Identification of programmed cell death-related subtypes reveals immune heterogeneity and therapeutic divergence in colon cancer - PubMed
4 days ago
- #colon adenocarcinoma
- #therapy resistance
- #programmed cell death
- Identified three programmed cell death-related subtypes (PCDS) in colon adenocarcinoma (COAD): 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), showed the poorest prognosis and resistance to both chemotherapy and immunotherapy (>80% non-response).
- Discovered the MDK-SDC2 ligand-receptor axis activation in PCDS3, linked to T-cell dysfunction and exclusion, via single-cell and spatial transcriptomics data.
- Computational drug repositioning identified sunitinib as a potential treatment for PCDS3 tumors, with lower IC50 values and high-affinity binding to SDC2.
- The study suggests targeting the MDK-SDC2 axis with agents like sunitinib could overcome stromal-mediated immunotherapy resistance in PCDS3 tumors.