本研究调查了接受直接切除手术或在手术前接受以吉西他滨为基础的新辅助放化疗（nCRT）的胰腺导管腺癌（PDAC）患者的临床结局和肿瘤免疫特征的性别差异。患者来自PREOPANC随机对照试验。82名患者接受了直接手术切除，66名患者在切除前接受了nCRT。使用Cox比例风险模型研究了性别对总生存期（OS）的影响。利用转录组和空间蛋白组学分析绘制了肿瘤微环境（TME）中的免疫景观。在nCRT前切除术后，两性之间的5年总生存率存在差异，女性为43%，男性为22%。在多变量分析中，仅在nCRT组中，女性性别是有利的独立预后因子（HR 0.19；95% CI 0.07至0.52）。多变量异质性治疗效应分析显示了性别和治疗之间的显著相互作用，暗示在手术切除PDAC的女性中，nCRT的疗效增加。经转录组和空间蛋白组学验证，相较于男性，在nCRT后女性的TME中含有较少的促肿瘤CD163+MRC1+ M2巨噬细胞。女性的PDAC肿瘤对基于吉西他滨的nCRT更为敏感，切除术后存活时间更长，相较于男性。这可能是由于增强的免疫力阻碍了M2巨噬细胞对TME的浸润。我们的研究结果强调了考虑性别差异和减轻免疫抑制性巨噬细胞极化对个体化PDAC治疗的重要性。©作者（或其雇主）2023。在CC BY-NC许可下允许重新使用。非商业复用。由BMJ出版。

This study investigates sex disparities in clinical outcomes and tumour immune profiles in patients with pancreatic ductal adenocarcinoma (PDAC) who underwent upfront resection or resection preceded by gemcitabine-based neoadjuvant chemoradiotherapy (nCRT).Patients originated from the PREOPANC randomised controlled trial. Upfront surgery was performed in 82 patients, and 66 received nCRT before resection. The impact of sex on overall survival (OS) was investigated using Cox proportional hazards models. The immunological landscape within the tumour microenvironment (TME) was mapped using transcriptomic and spatial proteomic profiling.The 5-year OS rate differed between the sexes following resection preceded by nCRT, with 43% for women compared with 22% for men. In multivariate analysis, the female sex was a favourable independent prognostic factor for OS only in the nCRT group (HR 0.19; 95% CI 0.07 to 0.52). Multivariate heterogeneous treatment effects analysis revealed a significant interaction between sex and treatment, implying increased nCRT efficacy among women with resected PDAC. The TME of women contained fewer protumoural CD163+MRC1+M2 macrophages than that of men after nCRT, as indicated by transcriptomic and validated using spatial proteomic profiling.PDAC tumours of women are more sensitive to gemcitabine-based nCRT, resulting in longer OS after resection compared with men. This may be due to enhanced immunity impeding the infiltration of protumoral M2 macrophages into the TME. Our findings highlight the importance of considering sex disparities and mitigating immunosuppressive macrophage polarisation for personalised PDAC treatment.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.