Lnc-H19-derived protein shapes the immunosuppressive microenvironment of glioblastoma

The immunosuppressive tumor microenvironment (TME) is a prominent feature of glioblastoma (GBM), the most lethal primary brain cancer resistant to current immunotherapies. The mechanisms underlying GBM-TME remain to be explored. We report that long non-coding RNA (LncRNA) H19 encodes an immune-related protein called H19-IRP. Functionally separated from H19 RNA, H19-IRP promotes GBM immunosuppression by binding to the CCL2 and Galectin-9 promoters and activating their transcription, thereby recruiting myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), leading to T cell exhaustion and an immunosuppressive GBM-TME. H19-IRP, overexpressed in clinical GBM samples, acts as a tumor-associated antigen (TAA) presented by major histocompatibility complex class I (MHC-I). A circular RNA vaccine targeting H19-IRP (circH19-vac) triggers a potent cytotoxic T cell response against GBM and inhibits GBM growth. Our results highlight the unrevealed function of H19-IRP in creating immunosuppressive GBM-TME by recruiting MDSCs and TAMs, supporting the idea of targeting H19-IRP with cancer vaccine for GBM treatment.