Loss of MNX1 Sensitizes Tumors to Cytotoxic T Cells by Degradation of PD‐L1 mRNA

Abstract Immune checkpoint blockade (ICB) therapy, targeting programmed cell death ligand‐1 (PD‐L1)/programmed cell death protein 1 (PD‐1) axis and cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4), has exhibited amazing clinical outcomes in various types of cancers. However, only a small portion of patients benefit from ICB therapy, indicating that the mechanism underlying immune checkpoint is still unclear. Here, it is reported that motor neuron and pancreas homeobox 1 (MNX1), a homeobox domain‐containing transcription factor, contributes to the tumor immune escape. MNX1 increases PD‐L1 expression in cancer cells by stabilizing PD‐L1 mRNA rather than activating transcription. Mechanistically, MNX1 exists in the cytoplasm of cancer cells and interacts with Y‐box binding protein 1 (YBX1), a multifunctional DNA/RNA‐binding protein, to enhance the binding of YBX1 to PD‐L1 mRNA. MNX1 ablation activates cytotoxic T cell‐mediated anti‐tumor immunity and sensitizes CTLA‐4 blockade therapy. Moreover, MNX1 also facilitates tumor progression in an immune‐independent manner in cancer cells. In addition, MNX1 is upregulated by its adjacent long non‐coding RNA MNX1‐AS1 via HECT and RLD domain containing E3 ubiquitin protein ligase 2 (HERC2). Together, these results reveal MNX1 as a novel immune checkpoint regulator with promising therapeutic potential.