Aging-associated differences in mammary tumor-initiating populations and immune evasion pathways in breast cancer [exome_seq]

Aging is a major risk factor for breast cancer, yet how it shapes tumor development, molecular phenotype, and immune evasion remains incompletely understood. Deciphering how aging influences cancer development is critical for improving risk assessment, prevention, and treatment. Here, using a N-nitroso-N-methylurea (NMU)-induced rat mammary tumor model that recapitulates key features of human breast cancer, we integrated bulk and single-cell transcriptomics, whole-exome sequencing, and histopathological analysis to dissect age-associated differences in tumorigenesis. We found that age at NMU exposure critically influences tumor incidence, mutational burden, subtype, and immune microenvironment. Tumors arising in aged rats originate from luminal progenitor-like cells with increased genomic instability, suppressed immune infiltration, and impaired antigen presentation linked to loss of heterozygosity at Chr 20p. These age-associated epithelial and immune changes were conserved in human breast cancers, where loss of the homologous Chr 6p region correlated with reduced lymphocyte infiltration and shorter relapse-free survival. These findings reveal that aging alters the tumor-initiating cell population and promotes immune-evasive tumor states through chromosomal instability-driven antigen presentation defects. Our work provides mechanistic insight into the reduced efficacy of immunotherapy in older patients.衰老是乳腺癌的重要危险因素，然而衰老如何调控肿瘤发生发展、分子表型及免疫逃逸，目前仍未完全阐明。解析衰老对癌症发生的影响机制，对于优化癌症风险评估、预防与治疗策略至关重要。本研究利用可重现人类乳腺癌关键特征的N-亚硝基-N-甲基脲（N-nitroso-N-methylurea, NMU）诱导大鼠乳腺肿瘤模型，整合批量转录组学、单细胞转录组学、全外显子测序及组织病理学分析方法，解析肿瘤发生过程中与衰老相关的差异特征。研究发现，NMU暴露时的大鼠年龄会显著影响肿瘤发生率、突变负荷、肿瘤亚型及免疫微环境。老年大鼠体内产生的肿瘤起源于管腔祖细胞样细胞，这类细胞伴随基因组不稳定程度升高、免疫浸润受抑以及抗原呈递功能受损，该表型与20号染色体短臂（Chr 20p）的杂合性缺失相关。上述与衰老相关的上皮细胞及免疫微环境改变在人类乳腺癌中同样保守存在：同源的6号染色体短臂（Chr 6p）区域杂合性缺失，与淋巴细胞浸润减少及无复发生存期缩短显著相关。本研究结果揭示，衰老通过染色体不稳定介导的抗原呈递缺陷，改变肿瘤起始细胞群，并促进肿瘤形成免疫逃逸表型。本研究为老年患者免疫治疗疗效不佳的机制提供了新的见解。