HDAC10 suppresses anti-tumour immunity by inhibiting ILF3-CXCL9 axis to block CD8+ T cell infiltration and activation in bladder cancer.

Although immune checkpoint blockade has offered new hope to patients with bladder cancer, its overall response rate remains modest. In this setting, the quantity and functional status of CD8+T cells largely dictate therapeutic efficacy. Integrative bioinformatics analyses, validated in our institutional tissue cohort, we demonstrated that histone deacetylase 10 (HDAC10) was markedly up-regulated in bladder cancer and inversely correlated with CD8+T cells infiltration. In vivo experiments, using Hdac10-KO cell line, we revealed that Hdac10-KO significantly inhibited tumour growth and promoted the infiltration and activity of CD8+T cells. Mechanically, HDAC10 deacetylated the K342 site of interleukin enhancer-binding factor 3 (ILF3), thereby inducing the ubiquitination and degradation of it by WWP2. This reduced the stability regulation of CXCL9 mRNA by ILF3, decreasing CXCL9 expression and weakening CD8+T cell infiltration and activation. Notably, we found that the probiotic Clostridium butyricum (C.B.) can inhibit the expression of HDAC10 by increasing the short-chain fatty acid butyric acid, thereby sensitizing immunotherapy for bladder cancer in mouse models. This study revealed the specific mechanism by which HDAC10 led to immunotherapy resistance in bladder cancer and proposed potential combined treatment strategies.