Coordinated post-transcriptional regulation facilitates PD-L1 protein production and tumor immune suppression

PD-L1 drives T cell exhaustion and tumor immune evasion and is transcriptionally induced by immune cell-derived IFN-γ. Here, we find that the RNA-binding protein PUM1 recognizes a conserved 3'UTR motif in PD-L1 and is itself induced by IFN-γ. In PUM1-deficient cells, PD-L1 fails to accumulate with IFN-γ stimulation, revealing that IFN-γ also regulates PD-L1 through PUM1-mediated post-transcriptional mechanisms. Mechanistically, we identify HNRNPA2B1 as a direct competitor of PUM1 for PD-L1 mRNA binding, thereby controlling RNA stability and protein expression. In syngeneic colon cancer models, PUM1 deficiency reduces PD-L1, slows tumor growth, and enhances CD8⁺ T cell infiltration, whereas HNRNPA2B1 depletion restores PD-L1 and suppresses CD8⁺ T cells. Mutation of the endogenous PUM1-binding site similarly reduces PD-L1 and restrains tumor progression. Consistently, single-cell analysis of colorectal tumors shows PUM1 positively correlates with PD-L1 and inversely with CD8⁺ T cell infiltration. Together, our study defines a novel IFN-γ-responsive post-transcriptional regulation that controls PD-L1 expression and tumor immune suppression.