Unveiling the Paradoxical Tumor-Suppressive Role of CCL2/CCR2 in Bladder Cancer: A Novel Immunotherapeutic Strategy

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.