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The tumor microenvironment (TME) modulates therapeutic response and prognosis in patients with bladder cancer (BC). The roles of two phospholipase D (PLD) isoforms, PLD1 and PLD2 (hydrolysis of phosphatidylcholine to phosphatidic acid), in cancer cells have been well-studied in numerous cancer types, but their roles in the TME remain unclear. We used a mouse BC Pld2-KO carcinogenesis model and global transcriptomic analysis to reveal that PLD2 was significantly involved in BC progression through immunosuppressive pathways in the TME. We therefore focused on PLD2 and tumor-associated macrophages (TAMs), which were increased in Pld2-KO mice and further associated with poor prognoses in BC patients. In vitro, we found that Pld2-KO mouse TAMs had significantly enhanced proliferation, correlating closely with increased interleukin-1β (IL-1β) production. These results indicate that PLD2 suppresses BC progression by regulation of IL-1β secretion from TAMs in the TME, suggesting that PLD2 could serve as a potential therapeutic target for modifying the TME in BC., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)