PO.BCS01.10 · 生物信息与计算
TP53功能失调通过mTORC1激活与自噬抑制驱动结直肠癌的免疫代谢重塑
TP53 dysfunction drives immunometabolic rewiring via mTORC1 activation and autophagy suppression in colorectal cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
肿瘤抑制蛋白p53通过对mTORC1-自噬轴的控制来调节代谢与免疫；然而TP53功能失调在微卫星稳定型结直肠癌（MSS CRC）中的机制性后果仍不明确。我们采用一种整合性转录组学方法，结合bulk RNA-seq（GSE146009）、TCGA-COAD/READ（n=647）及单细胞RNA-seq数据（GSE108989），以研究TP53缺失如何改变CRC中的代谢-免疫耦合。在野生型肿瘤中，p53与自噬被共同激活，而mTORC1信号保持受限。这一模式维持了代谢稳定性，并支持了有利的CD8⁺/FOXP3⁺免疫比值。相比之下，TP53突变型与缺失型肿瘤表现出p53与mTORC1的解耦，导致持续的合成代谢信号、自噬抑制以及促炎细胞因子（IL1B、IFNG）的上调，这与FOXP3⁺调节性T细胞的富集及免疫排斥同时出现。单细胞分析证实，mTORC1与自噬在主要T细胞亚群中保持共激活。然而，在耗竭型与调节型群体中，免疫-代谢协调较弱。主成分与相关性分析揭示了两个不同的轴——代谢强度与免疫极性——它们描述了TP53依赖性的免疫代谢分化。综上所述，结果表明TP53功能失调通过mTORC1激活与自噬抑制促进了相互关联的代谢与免疫重编程，导致一个以FOXP3为主导的免疫冷肿瘤微环境。这一机制性洞见为在TP53缺陷的MSS CRC中将mTORC1与自噬抑制同免疫检查点阻断相结合提供了理论依据。
查看英文原文 English abstract
The tumor suppressor protein p53 regulates both metabolism and immunity through its control of the mTORC1-autophagy axis; yet the mechanistic consequences of TP53 dysfunction in microsatellite-stable colorectal cancer (MSS CRC) remain unclear. We used an integrative transcriptomic approach that combined bulk RNA-seq (GSE146009), TCGA-COAD/READ (n = 647), and single-cell RNA-seq data (GSE108989), to investigate how TP53 loss alters metabolic-immune coupling in CRC. While p53 and autophagy were activated together in wild-type tumors, mTORC1 signaling remained restrained. This pattern preserved metabolic stability and supported a favorable CD8⁺/FOXP3⁺ immune ratio. In contrast, TP53-mutant and null tumors exhibited a decoupling of p53 from mTORC1, leading to sustained anabolic signaling, autophagy suppression, and upregulation of pro-inflammatory cytokines (IL1B, IFNG), which coincided with enrichment of FOXP3⁺ regulatory T-cells and immune exclusion. Single-cell profiling confirmed that mTORC1 and autophagy remain co-activated across major T-cell subsets. However, immune-metabolic coordination was weaker in exhausted and regulatory populations. Principal-component and correlation analyses revealed two distinct axes, metabolic intensity and immune polarity, that describe TP53-dependent immunometabolic divergence.Taken together, the results suggest that TP53 dysfunction promotes linked metabolic and immune reprogramming through mTORC1 activation and autophagy suppression, resulting in a FOXP3-dominant, immune-cold tumor microenvironment.. This mechanistic insight provides a rationale for combining mTORC1 and autophagy inhibition with immune-checkpoint blockade in TP53-deficient MSS CRC.
利益披露 Disclosure
E. Lee, None..
D. Al-Assi, None..
R. Rueda-Rivera, None.