e15521 Background: Loss of TP53 is one of the most common alterations in microsatellite-stable colorectal cancer (MSS CRC). It is known to affect both cellular metabolism and immune regulation, yet how these processes interact remains unclear. This study explored how TP53 loss shapes tumor metabolism, autophagy, and immune balance using multi-omics integration. Methods: We analyzed four public datasets: GSE146009 (paired tumor-normal RNA-seq), TCGA-COAD/READ (n=647, mutation-annotated), GSE108989 (11,138 single-cell T cells), and CPTAC colon proteome/phosphoproteome cohorts. Pathway activity was quantified by single-sample gene-set enrichment (ssGSEA) and Seurat module scoring. Group comparisons used Kruskal-Wallis and Wilcoxon tests with false-discovery-rate correction. Results: In the TCGA cohort, TP53-mutant tumors showed higher mTORC1 signaling and lower autophagy activity compared with wild-type tumors (FDR<0.01). FOXP3 expression increased across wild-type, missense, and null classes, while CD8A levels remained stable, producing a progressive drop in the CD8A/FOXP3 ratio (p<0.001). In GSE146009, tumors displayed higher FOXP3, CTLA4, and CD274 and a lower CD8A/FOXP3 ratio than adjacent normal tissue (FDR<0.05). Single-cell analysis confirmed that regulatory and exhausted CD8⁺ T cells had stronger mTORC1 and autophagy signaling but weaker IFNG activity compared with effector subsets. Proteomic data from CPTAC cohorts supported these findings: p53-low tumors showed increased phosphorylation of EIF4EBP2 (S65) and RPS6KB1 (T421/S424) and reduced inhibitory phosphorylation of RPTOR (S705/T725/S726), consistent with sustained mTORC1 activation and suppressed autophagy. Conclusions: Across transcriptomic, single-cell, and proteomic layers, TP53 loss is linked to metabolic activation and immune suppression through the mTORC1-autophagy pathway. This mechanism creates a FOXP3-dominant, immune-cold microenvironment and suggests that targeting mTORC1 and autophagy may help overcome immunotherapy resistance in TP53-mutant MSS CRC. Summary of key metabolic and immune pathway differences by TP53 status in colorectal cancer. Metric Comparison Effect p/FDR mTORC1 score TP53 mutant vs WT +0.13 <0.001 Autophagy score TP53 mutant vs WT -0.12 0.004 FOXP3 expression WT→missense→null ↑trend 0.005 CD8A/FOXP3 ratio WT→missense→null 1.28→0.96 <0.001 EIF4EBP2 S65 phospho p53-low vs high +1.1 trend RPTOR S705/T725/S726 p53-low vs high -0.6→-1.6 trend Values represent median group differences. P-values adjusted using false discovery rate (FDR) correction.
Lee et al. (Thu,) studied this question.