Importantly, the administration of 12C8 inhibited CD147‐K148me2‐mediated CCL5 increase and the CCL5/CCR5 axis‐dependent intercellular crosstalk between tumor cells and macrophages, which decreased the infiltration of M2‐TAMs in tumor tissues and showed a notable anti‐tumor effect in in vivo tests. Here, CCL5 is linked to neoplasm.