Integrated multi-omics analysis reveals PTM networks as key regulators of colorectal cancer progression and immune evasion
Guiting Yang, Ji Liu, Changjun Lv, Zhao Chen, Riliang Ma, Minghao Yin, Yanyan Hu, Linghui Pan
Abstract
BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer mortality, with treatment resistance often driven by molecular heterogeneity and an immunosuppressive tumor microenvironment (TME). Post-translational modifications (PTMs) regulate key oncogenic processes, but their comprehensive role in CRC progression and immune evasion remains unexplored. METHODS: We integrated multi-omics data from bulk RNA-seq (GEO/TCGA, n = 1,783), single-cell transcriptomics (41,143 cells), and Mendelian randomization. Differential expression, GSVA, and machine learning (LASSO/SVM/Random Forest) were used to identify PTM-associated signatures. Functional validation included spatial transcriptomics, and immune profiling. RESULTS: Multi-omics analysis identified dysregulation in 80% of PTM pathways in CRC, with ubiquitination sustaining Wnt/β-catenin signaling and GALNT6-mediated glycosylation driving immune evasion through PD-L1 stabilization and CD8 + T cell exclusion. Single-cell analysis revealed GALNT6-specific enrichment in immune-excluded goblet cells (p < 0.05). Machine learning derived a 5-gene PTM Activity Signature (CCNB1IP1, GALNT6, NEDD4L, PSMD14, UBE2C) that distinguish between patients with diseases and those without (AUC = 1.00). GALNT6 was validated as a causal risk factor (OR = 1.10, 95%CI:1.01-1.18), with its inhibition synergizing with anti-PD-1 to enhance CD8 + T cell infiltration (p < 0.01). CONCLUSION: This study establishes PTM networks as central regulators of CRC progression and immune resistance. The PTM-AS framework enables precision subtyping, while GALNT6 emerges as a novel therapeutic target for overcoming immunotherapy resistance.