IL-10+regulatory B cells (Bregs) play a significant role in cancer immunotherapy and their presence is an indicator of negative outcome. We found that PPARδ is significantly upregulated in tumor-induced IL-10+Bregs with a phenotype of CD19+CD24hiIgDlo/−CD38loor CD19+CD24hiIgDlo/−CD38hiin both mice and humans, and the level of PPARδ expression was correlated with their potential to produce IL-10 and to inhibit T cell activation. Genetic inactivation of PPARδ in B cells impaired the development and function of IL-10+B cells, and treatment with PPARδ inhibitor diminished the induction of IL-10+Bregs by tumor and CD40 engagement. Importantly, immunotherapy with anti-CD40 or anti-PD1 antibody achieved a markedly improved outcome in tumor-bearing mice with PPARδ deficiency in B cells or treated with PPARδ inhibitor. This study shows that PPARδ is required for the development and function of IL-10+Bregs, providing a new and effective target for selectively blocking Bregs and improving antitumor immunotherapy.