A pan-cancer single-cell transcriptomic atlas of human bone metastases.

Bone is a common site for cancer metastasis, yet the mechanisms driving human spinal bone metastases (BMs) are poorly understood. Here, we obtained a single-cell RNA sequencing (scRNA-seq) atlas of 62 BMs across 13 different origins, along with paired primary tumor and normal bone marrow. Unsupervised clustering of cancer cell functional programs revealed 3 groups with distinct prognosis and tumor microenvironment. Integrative analysis with large-scale primary and metastatic pan-cancer and healthy bone marrow scRNA-seq datasets revealed SELE-positive endothelial cells, osteoblasts, and osteoclasts associated with cancer cell proliferation. We also identified BM-enriched exhausted CD8+ T cells with increased expression of immune checkpoint genes. In bone metastatic mouse models, a combined anti-PD-1/TIGIT immune therapy effectively suppressed tumor cell proliferation and significantly enhanced the cytotoxic activity of CD8+ T cells. Our results provide a systematic view of the molecular basis of BM and suggest future avenues for immunotherapy optimization for BM patients.