Although the interaction between tumors and tumor-associated macrophages (TAMs) has been reported to facilitate the targeted drug resistance and progression of clear cell renal cell carcinoma (ccRCC), the related mechanisms remain unknown. Here, we report that SOX17 serves as a novel tumor suppressor in ccRCC and a positive regulatory loop, SOX17^low/YAP/TEAD1/CCL5/CCR5/STAT3, facilitates the ccRCC-TAM interaction. SOX17 expression was commonly downregulated and negatively correlated with TAM infiltration in ccRCC specimens, and the integration of SOX17 and TAMs with the existing clinical indicators TNM stage or SSIGN score achieved better accuracy for predicting the prognosis of ccRCC patients. Mechanistically, SOX17 knockdown activated YAP signaling by promoting the transcription and nuclear distribution of YAP, which recruited TEAD1 to trigger CCL5 transcription. Then, CCL5 educated macrophages toward TAMs, which reciprocally enhanced ccRCC progression through CCL5/CCR5 and activated STAT3/SOX17^low/YAP. However, SOX17 overexpression in ccRCC achieved the opposite effect. Thus, a positive regulatory loop, SOX17^low/YAP/TEAD1/CCL5/CCR5/STAT3, was identified in the ccRCC-TAM interaction. Furthermore, targeting tumor-TAM interactions by blocking this positive regulatory network impaired the metastasis and targeted drug resistance of ccRCC in in vivo mouse models of lung metastasis and orthotopic ccRCC. These findings provide a new mechanism underlying the tumor-TAM interplay in ccRCC progression and present a potential target for inhibiting targeted drug resistance and metastasis in advanced ccRCC.