Palmitoylation remodels the metastatic niche and drives basal-to-luminal progenitor transition in breast cancer

<title>Abstract</title> <p>Background Distant metastasis is the primary cause of breast cancer-related death. Patients with liver or brain metastases have extremely poor prognoses and low immunotherapy response, highlighting an urgent need for effective therapeutic targets. Palmitoylation, a reversible lipid modification, plays key roles in tumor progression and immune regulation, but its role in breast cancer metastatic niches remains unclear. Methods Single-cell RNA sequencing was used to profile lymph node, liver, and brain metastatic microenvironments. Palmitoylation proteomics identified metastasis-associated targets. Virtual knockout by “scTenifoldKnk” analysis explored key palmitoyltransferases. The inhibitor 2-bromopalmitate (2BP) was tested in 4T1 and MMTV-PyMT mouse models, with single-cell sequencing and flow cytometry assessing therapeutic effects. Results Breast cancer metastatic niches exhibit prominent T cell dysfunction. ZDHHC9, ZDHHC13 and ZDHHC23 were closely associated with liver and brain metastasis. 2BP significantly inhibited tumor growth, enhanced T-cell activation, and improved antigen presentation by macrophages and neutrophils. Single-cell analysis showed that 2BP treatment shifted the tumor niche from basal progenitor to luminal progenitor dominance. Conclusions This study demonstrates that palmitoylation shapes the breast cancer metastatic microenvironment. Targeting palmitoylation reprograms anti-tumor immunity and drives basal-to-luminal progenitor transition, providing a potential therapeutic approach for metastatic breast cancer, particularly liver and brain metastases.</p>