Tumor-associated neutrophils promote breast cancer progression via RLN2/RXFP1-C6orf99-STAT3 axis

Tumor-associated neutrophils (TANs) play a critical role in breast cancer progression. This study demonstrated that high CD66b⁺ TANs infiltration correlated with poor disease-free survival (DFS) and promoted proliferation, migration, and invasion of breast cancer cells in vitro. Conversely, the immune-related long non-coding RNA C6orf99 was downregulated in breast cancer and associated with favorable DFS. Functional assays revealed that C6orf99 suppressed tumor growth and metastasis by inhibiting STAT3 phosphorylation. Mechanistically, TANs-derived RLN2 downregulated C6orf99 through the RXFP1 receptor, thereby phosphorylating STAT3. Clinically, C6orf99 expression negatively correlated with TANs density and phospho-STAT3 levels in breast cancer tissues. These findings highlight the critical role of TANs in breast cancer progression through the regulation of C6orf99, offering potential therapeutic targets to disrupt the RLN2/RXFP1-C6orf99-STAT3 axis in breast cancer.