TGF-β Signaling in Cancer Immunity: Immune Suppression, Stromal Remodeling, and Therapeutic Targeting
DOI:
https://doi.org/10.66505/cbtt.v1i2.17Keywords:
TGF-β signaling, tumor microenvironment, cancer immunotherapy, immune checkpoint blockade, PD-1 pathway, stromal exclusionAbstract
Transforming growth factor-β (TGF-β) is a pleiotropic cytokine with context-dependent roles in cancer. TGF-β signaling regulates cell proliferation, immune responses, extracellular matrix remodeling, and tissue homeostasis through SMAD-dependent and noncanonical pathways. Although TGF-β functions as a tumor suppressor during early tumorigenesis by limiting epithelial proliferation and preserving tissue integrity, advanced tumors frequently exploit this pathway to promote immune evasion, stromal remodeling, and metastatic progression. Increasing evidence identifies TGF-β as a central regulator of the tumor microenvironment (TME), where it suppresses cytotoxic lymphocyte activity, expands immunosuppressive myeloid populations, and activates stromal programs that exclude effector T cells from tumor nests. Through these coordinated mechanisms, TGF-β establishes an immunosuppressive milieu that contributes to resistance to immune checkpoint blockade and other immunotherapies. In this review, we summarize current understanding of how TGF-β shapes tumor immunity through its effects on T cells, natural killer cells, myeloid-derived suppressor cells, tumor-associated macrophages, and cancer-associated fibroblasts. We also discuss emerging therapeutic strategies targeting the TGF-β pathway, including receptor kinase inhibitors, ligand traps, and bifunctional molecules that simultaneously inhibit TGF-β and immune checkpoints. While early clinical studies have demonstrated promising immunomodulatory activity, recent trials highlight the challenges of targeting a pathway that also regulates normal tissue homeostasis. Improved mechanistic insights and biomarker-driven patient stratification will be essential for maximizing the therapeutic potential of TGF-β inhibition in cancer immunotherapy. Collectively, these findings position TGF-β signaling as a central axis linking tumor cells, stromal remodeling, immunosuppression, and therapeutic resistance across diverse solid and hematologic malignancies.
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