Mechanistic insights into SLAMF8-mediated prostate cancer metastasis via the TLR4-NF-κB pathway.

[BACKGROUND] SLAMF8 functions as a cancer-promoting immune checkpoint and could be targeted for therapy in multiple cancer types. Its effect on the immune microenvironment and metastasis of prostate cancer (PCa) is not well understood.

[METHOD] We analyzed SLAMF8 distribution in PCa and normal tissues using TIMER and examined its role in drug sensitivity and immunotherapy for PCa. The prognostic value and clinical relevance of SLAMF8 in PCa were assessed using multiple datasets. GO, KEGG, and GSEA analyses identified dysregulated pathways in tumors with varying SLAMF8 levels. Tumor purity and immune cell infiltration, and their correlation with SLAMF8 overexpression, were analyzed and confirmed in PCa samples. Additionally, CCK-8, flow cytometry, and transwell assays evaluated the viability, apoptosis, and invasion capacity of SLAMF8-overexpressing PCa cells. Allograft models in C57BL/6 mice were used to study the effects of SLAMF8 overexpression on tumor growth and immune cell infiltration.

[RESULTS] Compared to non-tumor tissues, SLAMF8 was overexpressed in PCa tumors. High SLAMF8 levels are linked to poor distant metastasis-free survival (DMFS), higher Gleason scores (GS), and advanced T stage. SLAMF8 expression in PCa tumors negatively correlates with tumor purity but positively correlates with the infiltration of B cells, T cells, dendritic cells, and macrophages. SLAMF8 overexpression in prostate cancer cells promoted cell growth, lowered apoptosis rates, and boosted invasion in vitro, alongside hastening tumor development in mice. This study demonstrates that SLAMF8 enhances PCa metastasis via the TLR4-NF-κB pathway. SLAMF8 is a potential predictor of distant metastasis and a promising target for PCa immunotherapy.