LINC01004-SPI1 axis-activated SIGLEC9 in tumor-associated macrophages induces radioresistance and the formation of immunosuppressive tumor microenvironment in esophageal squamous cell carcinoma

Radioresistance and immunosuppression remain the major obstacles in the anti-cancer treatments. This work studies the functions of sialic acid binding Ig like lectin 9 (SIGLEC9) and its related molecules in radioresistance and immunosuppression in esophageal squamous cell carcinoma (ESCC). The single-cell analysis showed that SIGLEC9 was mainly expressed on tumor-associated macrophages (TAMs). Monocytes-derived macrophages were co-cultured with ESCC cells and subjected to radiotherapy. High or low doses of radiotherapy induced SIGLEC9 upregulation and M2 polarization of TAMs. Artificial inhibition of SIGLEC9 in TAMs suppressed the radioresistance and immunosuppressive tumor microenvironment (TME) in the co-cultured ESCC cells. Upstream molecules of SIGLEC9 were predicted via bioinformatics. LINC01004 recruited Spi-1 proto-oncogene (SPI1) in nucleus of TAMs to induce transcriptional activation of SIGLEC9. SIGLEC9 interacted with mucin 1 (MUC1). MUC1 overexpression in ESCCs induced M2 skewing of TAMs, enhanced radioresistance and immunosuppression, and promoted nuclear translocation of β-catenin to suppress radiotherapy-induced ferroptosis of ESCC cells. These effects were blocked upon SIGLEC9 suppression. In vitro results were reproduced in the animal models with xenograft tumors. Taken together, this study demonstrates that the LINC01004-SPI1 axis-activated SIGLEC9 in TAMs induces radioresistance and the formation of immunosuppressive TME in ESCC.