Abstract 4191: TP53 dysfunction drives immunometabolic rewiring via mTORC1 activation and autophagy suppression in colorectal cancer

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. Citation Format: Eunseuk Lee, Dana Al-Assi, Randy Rueda-Rivera, . TP53 dysfunction drives immunometabolic rewiring via mTORC1 activation and autophagy suppression in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4191.