Abstract Renal cell carcinoma (RCC), the most common type of kidney cancer, relies heavily on the complex ecosystem of the Tumor Microenvironment (TME) for its progression. A critical cellular component within the TME is the Tumor-Associated Macrophage (TAM), which often adopts a pro-tumor, M2-like phenotype that supports angiogenesis, invasion, and immune suppression. This study investigates the role of tumor-derived exosomes (TDEs) in mediating this critical reprogramming event. In vitro experiments utilized human (786-O renal cancer cell line and THP-1 monocytes) and mouse (Renca RCC and RAW 264.7 monocytes/macrophage) cell lines. The macrophages were treated with RCC-derived exosomes, and the conditioned medium (CM) was used to treat parental RCC cells. Functional assays demonstrated that exosome-educated macrophage CM significantly increased the proliferation, migration, and invasion of both human and mouse RCC cells. Furthermore, Western blot and ELISA analysis confirmed that TDE treatment successfully reprogrammed macrophages, leading to altered cytokine profiles indicative of polarization toward a pro-tumor phenotype. In vivo, the impact of the TDE-educated macrophage CM was assessed in SCID and BALB/c mouse models using intracardial and intrarenal RCC injections. Bioluminescence imaging (BLI) confirmed that CM from exosome-treated macrophages significantly enhanced tumor progression and distant metastasis compared to controls. In conclusion, this research identifies tumor-derived exosomes as critical signaling vectors that effectively reprogram TAMs into pro-tumorigenic cells. This exosome-mediated communication promotes a highly permissive TME, leading to accelerated renal cancer progression and metastasis. These findings highlight the TDE-TAM axis as a potent therapeutic target for mitigating RCC malignancy. Citation Format: Jinlu Dai, Suguru Kadomoto, Tyler Robinson, Evan T. Keller. Tumor-derived exosomes promote renal cancer progression via reprogramming of tumor-associated macrophages abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3356.
Dai et al. (Fri,) studied this question.