Siglec15, short for sialic acid-binding immunoglobulin-like lectin 15, is a molecule of significance in immunology and cancer biology. It is highly prevalent in numerous solid tumor tissues and tumor-associated macrophages (TAMs), and is up-regulated across various cancer types. Siglec15 is involved in immune evasion, as it can repress T lymphocyte activation and proliferation, facilitating tumor cell immune escape. It is also implicated in osteoclast differentiation and bone remodeling [3].

In bladder cancer, high Siglec15 expression creates a non-inflamed tumor microenvironment (TME), negatively correlating with immunomodulators, tumor-infiltrating immune cells (TIICs), and other immunological factors. Bladder cancer with high Siglec15 expression is less sensitive to cancer immunotherapy but may respond better to anti-angiogenic and certain targeted therapies. An immune risk score (IRS) related to Siglec15 can predict prognosis and response to immunotherapy [1].

In breast cancer, osteoclast-derived apoptotic bodies inhibit naive CD8+ T cell activation via Siglec15, promoting secondary metastasis, and treatment with Siglec15 neutralizing antibodies reduces secondary metastases [2].

In anaplastic thyroid cancer, anti-Siglec15 antibody treatment increases the cytotoxic ability of CD8+ T cells, inhibits tumor growth, and prolongs mouse survival [4].

In hepatocellular carcinoma, Siglec15 promotes immune evasion by inducing CD8+ T cell apoptosis, and its inhibition can reinvigorate CD8+ T cell cytotoxicity [5].

In pancreatic cancer, Siglec15+ tumor-associated macrophages present an M2-like phenotype, accelerating tumor growth and immunosuppressive microenvironment, and SYK inhibitor can abolish this effect [6].

In bladder cancer, overexpression of Siglec15 reduces CD8+ T cell infiltration, inhibits effector T cell cytotoxicity, and promotes resistance to immunotherapy [7].

In conclusion, Siglec15 plays a crucial role in immune evasion across multiple cancer types, mainly by suppressing T-cell function. The use of gene knockout or other loss-of-function models in these studies has revealed its role in promoting tumor growth and metastasis, and resistance to immunotherapy in various cancers, suggesting Siglec15 as a potential target for cancer immunotherapy.