IL-8 positive cancer-associated fibroblasts drive breast cancer progression and immune evasion: insights from GWAS and single-cell transcriptomics

Interleukin-8 (IL-8) is a key inflammatory mediator in the tumor microenvironment (TME), where cancer-associated fibroblasts (CAFs) drive breast cancer progression by secreting various cytokines. This study investigates the role of IL-8 positive CAFs in breast cancer pathogenesis and explores their underlying molecular mechanisms. We performed Mendelian randomization (MR) analysis to evaluate the potential causal relationship between IL-8 levels and breast cancer risk using genome-wide association study (GWAS) data. Subpopulations of IL-8 + CAFs were identified through single-cell RNA sequencing from the GSE228499 dataset. The scPagwas algorithm was used to integrate single-cell RNA sequencing data with GWAS data to investigate the relationship between IL-8 + CAFs and breast cancer. Using the BayesPrism package, we performed Bayesian deconvolution to classify patients into high and low IL-8 + CAFs groups for prognostic and therapeutic sensitivity analyses. Cell-cell interactions were examined using the CellChat package. Additionally, in vitro experiments were performed to confirm the pro-tumor effects of IL-8 + CAFs. The MR analysis revealed a causal effect between IL-8 exposure and increased breast cancer risk (OR = 1.251). Compared to IL-8-CAFs, IL-8 + CAFs exhibited a significant association with breast cancer. Survival analysis revealed that patients with high abundance of IL-8 + CAFs experienced a poorer prognosis. Moreover, patients in the high IL-8 + CAFs group were sensitive to most chemotherapy drugs, but demonstrated significant resistance to immunotherapy and immune evasion. Notably, significant interactions were observed between IL-8 + CAFs and various cells within the TME. Patients with high abundance of IL-8 + CAFs presented with increased stromal, immune, and ESTIMATE scores, along with reduced tumor purity scores. In vitro experiments confirmed that IL-8 significantly promoted tumor cell proliferation, colony formation, migration, and invasion. IL-8 + CAFs represent a pivotal cellular subpopulation driving breast cancer progression and immune evasion, highlighting their potential as targets for personalized therapeutic strategies.