Oligomeric cystatin C supports the immunosuppressive activity of myeloid cells through interaction with inhibitory receptors.

Amyloid proteins are linked to various diseases; however, their functional roles in immunity and cancer remain unclear. Here, we establish a direct link between oligomeric cystatin C-a cysteine cathepsin inhibitor and a well-characterized amyloidogenic protein-within the tumor microenvironment and the immune inhibitory receptors LILRB2 and LILRB5 on myeloid cells. We demonstrated that human LILRB2 and LILRB5, along with their murine counterpart PIRB, serve as functional receptors for cystatin C oligomers. Engagement of these inhibitory receptors by oligomeric cystatin C enhances the immunosuppressive activity of myeloid cells, leading to T-cell suppression and tumor progression. Deletion of the CST3 gene, which encodes cystatin C, in host mice and tumor cells impaired tumor growth, whereas its overexpression accelerated cancer progression in LILRB2 and LILRB5 transgenic mice. Mechanistically, cystatin C-LILRB2 signaling is driven by both canonical phosphatases and the enhanced TGF-β pathway. Additionally, we identified interactions between LILRB receptors and transthyretin oligomers, another amyloid linked to transthyretin amyloidosis, suggesting a broader paradigm of amyloid-LILRB interactions. Our findings reveal an unexpected role of oligomeric cystatin C in enhancing myeloid cell immunosuppression, expand the functional spectrum of amyloid proteins and underscore the importance of these proteins in immune evasion and cancer development.