寻找能够从本质上抑制肿瘤细胞并提高免疫应答的癌基因，将是未来肾癌综合治疗的方向。经过患者样本分析和信号通路检查，我们建议 p21 激活激酶 4 (PAK4) 作为肾癌的潜在靶点药物。 PAK4在患者样本中表现出高表达水平，并在免疫微环境中发挥调节作用。利用AI软件进行肽药物设计，我们设计了一种专门针对PAK4的肽蛋白水解靶向嵌合体（PROTAC）药物。为了解决与药物递送相关的挑战，我们开发了一种用于有效运输肽PROTAC药物的纳米硒递送系统，称为PpD（PAK4肽降解剂）。我们成功设计了靶向PAK4的肽PROTAC药物。 PpD 以高选择性有效降解 PAK4，避免干扰其他同源蛋白。 PpD 在体外和体内均显着减弱肾癌增殖。值得注意的是，PpD 在完全免疫的小鼠模型中表现出对肿瘤增殖的显着抑制作用，同时增强免疫细胞反应。此外，PpD在mini-PDX和PDO模型中表现出良好的肿瘤生长抑制作用，进一步凸显了其临床应用潜力。这种PAK4靶向肽PROTAC药物不仅可以抑制肾癌细胞增殖，还可以改善免疫微环境，增强免疫反应。我们的研究为肾癌治疗的创新靶向治疗铺平了道路。这项工作得到了非营利组织的研究资助的支持，如致谢中所述。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

Finding the oncogene, which was able to inhibit tumor cells intrinsically and improve the immune answers, will be the future direction for renal cancer combined treatment. Following patient sample analysis and signaling pathway examination, we propose p21-activated kinase 4 (PAK4) as a potential target drug for kidney cancer. PAK4 exhibits high expression levels in patient samples and plays a regulatory role in the immune microenvironment.Utilizing AI software for peptide drug design, we have engineered a specialized peptide proteolysis targeting chimera (PROTAC) drug with selectivity for PAK4. To address challenges related to drug delivery, we developed a nano-selenium delivery system for efficient transport of the peptide PROTAC drug, termed PpD (PAK4 peptide degrader).We successfully designed a peptide PROTAC drug targeting PAK4. PpD effectively degraded PAK4 with high selectivity, avoiding interference with other homologous proteins. PpD significantly attenuated renal carcinoma proliferation in vitro and in vivo. Notably, PpD demonstrated a significant inhibitory effect on tumor proliferation in a fully immunocompetent mouse model, concomitantly enhancing the immune cell response. Moreover, PpD demonstrated promising tumor growth inhibitory effects in mini-PDX and PDO models, further underscoring its potential for clinical application.This PAK4-targeting peptide PROTAC drug not only curtails renal cancer cell proliferation but also improves the immune microenvironment and enhances immune response. Our study paves the way for innovative targeted therapies in the management of renal cancer.This work is supported by Research grants from non-profit organizations, as stated in the Acknowledgments.Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.