KDM4A-induced tumor senescence enhances the efficacy of immunotherapy by inhibiting AGT-PHB1 axis-mediated mitophagy in colorectal cancer

作者：Tanxing Cai, Zhenxing Liang, Zhiping Chen, Yang Li, Xiao Wei, Wenfeng Liang, Hao Xie, Huashan Liu, Ziwei Zeng, Xin Yang, Shuanglin Luo, Xiaobin Zheng, Keli Zhong, Liang Huang, Xiong Li, Liang Kang · 发表于：Autophagy · 年份：2025 · DOI：10.1080/15548627.2025.2551680 · 被引用次数：11 · 研究领域：Cancer Immunotherapy and Biomarkers、Ferroptosis and cancer prognosis、Immune cells in cancer

Immune checkpoint inhibitors (ICIs) can re-active the immune response and induce a complete response in mismatch repair-deficient and microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC). However, most CRCs exhibit proficient mismatch repair and microsatellite stable (pMMR/MSS) phenotypes with limited immunotherapy response because of sparse intratumoral CD8+ T-lymphocyte infiltration. Cellular senescence has been reported to involve immune cell infiltration through a senescence-associated secretory phenotype (SASP). However, the relationship between CRC cellular senescence and CD8+ T-lymphocyte infiltration remains unclear. Through integrated analysis of clinical cohorts and transcriptomic data across mismatch repair (MMR) subtypes, we identified cellular senescence as a hallmark of dMMR tumors, accompanied by elevated expression of KDM4A (lysine demethylase 4A). Clinically, KDM4Ahigh CDKN2A/p16high expression correlated with improved CRC patient prognosis. Mechanistically, KDM4A upregulated AGT (angiotensinogen) expression through H3K9me3 demethylation and promoted CRC cellular senescence. Meanwhile, KDM4A-driven senescence suppressed tumor growth and enhanced intratumoral CD8+ T-lymphocyte infiltration via enhancing SASP-associated secretion. Furthermore, AGT disrupted PHB1 (prohibitin 1)-mediated basal mitophagy, triggering cytoplasmic mitochondrial DNA (mtDNA) accumulation that activated CGAS-STING1 signaling and enhanced SASP secretion. Crucially, KDM4A ...