SMAD3 and neoplasm: Previous studies have shown that CRC patients with oncogenic TGF-β pathway alterations have shorter OS compared to those without such mutations.15 SMAD2 and SMAD3, key components of this pathway, form nuclear complexes with SMAD4 to regulate gene expression, influencing tumor progression and immune responses.21,22 Our analysis identified a positive correlation between higher baseline pSMAD2/3 levels and better clinical outcomes, with improved ORR (50.0% vs. 44.4%) and longer PFS (8.5 vs. 7.3 months) for patients with an H-score ≥80% compared to <80%.