磷酸酶和张力蛋白同源物（PTEN）的缺失与免疫抑制性肿瘤微环境有关，但其潜在机制在很大程度上仍然是个谜。在这里，我们报道 PTEN 可以通过含有跨膜 emp24 结构域的蛋白 10 (TMED10) 通道的蛋白分泌途径分泌。抑制肿瘤细胞分泌PTEN有助于免疫抑制并削弱PTEN的抑癌作用，而瘤内注射PTEN蛋白可促进小鼠的抗肿瘤免疫并抑制肿瘤生长。从机制上讲，细胞外 PTEN 与巨噬细胞上含有丛蛋白结构域的蛋白 2 (PLXDC2) 结合，触发 JAK2-STAT1 信号传导的后续激活，从而将肿瘤相关巨噬细胞 (TAM) 从免疫抑制表型转变为炎症表型，从而增强 CD8 的激活T 细胞和自然杀伤细胞。重要的是，PTEN 治疗还增强了小鼠抗 PD-1 治疗的疗效，并逆转了患者来源的原发 TAM 的免疫抑制表型。这些数据确定了 PTEN 在免疫激活和肿瘤抑制中的细胞因子样作用，并证明了 PTEN 在癌症免疫治疗中细胞外给药的治疗潜力。版权所有 © 2024 Elsevier Inc. 保留所有权利。

Loss of phosphatase and tensin homolog (PTEN) has been linked to an immunosuppressive tumor microenvironment, but its underlying mechanisms remain largely enigmatic. Here, we report that PTEN can be secreted by the transmembrane emp24 domain-containing protein 10 (TMED10)-channeled protein secretion pathway. Inhibiting PTEN secretion from tumor cells contributes to immunosuppression and impairs the tumor-suppressive role of PTEN, while intratumoral injection of PTEN protein promotes antitumor immunity and suppresses tumor growth in mice. Mechanistically, extracellular PTEN binds to the plexin domain-containing protein 2 (PLXDC2) on macrophages, triggering subsequent activation of JAK2-STAT1 signaling, which switches tumor-associated macrophages (TAMs) from the immunosuppressive to inflammatory phenotype, leading to enhanced activation of CD8+ T and natural killer cells. Importantly, PTEN treatment also enhances the therapeutic efficacy of anti-PD-1 treatment in mice and reverses the immune-suppressive phenotype of patient-derived primary TAMs. These data identify a cytokine-like role of PTEN in immune activation and tumor suppression and demonstrate the therapeutic potential for extracellular administration of PTEN in cancer immunotherapy.Copyright © 2024 Elsevier Inc. All rights reserved.