Abstract 5821: Targeting adenosine receptor signaling enhances anti-PD-L1 therapy efficacy in MTAP-deficient urothelial cancer via reprogramming tumor-associated macrophages

Abstract Methylthioadenosine phosphorylase (MTAP) deficiency in urothelial cancer (UC) correlates with poor clinical outcomes and reduced response rates to immune checkpoint inhibitor (ICI) therapy. Understanding the mechanisms by which MTAP loss contributes to ICI resistance and identifying therapeutic strategies to enhance ICI efficacy in MTAP-deficient tumors is of critical importance. Using CRISPR-Cas9, we deleted MTAP in the MB49 murine UC cell line and established orthotopic bladder tumors with wild-type (WT) and MTAP knock-out MB49 cells. CyTOF analysis revealed that MTAP-deficient tumors showed a marked reduction in M1-like macrophages (∼50%) and a substantial increase in M2-like macrophages (∼3-fold). Mechanistically, MTAP-deficient tumors accumulated elevated levels of methylthioadenosine (MTA, >100-fold) in the tumor microenvironment (TME), which drove the polarization of tumor-associated macrophages (TAMs) towards a pro-tumorigenic M2-like phenotype via adenosine receptor (A2A/A2B) signaling. Notably, inhibition of A2A/A2B adenosine receptors significantly enhanced anti-PD-L1 therapy efficacy, achieving an overall tumor growth inhibition of 50% compared to anti-PD-L1 monotherapy. These findings suggest that targeting the adenosine pathway may provide a promising strategy to improve therapeutic outcomes in MTAP-deficient urothelial cancer. Citation Format: Ying Mei, Jianfeng Chen, Yuxue Zhang, Yu-Yi Chu, Omar Alhalabi, Jianjun Gao. Targeting adenosine receptor signaling enhances anti-PD-L1 therapy efficacy in MTAP-deficient urothelial cancer via reprogramming tumor-associated macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5821.