Transforming growth factor beta (TGF-β)

Overview

Transforming growth factor beta (TGF-β) is a secreted signaling protein — a multifunctional cytokine that exists in mammals as three closely related isoforms (TGF-β1, TGF-β2, TGF-β3). It is synthesized as a latent complex that must be activated before it can bind its receptors; release of the mature ligand from this latent form is a key regulatory step, mediated in part by integrins such as αvβ6, which is induced on epithelial cells during chronic tissue injury. Active TGF-β binds type II and type I serine/threonine kinase receptors, and the activated type I receptor phosphorylates receptor-regulated Smad proteins, which complex with Smad4 and accumulate in the nucleus to control transcription. Non-canonical branches, including MAPK signaling, operate alongside this canonical Smad route.

Biologically, TGF-β governs cell proliferation, differentiation, extracellular matrix deposition, immune regulation, and wound repair, and its effects are strongly context-dependent. In fibrosis, TGF-β/Smad signaling drives activation of stellate and other mesenchymal cells, collagen production, and epithelial-mesenchymal transition — processes central to liver fibrosis in metabolic dysfunction-associated steatohepatitis, intestinal fibrosis in chronic colitis, myocardial and renal fibrosis, and airway scarring; SIRT1-linked metabolic regulation has been implicated upstream of this axis. In cancer, TGF-β acts both as a tumor suppressor in early epithelial lesions and as a driver of invasion, metastasis, and immune evasion in established tumors, where it remodels the tumor microenvironment, promotes regulatory T cell differentiation, and suppresses the cytotoxic function of natural killer cells and CD8+ T cells, contributing to resistance to checkpoint inhibitors such as anti-PD-1 and anti-PD-L1 agents. This dual biology makes TGF-β both a mechanistic readout of fibrotic and immunosuppressive disease states and an active therapeutic target: strategies span small-molecule ATP-competitive inhibitors of the type I receptor kinase, ligand- and integrin-directed blockade, targeted protein degradation of pathway components, and cell-engineering approaches that render adoptively transferred immune cells insensitive to TGF-β-mediated suppression.

Recent Publications Focus

Transforming growth factor-beta (TGF-β) has emerged as a multifunctional therapeutic target across diverse disease contexts, ranging from fibrotic disorders to cancer and cardiovascular pathology. Recent research demonstrates that TGF-β modulation represents a viable strategy for addressing hepatic fibrosis progression, with indole-3-carbaldehyde shown to suppress fibrosis in metabolic dysfunction-associated steatohepatitis (MASH) by suppressing the TGF-β/SMAD signaling pathway 42435945Jul. Similarly, integrin αvβ6-targeted imaging identified epithelial remodeling associated with TGF-β1 activation in MASH progression 42426821Jul, while umbilical cord blood-derived platelet-rich plasma (UCB-PRP) attenuated TGF-β-driven hepatic stellate cell activation and fibrogenesis 41844050Mar. TGF-β/SMAD-mediated mechanisms also drive pathological remodeling in other organs; in diabetic kidney disease, the Yitangkang decoction targets TGF-β/Smad signaling pathways to mitigate glomerular filtration barrier damage 41740333Feb, and in pulmonary fibrosis, suppression of ADORA2B-induced TGF-β secretion reduces M2 macrophage infiltration and fibrotic progression 41992617Apr.

The canonical role of TGF-β in epithelial-mesenchymal transition (EMT) and fibrotic remodeling extends across multiple pathologies. In atherosclerosis, TGF-β drives endothelial-to-mesenchymal transition (EndMT), a process counterbalanced by protective signaling pathways 42313121Jun. In thoracic aortic aneurysm, modulating TGF-β signaling and reducing mTOR activity appear critical for limiting aneurysmal expansion 42222959Jun. Targeted degradation of JNK1, a core regulator of TGF-β-induced EMT, effectively inhibited this transition in fibrotic and cancer metastasis contexts 41856067Mar. Post-operative tracheal stenosis was addressed through a composite membrane that downregulated TGF-β and α-smooth muscle actin expression, promoting normal tissue regeneration while suppressing hypertrophic scar fibroblast activity 42107578May. In wound healing applications, methacrylated hyaluronic acid-platelet-rich fibrin microneedles sustained TGF-β release, achieving accelerated wound closure with enhanced collagen deposition 42229655Jun.

TGF-β blockade and modulation have become central strategies in cancer immunotherapy, where TGF-β functions as both a tumor-promoting factor and a driver of immune evasion within the tumor microenvironment. A bifunctional anti-PD-L1/TGF-β fusion protein demonstrated clinical efficacy in recurrent cervical cancer through IL-17 and TGF-β signaling pathway modulation 41866914Mar. TGF-β inhibition potentiated osimertinib-induced antitumor immunity in epidermal growth factor receptor (EGFR)-mutant lung cancer by reducing immunosuppressive signals and increasing effector T cell infiltration 41757675Feb. In Ewing sarcoma, circumventing TGF-β-mediated natural killer cell immunosuppression through TGF-β1-imprinting of CAR-modified NK cells, combined with IL-15 agonist and anti-GD2 antibody, overcame tumor microenvironment resistance 42398968Jul. TGF-β also emerged as a tumor microenvironment antigen target in immunomodulatory vaccines designed to expand anti-regulatory T cells and remodel suppressive cellular networks in solid tumors 41963297Apr. Additionally, TGF-β signaling regulated immune checkpoint expression; CARM1 inhibition enhanced dendritic cell function through TGF-β-dependent mechanisms 42424445Jul, while in intrahepatic cholangiocarcinoma, miR-7-5p suppressed TGF-β-dependent glycolysis and proliferation by targeting MyD88 42400723Jul.

Advanced therapeutic approaches targeting the TGF-β axis have evolved from traditional occupancy-based kinase inhibitors toward event-driven targeted protein degradation (TPD) strategies, including proteolysis-targeting chimeras (PROTACs) and lysosomal targeting chimeras (LYTACs), optimized through rational structure-activity relationship (SAR) design and artificial intelligence-guided molecular docking 42411223Jul. Metabolic regulation of TGF-β signaling has revealed immunometabolic checkpoints; elevated intratumoral SAICAR sustained TGF-β-SMAD3 signaling to promote regulatory T cell differentiation and resistance to anti-PD-1 therapy, while low-dose 6-mercaptopurine disrupted this pathway and synergized with checkpoint blockade 41671386Feb. In pancreatic ductal adenocarcinoma, nanotheranostic particles mitigated radiation-induced fibrosis by deactivating TGF-β-induced pancreatic stellate cell activation 41455284Dec, and in Duchenne muscular dystrophy, mitochondrial-targeted peptides suppressed TGF-β expression via mitoROS-mediated NF-κB inhibition to promote myogenesis while attenuating fibrosis 41875825Mar. These diverse therapeutic strategies underscore TGF-β as a convergent node in multiple disease pathways, with emerging evidence that integrating TGF-β modulation with complementary therapeutic approaches enhances efficacy across fibrotic, malignant, and inflammatory disease contexts.

What Changes, What Holds

1. TGF-β remains a central fibrotic node, but the newest work broadens the set of upstream and adjunctive ways to restrain it
REINFORCES Indole-3-carbaldehyde, UCB-PRP, and the kidney and lung studies all fit the established view that TGF-β/SMAD signaling drives fibrogenesis and can be therapeutically damped in organ-specific disease. The main change is not direction but practical scope: these reports strengthen the case that TGF-β is a convergent readout and intervention point across liver, kidney, and lung fibrosis, including MASH-associated remodeling and macrophage-linked progression 42435945Jul41844050Mar.

2. TGF-β-driven remodeling now looks even more broadly deployable across vascular, airway, and repair settings
REINFORCES The new studies extend the same core biology the Overview already assigns to TGF-β: EMT/EndMT, fibroblast activation, and scar formation. What they add is breadth, not contradiction, showing that the pathway remains a common mechanistic handle in atherosclerosis, aneurysm expansion, tracheal stenosis, and wound repair. The evidence also reinforces that manipulating TGF-β can either limit pathological remodeling or be harnessed to improve regeneration, depending on context 42313121Jun42107578May.

3. TGF-β blockade is moving from a theoretical immunotherapy adjunct to a clinically useful way to reverse immune suppression
REINFORCES These reports sharpen the established cancer biology rather than overturn it: TGF-β still appears to promote immune evasion, suppress effector cells, and support a suppressive tumor microenvironment. What changes is the therapeutic confidence that combining TGF-β inhibition with checkpoint blockade, targeted agents, or engineered immune cells can restore antitumor activity in difficult tumors. The vaccine and dendritic-cell findings also reinforce TGF-β as a network-level immunologic target, not just a stromal one 41866914Mar41757675Feb.

4. TGF-β is becoming a platform for combination design and targeted degradation rather than only kinase inhibition
NEW DIRECTION The Overview already mentions ATP-competitive inhibitors, ligand blockade, and cell engineering, but not event-driven degradation or metabolic checkpoint control. These studies therefore expand the therapeutic repertoire rather than contradicting it, showing that TGF-β can be attacked through PROTAC/LYTAC strategies and through upstream metabolic nodes that sustain SMAD3 signaling and regulatory T-cell differentiation. The implication is that future TGF-β therapy may be defined by combination logic and modality choice, not by receptor blockade alone 42411223Jul41671386Feb.

Overview update candidates: targeted degradation strategies for TGF-β pathway components; metabolic control of TGF-β-SMAD3 signaling as a resistance mechanism in cancer immunotherapy.