Immune checkpoint inhibitors (ICIs) targeting PD-L1 immunotherapy are state-of-the-art treatments for advanced non–small cell lung cancer (NSCLC). However, the treatment response of certain patients with NSCLC is unsatisfactory because of an unfavorable tumor microenvironment (TME) and poor permeability of antibody-based ICIs. In this study, we aimed to discover small-molecule drugs that can modulate the TME to enhance ICI treatment efficacy in NSCLC in vitro and in vivo. We identified a PD-L1 protein-modulating small molecule, PIK-93, using a cell-based global protein stability (GPS) screening system. PIK-93 mediated PD-L1 ubiquitination by enhancing the PD-L1–Cullin-4A interaction. PIK-93 reduced PD-L1 levels on M1 macrophages and enhanced M1 antitumor cytotoxicity. Combined PIK-93 and anti–PD-L1 antibody treatment enhanced T cell activation, inhibited tumor growth, and increased tumor-infiltrating lymphocyte (TIL) recruitment in syngeneic and human peripheral blood mononuclear cell (PBMC) line–derived xenograft mouse models. PIK-93 facilitates a treatment-favorable TME when combined with anti–PD-L1 antibodies, thereby enhancing PD-1/PD-L1 blockade cancer immunotherapy.

中文翻译：

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小分子PIK-93调节肿瘤微环境改善免疫检查点阻断反应

以 PD-L1 免疫疗法为靶点的免疫检查点抑制剂 (ICI) 是晚期非小细胞肺癌 (NSCLC) 的最先进疗法。然而，由于不利的肿瘤微环境（TME）和基于抗体的 ICI 的渗透性差，某些 NSCLC 患者的治疗反应并不令人满意。在这项研究中，我们旨在发现可以调节 TME 的小分子药物，以增强 ICI 在体外和体内对 NSCLC 的治疗效果。我们使用基于细胞的全球蛋白质稳定性 (GPS) 筛选系统鉴定了一种 PD-L1 蛋白调节小分子 PIK-93。PIK-93 通过增强 PD-L1–Cullin-4A 相互作用介导 PD-L1 泛素化。PIK-93 降低了 M1 巨噬细胞上的 PD-L1 水平并增强了 M1 抗肿瘤细胞毒性。PIK-93 和抗 PD-L1 抗体联合治疗增强了 T 细胞活化，抑制肿瘤生长，并增加同基因和人外周血单核细胞 (PBMC) 系衍生的异种移植小鼠模型中的肿瘤浸润淋巴细胞 (TIL) 募集。PIK-93 与抗 PD-L1 抗体联合使用可促进有利于治疗的 TME，从而增强 PD-1/PD-L1 阻断性癌症免疫疗法。