothelial cells after TNT.