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We read with great interest the recent publication by Aoise et al, titled “Stromal cells modulate innate immune cell phenotype and function in colorectal cancer via the Sialic acid/Siglec axis”.1 The authors provide compelling evidence that stromal cell sialylation, regulated by the sialyltransferase ST6GALNAC6, serves as a key driver of innate immune suppression via the sialic acid/Siglec axis. CMS4 colorectal cancer (CRC) stromal cells, including cancer-associated fibroblasts (CAFs) and tumor-conditioned mesenchymal stromal cells, exhibit high levels of sialylation—even higher than epithelial cancer cells—and induce Siglec-10 expression on macrophages and natural killer (NK) cells. This interaction hinders the phagocytic activity of macrophages and the cytotoxic function of NK cells, both of which are essential antitumor mechanisms within the innate immune system. This work provides valuable insights into the role of stromal cell sialylation in CRC immunosuppression, but several limitations merit discussion to enhance the interpretation and translation of its findings.