Noteworthily, the M2 skewing of TAMs, radioresistance, activity and ferroptosis resistance of ESCC cells, and the nuclear translocation of β-catenin mediated by MUC1 were blocked upon SIGLEC9 inhibition, signifying the indispensable role of SIGLEC9 in the MUC1-mediated radioresistance and immunosuppressive TME formation. Here, SIGLEC9 is linked to esophageal squamous cell carcinoma.