尽管已报道肾细胞癌（RCC）的发展和进展存在性别偏差，但其潜在机制仍然神秘。在这里，我们调查了 RCC 肿瘤微环境（TME）中的性别差异，并探索了一种有效增强免疫疗法疗效的药物组合方案。我们分析了四个已发表数据集的单细胞 RNA 测序（scRNA-seq）数据，以调查 RCC 患者的性别差异，并通过多重免疫荧光（MxIF）和流式细胞术（FCM）收集肿瘤组织以验证性别差异。在体内和体外实验中探究了雄激素 - 雄激素受体轴在性别差异中的作用。我们对来自220,156个细胞的scRNA-seq数据进行了分析，以及MxIF和FCM试验，发现CD8 + T细胞高度浸润在男性 RCC 的 TME 中，但大部分处于一种衰竭和功能不全的状态。体内和体外实验表明，男性 TME 中 CD8 + T 细胞的功能不全和衰竭是由雄激素诱导的。临床上，较高的血清雄激素与男性 RCC 患者接受免疫疗法的预后较差显著相关。雄激素受体抑制剂能够激活肿瘤浸润的 CD8 + T 细胞，在体内增强 RCC 的免疫疗法疗效。我们的研究揭示了男性和女性 RCC 患者之间 TME 的差异，并证明雄激素 - 雄激素受体轴在男性 RCC 的免疫抑制中起重要作用。我们的发现表明，雄激素受体抑制剂与免疫疗法的联用可能是男性 RCC 患者的一种有前途的治疗选择。© 2023. Society for Women's Health Research and BioMed Central Ltd.

Although sex bias has been reported in the development and progression of renal cell carcinoma (RCC), the underlying mechanisms remain enigmatic. Here, we investigated the sex differences in the tumor microenvironment (TME) of RCC and explored a promising combination drug regimen to enhance the efficacy of immunotherapy.Single-cell RNA sequencing (scRNA-seq) data from four published datasets were analyzed to investigate the sex differences in RCC patients, and tumor tissues were collected to validate the sex differences using multiplex immunofluorescence (MxIF) and flow cytometry (FCM). The function of the androgen-androgen receptor axis in sex differences was explored in vivo and in vitro experiments.Our analysis of scRNA-seq data from 220,156 cells, as well as MxIF and FCM assays, revealed that CD8+ T-cells infiltrated highly in the TME of male RCC, but were mostly in an exhausted and dysfunctional state. In vitro and in vivo experiments indicated that the dysfunction and exhaustion of CD8+ T-cells in male TME were induced by androgen. Clinically, higher serum androgen was significantly associated with a worse prognosis in male RCC patients receiving immunotherapy. Androgen receptor inhibitors could activate tumor-infiltrating CD8+ T-cells and enhance the efficacy of immunotherapy of RCC in vivo.Our study delineated the difference in TME between male and female patients with RCC, and demonstrated that the androgen-androgen receptor axis plays an important role in immunosuppression in male RCC. Our findings suggest that androgen receptor inhibitors in combination with immunotherapy may be a promising treatment option for male RCC patients.© 2023. Society for Women's Health Research and BioMed Central Ltd.