Comprehensive genomic profiling of triple-negative breast cancer metastases identifies role of PKD1 in immunotherapy resistance.

The multi-omics data represented by genomic data from patients with metastatic triple-negative breast cancer (TNBC) is crucial for precision treatment, yet data on genomic alterations in metastatic cohorts and Chinese populations remains limited. We performed targeted sequencing of 296 metastatic TNBC samples from 296 patients treated at Fudan University Shanghai Cancer Center (October 2018 to November 2020) using a 484-gene panel, identifying 796 metastatic events across 18 organ sites. We characterized the genomic landscape of TNBC metastases and identified marked enrichment of polycystin-1 (PKD1) mutations in metastatic lesions - a finding validated in an independent paired primary metastasis cohort (n = 105). Notably, PKD1 mutations were associated with resistance to anti-PD-1 therapy, as validated across 3 clinical trials (NCT03805399, NCT04129996, and NCT04395989). Multi-omics analyses, combined with functional in vitro and in vivo mechanistic studies, revealed that PKD1 modulated the "desert" tumor immune microenvironment via C-C motif chemokine ligand 2 (CCL2), and targeting CCL2 could reverse immunotherapy resistance. This comprehensive genomic characterization of metastases enhances our understanding of tumor evolution, identifies PKD1 as a previously uncharacterized regulator of immune evasion to our knowledge, and suggests a potential therapeutic strategy to overcome immunotherapy resistance.