PTEN is a dual-specificity phosphatase that is frequently mutated in human cancer, and its deficiency in cancer has been associated with therapy resistance and poor survival. Although the intrinsic tumour-suppressor function of PTEN has been well established, evidence of its role in the tumour immune microenvironment is lacking. Here, we show that chemotherapy-induced antitumour immune responses and tumour suppression rely on myeloid-cell PTEN, which is essential for chemotherapy-induced activation of the NLRP3 inflammasome and antitumour immunity. PTEN directly interacts with and dephosphorylates NLRP3 to enable NLRP3-ASC interaction, inflammasome assembly and activation. Importantly, supplementation of IL-1β restores chemotherapy sensitivity in mouse myeloid cells with a PTEN deficiency. Clinically, chemotherapy-induced IL-1β production and antitumour immunity in patients with cancer is correlated with PTEN expression in myeloid cells, but not tumour cells. Our results demonstrate that myeloid PTEN can determine chemotherapy responsiveness by promoting NLRP3-dependent antitumour immunity and suggest that myeloid PTEN might be a potential biomarker to predict chemotherapy responses.

中文翻译：

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髓系PTEN促进化学疗法诱导的NLRP3炎性小体活化和抗肿瘤免疫。

PTEN是一种双特异性磷酸酶，在人类癌症中经常发生突变，其在癌症中的缺乏与治疗耐药性和不良的生存率有关。尽管已经很好地确定了PTEN的固有的肿瘤抑制功能，但仍缺乏在肿瘤免疫微环境中发挥作用的证据。在这里，我们显示化学疗法诱导的抗肿瘤免疫反应和肿瘤抑制依赖于髓样细胞PTEN，这对于化学疗法诱导的NLRP3炎性体激活和抗肿瘤免疫至关重要。PTEN直接与NLRP3相互作用并使其脱磷酸，从而实现NLRP3-ASC相互作用，炎症小体组装和激活。重要的是，补充IL-1β可恢复PTEN缺乏症的小鼠骨髓细胞的化学敏感性。临床上 癌症患者中化疗诱导的IL-1β产生和抗肿瘤免疫力与髓样细胞而非肿瘤细胞中的PTEN表达相关。我们的结果表明，髓系PTEN可以通过促进NLRP3依赖性抗肿瘤免疫来确定化疗反应，并提示髓系PTEN可能是预测化疗反应的潜在生物标志物。