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.

尽管据报道肿瘤和肿瘤相关巨噬细胞（TAM）之间的相互作用可以促进透明细胞肾细胞癌（ccRCC）的靶向耐药性和进展，但相关机制仍不清楚。在此，我们报告 SOX17 作为 ccRCC 中的新型肿瘤抑制因子，并且正向调节环 SOX17 ^low /YAP/TEAD1/CCL5/CCR5/STAT3 促进 ccRCC-TAM 相互作用。ccRCC标本中SOX17的表达普遍下调，并与TAM浸润呈负相关，SOX17和TAM与现有临床指标TNM分期或SSIGN评分的结合对于预测ccRCC患者的预后具有更好的准确性。从机制上讲，SOX17 敲低通过促进 YAP 的转录和核分布来激活 YAP 信号传导，从而招募 TEAD1 来触发 CCL5 转录。然后，CCL5 将巨噬细胞引导至 TAM，TAM 通过 CCL5/CCR5 相互促进 ccRCC 进展，并激活 STAT3/SOX17 ^low /YAP。然而，SOX17 在 ccRCC 中过度表达却达到了相反的效果。因此，在 ccRCC-TAM 相互作用中鉴定出正向调节环 SOX17 ^{low /YAP/TEAD1/CCL5/CCR5/STAT3。}此外，通过阻断这种正向调节网络来靶向肿瘤-TAM相互作用，会损害肺转移和原位ccRCC体内小鼠模型中ccRCC的转移和靶向耐药性。这些发现提供了 ccRCC 进展中肿瘤-TAM 相互作用的新机制，并提出了抑制晚期 ccRCC 靶向耐药性和转移的潜在靶点。