Macrophages in Tumor‐Associated Adipose Microenvironment Accelerate Tumor Progression

Abstract Adipose‐tissue macrophages (ATMs), a complex ensemble of diverse macrophage subtypes, are prevalent in the tumor‐adipose microenvironment (TAME) and facilitate tumor growth. However, the mechanisms in which the tumor‐adipocyte crosstalk may enable the properties and plasticity of macrophages remain unclear. The single‐cell RNA‐sequence profiling reveals that a subset of macrophages expressed CD163, CCL2, and CCL5 in TAME, exhibiting an immunosuppressive subtype. It is demonstrated that CD163⁺ macrophages aggregate to surround adipocytes in breast cancer tissues. The expressions of CCL2 and CCL5 are also elevated in TAME and enable the recruitment and polarize macrophages. Mechanically, the level of exosomal miRNA‐155 increased in the coculture of tumor cells and adipocytes, and then it promoted the generation and release of CCL2 and CCL5 from adipocytes by targeting the SOCS6/STAT3 pathway. Inhibition of exosomal miRNA‐155 in tumor cells reduced the CCL2 and CCL5 levels in tumor‐adipocytes coculture and further retarded tumor growth. Finally, the deletion of macrophages partially inhibited adipocyte‐induced tumor proliferation. Likewise, inhibiting chemokines and their receptors or suppressing the phosphorylation of STAT3 decreased tumor burden in preclinical models. These results demonstrate that the niche factors in TAME, such as exosomal miRNA‐155, regulate the function and polarity of macrophages to facilitate tumor progression.