Clear cell renal cell carcinoma (ccRCC) preferentially invades into perinephric adipose tissue (PAT), a process associated with poor prognosis. However, the detailed mechanisms underlying this interaction remain elusive. Here, we describe a bi-directional communication between ccRCC cells and the PAT. We found that ccRCC cells secrete parathyroid-hormone-related protein (PTHrP) to promote the browning of PAT by PKA activation, while PAT-mediated thermogenesis results in the release of excess lactate to enhance ccRCC growth, invasion, and metastasis. Further, tyrosine kinase inhibitors (TKIs) extensively used in the treatment of ccRCC enhanced this vicious cycle of ccRCC-PAT communication by promoting the browning of PAT. However, if this cross-communication was short circuited by the pharmacological suppression of adipocyte browning via H89 or KT5720, the anti-tumor efficacy of the TKI, sunitinib, was enhanced. These results suggest that ccRCC-PAT cross-communication has important clinical relevance, and use of combined therapy holds great promise in enhancing the efficacy of TKIs.

透明细胞肾细胞癌 (ccRCC) 优先侵入肾周脂肪组织 (PAT)，这是一个与预后不良相关的过程。然而，这种相互作用背后的详细机制仍然难以捉摸。在这里，我们描述了 ccRCC 单元和 PAT 之间的双向通信。我们发现 ccRCC 细胞分泌甲状旁腺激素相关蛋白 (PTHrP) 以通过 PKA 激活促进 PAT 的褐变，而 PAT 介导的产热导致释放过量的乳酸以增强 ccRCC 的生长、侵袭和转移。此外，广泛用于治疗 ccRCC 的酪氨酸激酶抑制剂 (TKI) 通过促进 PAT 的褐变增强了 ccRCC-PAT 通信的恶性循环。然而，如果通过 H89 或 KT5720 对脂肪细胞褐变的药理抑制使这种交叉通讯短路，则 TKI 舒尼替尼的抗肿瘤功效得到增强。这些结果表明，ccRCC-PAT 交叉交流具有重要的临床意义，联合治疗的使用在提高 TKI 的疗效方面具有很大的前景。