Background: Bladder cancer (BCa) is characterized by frequent recurrence and limited durable responses to immunotherapy, in part due to poor T-cell infiltration into tumors. While the chemokine CCL2 and its receptor CCR2 have traditionally been associated with recruitment of immunosuppressive myeloid cells and tumor promotion, we reveal an unexpected anti-tumor role for this pathway in BCa. Methods: Using orthotopic and carcinogen-induced murine BCa models, we demonstrate that genetic deletion or antibody blockade of CCL2 or CCR2 accelerates tumor progression, reduces intratumoral CD4+ and CD8+ T-cell infiltration, and shortens survival. Results: Mechanistic studies show that CCL2 promotes recruitment of CCR2+ effector T cells with enhanced activation and cytotoxicity. Mixed bone marrow chimeras, T-cell-specific CCR2 knockouts, and adoptive transfers confirm that CCR2 signaling within T cells is essential for their trafficking and anti-tumor function. In human BCa, CCL2 expression is reduced in tumors compared to adjacent urothelium, correlating with diminished T-cell infiltration. Importantly, high tumor CCL2 levels are associated with improved recurrence-free survival in patients with BCa. To therapeutically leverage this pathway, we developed a novel intravesical recombinant CCL2 (rCCL2) approach. rCCL2 delivery significantly increased CCR2+ T-cell infiltration, reduced tumor burden, and extended survival in both syngeneic MB49 and double-humanized patient-derived xenograft (PDX) BCa models. Conclusions: These findings redefine the CCL2-CCR2 axis as a T-cell-mediated tumor-suppressive pathway in BCa and support rCCL2-based therapy as a strategy to enhance immune infiltration and improve outcomes in treatment-resistant BCa.
Cancers. 2026 Jul 15*** epublish ***
Neelam Mukherjee, Niannian Ji, Zaineb Hassouneh, Jaime Furman, Olivia Fisher, Jonathan Gelfond, Onika D V Noel, Gisele Morales, Xi Tan, Chun-Liang Chen, Solomon L Woldu, Yair Lotan, Robert S Svatek
Department of Urology, University of Texas Health San Antonio, San Antonio, TX 78229, USA., Department of Pathology, University of Texas Health San Antonio, San Antonio, TX 78229, USA., Department of Population Health Sciences, University of Texas Health San Antonio, San Antonio, TX 78229, USA., Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA., Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.