TP53 Dysfunction Drives Immunometabolic Rewiring via mTORC1 Activation in Colorectal Cancer

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.