Exosome RAB10 inhibits JAK1/STAT1 to hinder macrophage M1 polarization and promote tumor immune escape.

Exosomes are key mediators of communication between tumor cells and the tumor microenvironment(TME); however, the mechanisms underlying exosome-mediated crosstalk between tumor cells and macrophages remain largely unclear. This study investigated the effect of exosomal RAB10 on macrophage polarization and tumor growth. Mechanistically, RAB10 delivered by breast cancer cells binds to the interferon receptor IFNAR1 and inhibits JAK1/STAT1 pathway phosphorylation, thereby impeding M1 polarization and promoting M2 polarization. RAB10 expression was significantly upregulated in drug-resistant breast cancer cells and was correlated with poor patient prognosis. In vitro assays confirmed that RAB10 enhances cancer cell proliferation. In vivo knockdown of RAB10 suppressed tumor growth and reduced the expression of markers related to proliferation (Ki67, PCNA), invasion (MMP2), and epithelial-mesenchymal transition (Snail, Vimentin). Single-cell RNA sequencing revealed a marked decrease in the proportion of macrophages in the TME following RAB10 knockdown. This phenotypic shift increases the secretion of immunosuppressive factors such as PDL1, leading to reduced activity of CD8⁺ T cells. Animal studies further confirmed that combined targeting of RAB10 and PD-L1 produces a synergistic inhibitory effect on tumor growth. This study demonstrated that breast cancer cells can transfer RAB10 to macrophages via exosomes. RAB10 interacts with IFNAR1 to suppress the JAK1/STAT1 signaling pathway, thereby inhibiting M1 polarization and promoting M2 polarization of macrophages. Inhibition of RAB10, especially in combination with PD-L1 blockade, offers a promising strategy to enhance anti-tumor immunity and overcome therapeutic resistance in breast cancer.