免疫衰老已被证明在肿瘤进展中扮演重要角色。然而，对于免疫衰老相关途径的综合分析仍然不足。与此同时，癌症中的免疫衰老的性别差异仍然不明确。本研究中，我们分析了12,836个肿瘤样本的多组学数据，包括基因组、转录组、表观基因组、蛋白组和代谢组学。我们系统性地辨识出在癌症类型中被打乱的免疫衰老途径。我们发现免疫衰老途径的突变和拷贝数变化在全癌中更活跃。我们重构了免疫衰老核心途径 (ISC-途径)，以提升对33种癌症类型的预后分层能力。我们还发现头颈鳞状细胞癌(HNSC)中存在丰富的性别特异性免疫衰老特征，并且在存活方面存在性别差异。我们发现OSI-027是HNSC肿瘤中一种潜在的性别特异性药物，通过靶向PI3K-Akt信号通路中的MTOR基因，在男性HNSC中更具疗效。总之，我们的研究提供了免疫衰老途径的系统认识，并揭示了全癌中免疫衰老的全球特征。我们强调MTOR基因可以成为HNSC的强大免疫衰老生物标志物，有助于开发性别特异性的免疫衰老药物。© 2023. 作者 (们), 接受Springer-Verlag GmbH德国部分属于Springer Nature的独家许可。

Immunosenescence has been demonstrated to play an important role in tumor progression. However, there is lacking comprehensive analyses of immunosenescence-related pathways. Meanwhile, the sex disparities of immunosenescence in cancer are still poorly understood. In this study, we analyzed the multi-omics data of 12,836 tumor samples, including genomics, transcriptomics, epigenomics, proteomics, and metabolomics. We systematically identified immunosenescence pathways that were disordered across cancer types. The mutations and copy number variations of immunosenescence pathways were found to be more active in pan-cancer. We reconstructed the immunosenescence core pathways (ISC-pathways) to improve the ability of prognostic stratification in 33 cancer types. We also found the head and neck squamous carcinoma (HNSC) contained abundant sex-specific immunosenescence features and showed sex differences in survival. We found that OSI-027 was a potential sex-specific drug in HNSC tumors, which tended to be more effective in male HNSC by targeting the MTOR gene in the PI3K-Akt signaling pathway. In conclusion, our study provided a systematic understanding of immunosenescence pathways and revealed the global characteristics of immunosenescence in pan-cancer. We highlighted MTOR gene could be a powerful immunosenescence biomarker of HNSC that helps to develop sex-specific immunosenescence drugs.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.