Identification of programmed cell death-related subtypes reveals immune heterogeneity and therapeutic divergence in colon cancer

Rationale: Therapy resistance remains a critical challenge in colon adenocarcinoma (COAD). The dysregulation of programmed cell death (PCD) pathways significantly influences therapeutic response, but its integrated role in shaping the tumor microenvironment (TME) and driving clinical heterogeneity in COAD is poorly defined. Methods: We established a Programmed Cell Death-related Subtype (PCDS) classification by integrating 12 PCD pathways across transcriptomic data from 1,140 COAD patients using non-negative matrix factorization (NMF). The subtypes were validated in independent RNA-sequencing cohorts. We characterized the genomic, TME, and therapeutic features of each PCDS using multi-omics data analysis, and computational drug repositioning. Molecular docking and in silico drug sensitivity analyses were employed to evaluate candidate drugs. Results: We identified three robust subtypes, including PCDS1 (immune-activated), PCDS2 (WNT and TP53 signaling activation), and PCDS3 (mesenchymal and T-cell dysfunction/exclusion). PCDS3, enriched with inflammatory cancer-associated fibroblasts (iCAFs), exhibited the poorest prognosis and dual resistance to both chemotherapy and immunotherapy (>80% non-response). Analysis of single-cell and spatial transcriptomics data revealed the activation of MDK-SDC2 ligand-receptor axis between tumor cells and fibroblasts in PCDS3, spatially associated with T-cell dysfunction and exclusion. Computational drug repositioning identified the sunitinib as having selective potency against PCDS3 tumors, showing significantly lower IC50 values and high-affinity binding to SDC2 in molecular docking. Conclusions: This study defines a novel molecular subtype for COAD, linking PCD dysregulation to distinct TME remodeling and therapeutic outcomes. Targeting the MDK-SDC2 axis with agents such as sunitinib may offer a promising strategy to overcome stromal-mediated immunotherapy resistance in the most lethal PCDS3 tumors.