SMAD signaling in cancer: integrative roles in tumor progression, immune evasion, and therapeutic resistance.

Transforming growth factor-beta (TGF-β)/SMAD signaling exerts pleiotropic effects in cancer, orchestrating epithelial-mesenchymal transition (EMT), immune evasion, stemness, and therapeutic resistance. While canonically regarded as tumor-suppressive, emerging data reposition SMAD proteins, particularly SMAD2, SMAD3, and SMAD4, as central effectors of pro-tumorigenic reprogramming in advanced malignancies. Here, we delineate the multifaceted contributions of SMAD signaling across tumor-intrinsic and microenvironmental contexts, highlighting post-translational regulation, immune remodeling, and crosstalk with non-coding RNAs. We show how SMADs mediate dynamic EMT programs, modulate innate and adaptive immune landscapes, and drive chemoresistance through transcriptional and metabolic rewiring. In the tumor microenvironment (TME), SMAD-driven axes involving macrophages, neutrophils, and CAFs reinforce immune suppression and metastasis. Moreover, engineering SMAD pathways in CAR-T and NK cells enhances immunotherapeutic efficacy. We also identify SMAD-based transcriptional and epigenetic signatures with prognostic and predictive utility across multiple tumor types. This integrative review provides a unified framework for understanding the SMAD signaling network as both a mechanistic driver and therapeutic vulnerability in cancer.