AbstractBackgroundBladder cancer (BLCA) is one of the most diagnosed cancers in humans worldwide. Recently, immunotherapy has become a main treatment option for BC. However, most BLCA patients do not respond to immune checkpoint inhibitors or relapse after immunotherapy. Therefore, it is very important to identify novel biomarkers for the prediction of immunotherapy response in B patients.MethodsPancancer single‐cell RNA sequencing (scRNA‐seq) data were used to identify the clusters of CD4+T cells in the tumour microenvironment (TME). The clinical significance of key CD4+T‐cell clusters was evaluated based on the survival data of two independent immunotherapy bladder cancer (BLCA) cohorts. We also investigated the function of key clusters of CD4+T cell in the TME of BC cells in vitro.ResultsThis study identified two novel exhausted CD4+T‐cell subpopulations with the expression of PD1hiCD200hior PD1hiCD200lowin BC patients. Moreover, BLCA patients with a high level of PD1hiCD200hiCD4+exhausted T cell showed immunotherapy resistance. Cell function analysis demonstrated that PD1hiCD200hiCD4+exhausted T cell can promote epithelial–mesenchymal transition (EMT) and angiogenesis in BLCA cells. In addition, PD1hiCD200hiCD4+exhausted T cells were shown to communicate with malignant BLCA cells through the GAS6–AXL axis. Finally, we also found that GAS6 expression is upregulated in B cells by METTL3‐mediated m6A modification.ConclusionsPD1hiCD200hiCD4+exhausted T cell may serve as a novel biomarker for poor prognosis and immunotherapy resistance in B. Targeted inhibitors of PD1hiCD200hiCD4+exhausted T cells may help improve the efficacy of immunotherapy.