ZDHHC9: a promising therapeutic target for triple-negative breast cancer through immune modulation and immune checkpoint blockade resistance

Abstract Background Triple-negative breast cancer (TNBC) is a subtype of breast cancer with limited treatment options and poor prognosis. This study aimed to identify potential therapeutic targets based on the expression profiles of differentially expressed genes (DEGs) in TNBC. Methods The Limma package was used to identify DEGs in TCGA and GEO datasets. Immunohistochemical (IHC) analysis and western blotting were used to determine the expression of ZDHHC9 in TNBC tissues. Flow cytometry assay and tissue immunofluorescence analysis were used to detect infiltration of multiple immune cells in tumor tissue at different levels of ZDHHC9 expression. Results ZDHHC9 was identified as a key factor associated with resistance to ICB therapy through weighted gene co-expression network analysis (WGCNA) and single-cell RNA sequencing (scRNA-seq). Subsequently, immunohistochemical (IHC) analysis and western blotting verified that ZDHHC9 expression was elevated in TNBC cancer tissues and that elevated expression of ZDHHC9 was associated with the poor survival of patients with TNBC. Analysis of data from several public datasets revealed that patients with high ZDHHC9 expression had an increased proportion of Ki-67 + breast cancer cells and tended to be basal-like breast cancer. In addition, in vitro and in vivo experiments demonstrated that high expression of ZDHHC9 significantly predicted the efficacy and responsiveness of immunotherapy in TNBC. Conclusion These findings suggest that ZDHHC9 is a valuable marker for guiding the classification, diagnosis and prognosis of TNBC and developing specific targeted therapies.