ITGA5-expressing tumor cells interact with Schwann cells to drive nerve growth factor-mediated immunosuppression of NK cells.

Perineural invasion (PNI) complicates cancer treatment by promoting tumor spread and immune evasion through interactions between tumor cells and peripheral nerves in the tumor microenvironment (TME). This study investigates the role of tumor cells in PNI and their impact on neuro-immunomodulation. We identified a strong correlation between elevated ITGA5 expression and PNI, both associated with poor clinical outcomes due to their contribution to an immunosuppressive TME. Specifically, high ITGA5 expression in tumor cells increased nerve density and reduced natural killer cell infiltration, facilitating immune evasion. Functional assays revealed that the interaction between ITGA5 on tumor cells and fibronectin (FN1) in the SC extracellular matrix triggers the reprogramming of SCs to a reparative phenotype, enhancing nerve growth factor (NGF) secretion and promoting tumor neurogenesis. Increased NGF suppresses NK cell cytotoxicity by inhibiting interferon-γ, further supporting tumor growth. Additionally, cilengitide significantly improves anti-programmed cell death protein-1 immunotherapy efficacy, offering a potential therapeutic strategy to counteract PNI-driven immunosuppression. This study identifies ITGA5 as a key promoter of tumor invasion into nerves, enhancing NGF release from Schwann cells and altering the immune landscape to favor tumor growth. These findings open new avenues for therapies targeting these interactions in cancer progression.