高级别浆液性卵巢癌（HGSC）仍然是一种预后不良的疾病，对当前的免疫检查点抑制剂没有反应。尽管 PI3K 通路改变（例如 PTEN 丢失）在 HGSC 中很常见，但针对该通路的尝试并未成功。我们假设异常的 PI3K 通路激活可能会改变 HGSC 免疫微环境并提供靶向机会。单细胞 RNA 测序鉴定出小鼠模型中 Pten 缺失网膜肿瘤特异的常驻巨噬细胞群，并通过流式细胞术证实。这些巨噬细胞源自腹腔液巨噬细胞，具有独特的基因表达程序，其特点是血红素加氧酶-1 (HMOX1) 的高表达。靶向常驻腹膜巨噬细胞可阻止 HMOX1hi 巨噬细胞的出现并减少肿瘤生长。此外，直接抑制 HMOX1 可以延长体内存活时间。 RNA 测序发现 Pten-null 肿瘤细胞中的 IL33 可能是导致 HMOX1hi 巨噬细胞出现的候选驱动因素。人类 HGSC 肿瘤还含有 HMOX1hi 巨噬细胞以及相应的基因表达程序。此外，这些巨噬细胞的存在与 HGSC 患者中激活的肿瘤 PI3K/mTOR 信号传导和较差的总体生存率相关。相比之下，HMOX1hi 巨噬细胞数量较低的肿瘤的标志是适应性免疫反应基因表达增加。这些数据表明，针对 HMOX1hi 巨噬细胞作为治疗预后不良 HGSC 的潜在治疗策略。

High-grade serous ovarian carcinoma (HGSC) remains a disease of poor prognosis that is unresponsive to current immune checkpoint inhibitors. Although PI3K pathway alterations, such as PTEN loss, are common in HGSC, attempts to target this pathway have been unsuccessful. We hypothesized that aberrant PI3K pathway activation may alter the HGSC immune microenvironment and present a targeting opportunity. Single-cell RNA sequencing identified populations of resident macrophages specific to Pten-null omental tumors in murine models, which were confirmed by flow cytometry. These macrophages derived from peritoneal fluid macrophages and had a unique gene expression program, marked by high expression of the enzyme heme oxygenase-1 (HMOX1). Targeting resident peritoneal macrophages prevented the appearance of HMOX1hi macrophages and reduced tumor growth. Furthermore, direct inhibition of HMOX1 extended survival in vivo. RNA sequencing identified IL33 in Pten-null tumor cells as a likely candidate driver leading to the appearance of HMOX1hi macrophages. Human HGSC tumors also contained HMOX1hi macrophages with a corresponding gene expression program. Moreover, the presence of these macrophages correlated with activated tumoral PI3K/mTOR signaling and poor overall survival in HGSC patients. In contrast, tumors with low numbers of HMOX1hi macrophages were marked by increased adaptive immune response gene expression. These data suggest targeting HMOX1hi macrophages as a potential therapeutic strategy for treating poor prognosis HGSC.