Cancer progression is orchestrated by a series of signaling pathways that altogether regulate cell plasticity, immune evasion, metastasis, and chemotherapy resistance [[1], [2], [3]]. Among them, the TGF-β pathway has a long history, known to exhibit context-dependent dualism, with tumor-suppressive properties during early disease and pro-invasive and metastatic properties during advanced-stage disease [[4], [5], [6], [7]]. Central to this pleiotropic behavior are the SMAD family proteins, which serve as intracellular effectors of TGF-β and related ligands. The SMAD family of intracellular proteins serves as the principal signal transducers for the TGF-β superfamily [[8], [9], [10]], a group of cytokines that regulate key processes, including proliferation, differentiation, apoptosis, and immune homeostasis [[11], [12], [13], [14]]. Upon TGF-β receptor activation, receptor-regulated SMADs (R-SMADs such as SMAD2 and SMAD3) are phosphorylated. They then form heteromeric complexes with the common mediator SMAD4 and translocate to the nucleus, where they regulate target gene expression [[15], [16], [17]]. Inhibitory SMADs (I-SMADs: SMAD6 and SMAD7) act as negative feedback inhibitors, blocking R-SMAD activation or receptor degradation [[15], [16], [17]]. Non-canonical branches augment these canonical SMAD pathway targets, extending to MAPK, PI3K/AKT, and Rho-like GTPases, thereby enhancing the dynamic versatility of the TGF-β response [[17], [18], [19]].

In the context of cancer, SMAD signaling exhibits profound duality [18,20]. While it functions as a tumor suppressor in premalignant stages by enforcing growth arrest and apoptosis [[21], [22], [23]], it frequently acquires pro-tumorigenic features in advanced disease [24,25]. This includes promotion of EMT [26,27], enhancement of cancer stemness [28,29], remodeling of the TME [30,31], and modulation of anti-tumor immunity [32,33]. Notably, SMAD signaling is not limited to cancer cells. In the TME, SMAD-dependent signaling programs control macrophage polarization [33], neutrophil plasticity [34], T cell exhaustion [35], and NK cell dysfunction [36]. Additionally, pathologic SMAD activity sustains resistance to chemotherapy [37], immune checkpoint blockade [38], and cellular immunotherapies [39]. Its integration into non-coding RNAs [40], metabolic networks [41], and chromatin remodeling complexes [42] also reflects its central position in the cancer process.

In this review, we outline the multifaceted functions of SMAD signaling in cancer, spanning EMT, metabolic rewiring, immune modulation, and therapy resistance. We focus on emerging mechanistic paradigms in canonical and non-canonical SMAD pathways and discuss how selective modulation of these pathways might unlock new therapeutic strategies for immunologically “cold” and treatment-refractory tumors.