Disrupting Siglec-mediated interactions to develop immunotherapies for cancer treatment

Recent advances in cancer immunotherapy have improved patient outcomes, even in advanced stages of the disease. However, the effectiveness of current cancer immunotherapies remains limited to a small subset of patients because of resistance and an immunosuppressive tumor microenvironment. Research performed during the last years have identified immunosuppressive interactions between sialic acid-containing glycans and sialic acid-binding immunoglobulin-like lectin (Siglec) receptors as a potential new, targetable pathway to overcome resistance to immunotherapy. In addition, activatory Siglecs could be engaged to enhance anti-tumor immunity. In this review, we summarize accumulating preclinical evidence demonstrating the immunosuppressive role of sialoglycan-Siglec interactions in cancer. Additionally, we provide an overview of potential therapeutic strategies aimed at disrupting this immunosuppressive axis, including interventions currently being evaluated in early-phase clinical trials. Preclinical data strongly suggests that disrupting sialic acid-Siglec interactions could significantly improve cancer immunotherapy, in particular by changing the immunosuppressive microenvironment. Further biological understanding is needed to successfully develop new therapeutics. First trials are running that target these interactions and will hopefully inform, which patients are benefitting from this treatment.