Abstract
Immune checkpoint inhibitors (ICI) have transformed cancer therapy, yet their efficacy remains limited to a subset of patients, underscoring the need for robust predictive biomarkers and deeper mechanistic insights into treatment resistance. In this study, we identified a population of CCL5hiCD4+ T cells that were characterized by memory-like activation markers and strongly correlated with ICI therapeutic responses in bladder cancer. Functionally, these T cells enhanced antitumor immunity by promoting M1-like macrophage polarization through CCL5/CCR1 signaling. Importantly, tumor-derived prostaglandin E2 (PGE2) acted as a critical microenvironmental factor that suppressed the differentiation of CCR6hiCD4+ T cells into immunostimulatory CCL5hiCD4+ T cells, thereby driving resistance to ICI therapy. These findings extend the understanding of CD4+ T-cell heterogeneity and its role in shaping immune responses to ICI. By elucidating that CCL5hiCD4+ T cells enhance myeloid-mediated tumor control and that tumor-derived PGE2 disrupts CCL5hiCD4+ T-cell differentiation to promote immune evasion, this work highlights potential therapeutic strategies to improve ICI efficacy in bladder cancer. SIGNIFICANCE: CCL5 hiCD4+ T cells with memory-like activated characteristics enhance antitumor immunity in bladder cancer by reprogramming macrophages, supporting the potential of these cells as biomarkers and targets to enhance immunotherapy efficacy.