Transforming Growth Factor-β Signaling in Immunity and Cancer

BackgroundTransforming growth factor-β-mediated (TGF-β) pathways are implicated in the immunosuppressive activity of cancer cells.1–3 Due to its immunosuppressive nature, inhibition of TGF-β has become a topic of interest in cancer...

Simple SummaryThere is currently no effective treatment for patients with advanced pancreatic ductal adenocarcinoma (PDAC). Transforming Growth Factor β (TGFβ) signaling has been implicated in several hallmark features of PDAC pathobiology, and TGFβ inhibitors are beginning to show promise in the treatment of PDAC. Here, we discuss the known roles of TGFβ signaling in the pancreatic tumor microenvironment, as well as clinical trials evaluating TGFβ pathway inhibitors in PDAC patients.Pancreatic ductal adenocarcinoma (PDAC) is associated with poor clinical outcomes, largely attributed to incomplete responses to standard therapeutic approaches. Recently, selective inhibitors of the Transforming Growth Factor β (TGFβ) signaling pathway have shown early promise in the treatment of PDAC, particularly as a means of augmenting responses to chemo- and immunotherapies. However, TGFβ is a potent and pleiotropic cytokine with several seemingly paradoxical roles within the pancreatic tumor microenvironment (TME). Although TGFβ signaling can have potent tumor-suppressive effects in epithelial cells, TGFβ signaling also accelerates pancreatic tumorigenesis by enhancing epithelial-to-mesenchymal transition (EMT), fibrosis, and the evasion of the cytotoxic immune surveillance program. Here, we discuss the known roles of TGFβ signaling in pancreatic carcinogenesis, the biologic consequences of the genetic inactivation of select components of the TGFβ pathway, as well as past and present attempts to advance TGFβ inhibitors in the treatment of PDAC patients.

Polymerase Slippage Restoration of Frameshifted TGFBR2 in Colorectal Cancer: A Novel Paradigm

Transforming growth factor-β (TGF-β) signaling is essential in embryo development and maintaining normal homeostasis. Extensive evidence shows that TGF-β activation acts on several cell types, including epithelial cells, fibroblasts, and immune cells, to form a pro-fibrotic environment, ultimately leading to fibrotic diseases. TGF-β is stored in the matrix in a latent form; once activated, it promotes a fibroblast to myofibroblast transition and regulates extracellular matrix (ECM) formation and remodeling in fibrosis. TGF-β signaling can also promote cancer progression through its effects on the tumor microenvironment. In cancer, TGF-β contributes to the generation of cancer-associated fibroblasts (CAFs) that have different molecular and cellular properties from activated or fibrotic fibroblasts. CAFs promote tumor progression and chronic tumor fibrosis via TGF-β signaling. Fibrosis and CAF-mediated cancer progression share several common traits and are closely related. In this review, we consider how TGF-β promotes fibrosis and CAF-mediated cancer progression. We also discuss recent evidence suggesting TGF-β inhibition as a defense against fibrotic disorders or CAF-mediated cancer progression to highlight the potential implications of TGF-β-targeted therapies for fibrosis and cancer.

Increasing evidence points to an active stromal involvement in cancer initiation and progression. Cytokines derived from tumor cells are believed to modulate stromal cells to produce growth and angiogenic factors, which in turn provide the tumor with the necessary microenvironment for expansion and invasion. Transforming growth factor beta (TGFbeta) has been implicated as a candidate cytokine to mediate this communication. However, how its signaling in stromal cells regulates tumorigenesis and tumor progression remains unresolved. We show that normal, presenescent fibroblasts or prostate stromal cells cotransplanted with prostate carcinoma cells s.c. into nude mice reduced tumor latency and accelerated tumor growth. When their TGFbeta signaling was blocked, the fibroblasts and stromal cells still stimulated tumor initiation but no longer supported tumor growth as control cells did. The loss of the tumor growth-promoting activity of the stromal cells with attenuated TGFbeta signaling was not associated with altered cellular senescence or tumor angiogenicity. TGFbeta and the medium conditioned by the prostate carcinoma cells stimulated myofibroblast differentiation of the intact stromal cells, but not the stromal cells with attenuated TGFbeta signaling. Gene microarray and quantitative reverse transcription-PCR analyses showed that TGFbeta up-regulated a host of genes in stromal cells that are involved in tissue remodeling and wound healing. Thus, our study provides evidence for TGFbeta as a supporting agent in tumor progression through the induction of a perpetual wound healing process in the tumor microenvironment.

Transforming growth factor-β (TGF-β) signaling plays a complex and dual role in regulating cellular senescence and tumor progression. In normal tissues, TGF-β acts as a tumor suppressor by regulating the cell cycle, inducing apoptosis, and maintaining the integrity of the extracellular matrix (ECM). These functions collectively restrict tumor initiation and support tissue homeostasis. However, in the tumor microenvironment, sustained TGF-β signaling frequently switches to a tumor-promoting role, driving tumor cell proliferation, metastatic dissemination, immune evasion, and therapy resistance. This review aims to clarify the dual role of TGF-β signaling in cellular senescence and tumor progression. It focuses on the molecular mechanisms that drive its transition between tumor suppression and tumor promotion in various biological contexts. We analyze the key determinants governing this functional switch, including tumor type, cellular environment, and signaling crosstalk. Furthermore, we critically evaluate the clinical challenges of therapeutic TGF-β targeting. We highlight emerging strategies to therapeutically modulate TGF-β signaling, focusing on precision medicine approaches that reconcile its tumor-suppressive and oncogenic functions. By providing a comprehensive understanding of TGF-β's dual role, this review offers new insights that may guide personalized cancer therapies and optimize treatment strategies for improved clinical outcomes.

Transforming growth factor-β (TGF-β) signaling is an important pathway for promoting the pathogenesis of inflammatory diseases, including cancer. The roles of TGF-β signaling are heterogeneous and versatile in cancer development and progression, both anticancer and protumoral actions are reported. Interestingly, increasing evidence suggests that TGF-β enhances disease progression and drug resistance via immune-modulatory actions in the tumor microenvironment (TME) of solid tumors. A better understanding of its regulatory mechanisms in the TME at the molecular level can facilitate the development of precision medicine to block the protumoral actions of TGF-β in the TME. Here, the latest information about the regulatory mechanisms and translational research of TGF-β signaling in the TME for therapeutic development had been summarized.

See related article, pages 185–192 In response to hemodynamic overload, the heart undergoes a complex adaptive remodeling process that involves cardiac myocyte hypertrophy, transformation of fibroblast into myofibroblast, high-level expression of extracellular matrix (ECM) proteins, interstitial fibrosis, and cell death.1 Differentiation of cardiac fibroblasts into myofibroblasts is critical to the production and deposition of collagens and plays a decisive role in myocardial fibrosis and morphological alterations during the progression of adaptive myocardial hypertrophy to decompensation and heart failure.1,2 Among the plethora of identified fibrogenic factors, transforming growth factor (TGF)-β3 plays a fundamental role in hypertrophic and fibrotic remodeling of the heart, where it regulates cardiomyocyte growth, fibroblast activation, and ECM deposition.4,5 The expression of ventricular TGF-β mRNA and protein is increased in numerous models of pathological cardiac hypertrophy and in cardiac cells in response to putative hypertrophic stimuli.6,7 In vitro, TGF-β activates myofibroblast transformation and increases ECM production.7 Blockade of TGF-β signaling is predicted to blunt fibrosis.5 Recent studies from Chen et al8 convincingly demonstrated that disruption of TGF-β signaling by inducible dominant-negative mutation of the TGF-β receptor type II (TβRII) gene significantly reduced the pressure overload–induced myofibroblast transformation and interstitial fibrosis in mouse heart. Thus, there is considerable interest in understanding how signaling by TGF-β receptors is transduced and how the inevitable damage produced could be mitigated. Of the 3 isoforms of TGF-β expressed in mammals,9,10 TGF-β1 is expressed in the adult heart, where it is secreted by cardiomyocytes and myofibroblasts and retained in significant amounts in ECM as a latent cytokine. Recent advances have led to clear description of downstream of TGF-β signal transduction pathways initiated by binding of TGF-β to membrane-bound heteromeric receptor kinases (TβRI and TβRII) that transduce intracellular signals via both Smad and non-Smad pathways …

Transforming growth factor-β (TGF-β) signaling in cancer has been studied in great detail since observations more than two decades ago suggested that TGF-β may have a role in tumor suppression in epithelial cells, from which a majority of cancers arise (Tucker et al. 1984; Moses et al. 1985; Roberts et al. 1985). TGF-β also demonstrated the ability to contribute to transformation of fibroblast cell types, further confirming the importance for this pathway in cancer (Roberts and Sporn 1985). The early years of TGF-β research led to identification of pathways potentially regulated by TGF-β signaling in the cancer microenvironment, including immune evasion, angiogenesis, and modification of other central stromal components that contribute to disease progression (Roberts et al. 1988). These early postulates have been confirmed in many cancer models and clinical studies. It is now clear that TGF-β is a central signaling component in the tumor microenvironment. In cancer, the TGF-β1 ligand is expressed at higher levels than TGF-β2 or TGF-β3 (Derynck et al. 1987; Dickson et al. 1987). This preferential expression has resulted in a focus on the TGF-β1 ligand in a majority of the current literature. It is possible that there are unique roles for each isoform in the cancer microenvironment, but we herein focus on the TGF-β1 ligand to generalize signaling through this pathway. Up-regulation of TGF-β1 expression is common in cancer, and this increase in expression can be readily detected in tumors (Wojtowicz-Praga 2003). In addition, the increase in TGF-β abundance in tumor tissue is often accompanied...

Transforming growth factor beta (TGF-beta) and related growth factors are essential regulators of embryogenesis and tissue homeostasis. The signaling pathways mediated by their receptors and Smad proteins are precisely modulated by various means. Xenopus BAMBI (bone morphogenic protein (BMP) and activin membrane-bound inhibitor) has been shown to function as a general negative regulator of TGF-beta/BMP/activin signaling. Here, we provide evidence that human BAMBI (hBAMBI), like its Xenopus homolog, inhibits TGF-beta- and BMP-mediated transcriptional responses as well as TGF-beta-induced R-Smad phosphorylation and cell growth arrest, whereas knockdown of endogenous BAMBI enhances the TGF-beta-induced reporter expression. Mechanistically, in addition to interfering with the complex formation between the type I and type II receptors, hBAMBI cooperates with Smad7 to inhibit TGF-beta signaling. hBAMBI forms a ternary complex with Smad7 and the TGF-beta type I receptor ALK5/TbetaRI and inhibits the interaction between ALK5/TbetaRI and Smad3, thus impairing Smad3 activation. These findings provide a novel insight to understand the molecular mechanism underlying the inhibitory effect of BAMBI on TGF-beta signaling.

Background:Wnt and transforming growth factor-β (TGF-β) signaling pathways are known to be involved in the pathogenesis of androgenetic alopecia (AGA). However, the way that Wnt and TGF-β signaling is altered in patients with AGA and whether there exists a crosstalk between them in pathogenetic process of AGA remain unclear.Objectives:To investigate the expression of Wnt and TGF-β signaling and the crosstalk between these 2 signaling pathways in AGA.Methods:Fifteen male patients with AGA were recruited for our research. Fifteen scalp specimens of the balding were collected from frontal areas, and 9 nonbalding were collected from occipital areas. We analyzed the expression and activation of downstream Wnt and TGF-β signaling molecules in both balding and nonbalding hair follicles isolated from scalp specimens. Furthermore, we evaluated the activation of Wnt and TGF-β signaling after either of them was blocked with the inhibitor in balding and nonbalding dermal papilla (DP) cells.Results:Compared with the nonbalding counterparts, the mRNA level of Wnt10a and LEF1 was decreased. But TβRI and TβRII, and the protein expression of TGF-β1 was elevated in balding hair follicles. To investigate the crosstalk between Wnt and TGF-β signaling, we used SB431542 to inhibit the TGF-β signaling in balding DP cells and found that SB431542 significantly attenuated the phosphorylation of Smad2 and Akt. However, the mRNA level of Wnt10a, LEF1, and the nuclear translocation of β-catenin was increased. On the other hand, we suppressed the Wnt signaling by XAV939 in nonbalding DP cells, which displayed that the level of β-catenin and LEF1 was significantly inhibited; however, the level of active TGF-β1 and the phosphorylation of Smad2 and Akt were up-regulated.Conclusions:These data indicate that crosstalk between Wnt/β-catenin and TGF-β signaling pathways may exist as one of the important mechanisms contributing to AGA.

Atrophic acne scar, a persistent sequela from acne, is undesirably troubling to many patients due to its cosmetic and psychosocial aspects. Although there have been some reports emphasizing the role of early inflammatory responses in atrophic acne scarring, evolving perspectives on the detailed pathogenic processes are promptly needed. Examining the histological, immunological and molecular changes in early acne lesions susceptible to atrophic scarring can provide new insights to understand the pathophysiology of atrophic acne scar. We experimentally validated several early fundamental hallmarks accounting for the transition of early acne lesions to atrophic scars by comparing molecular profiles of skin and acne lesions between patients who were prone to scar (APS) or not (ANS). In APS, compared with ANS, devastating degradation of elastic fibres and collagen fibres occurred in the dermis, followed by their incomplete recovery. Abnormally excessive inflammation mediated by innate immunity with T helper 17 and T helper 1 cells was observed. Epidermal proliferation was significantly diminished. Transforming growth factor (TGF)-β1 was drastically elevated in APS, suggesting that aberrant TGF-β1 signalling is an underlying modulator of all of these pathological processes. These results may provide a basis for understanding the pathogenesis of atrophic acne scarring. Reduction of excessive inflammation and TGF-β1 signalling in early acne lesions is expected to facilitate the protection of normal extracellular matrix metabolism and ultimately the prevention of atrophic scar formation. What's already known about this topic? The dermis of atrophic acne scars shows alteration of extracellular matrix components such as collagen fibres. Inflammation in acne lesions is associated with the development of acne scars. What does this study add? Abnormalities in the metabolism of collagen fibres and elastic fibres were observed in the early developmental stages of acne lesions that were progressing into atrophic scars. Exacerbated inflammation and aberrant epidermal proliferation by increased transforming growth factor (TGF)-β1 signalling may affect the abnormal extracellular matrix metabolism. What is the translational message? Abnormal changes in elastic fibres and collagen fibres are found in the early developmental process of acne in patients who are prone to atrophic scarring. An early treatment regimen strongly inhibiting inflammation and TGF-β1 signalling to help the normal recovery of the extracellular matrix components is required to prevent atrophic scarring.

Transforming growth factor-β (TGF-β) signaling is required for normal vascular development. We aimed to discover the role of TGF-β signaling in embryonic smooth muscle cells (SMCs). We bred mice with smooth muscle (SM) 22α-Cre and Tgfbr2(flox) alleles to generate embryos in which the type II TGF-β receptor (TGFBR2; required for TGF-β signaling) was deleted in SMCs. Embryos were harvested between embryonic day (E) 9.5 and E18.5 and examined grossly, microscopically, and by histochemical and RNA analyses. SM22α-Cre(+/0) Tgfbr2(flox/flox) (knockout [KO]) embryos died before E15.5 with defects that included cardiac outflow tract abnormalities, persistence of the right dorsal aorta, and dilation of the distal aorta. Histological analyses suggested normal expression of SMC differentiation markers in KO aortas; however, RNA analyses showed that SMC differentiation markers were increased in KO cardiac outflow vessels but decreased in the descending aorta. KO aortas had only rare mature elastin deposits and contained abnormal aggregates of extracellular matrix proteins. Expression of several matrix proteins was significantly decreased in KO descending aortas but not in cardiac outflow vessels. TGF-β signaling in SMCs controls differentiation, matrix synthesis, and vascular morphogenesis. Effects of TGF-β on SMC gene expression appear to differ depending on the location of SMCs in the aorta.

Transforming growth factor-beta (TGF-β) signaling is one of the important cellular pathways that play key roles for tissue maintenance. In particular, it is important in the context of inflammation and tumorigenesis by modulating cell growth, differentiation, apoptosis, and homeostasis. TGF-β receptor type 2 (TGFBR2) mutations affected by a mismatch repair deficiency causes colorectal cancers (CRCs) with microsatellite instability, which is, however, associated with relatively better survival rates. On the other hand, loss of SMAD4, a transcription factor in the TGF-β superfamily signaling, promotes tumor progression. Loss of heterozygosity on chromosome 18 can case SMAD4-deficient CRC, which results in poorer patients’ survival. Such bidirectional phenomenon driven by TGF-β signaling insufficiency reflects the complexity of this signaling pathway in CRC. Moreover, recent understanding of CRC at the molecular level (consensus molecular subtype classification) provides deep insight into the important roles of TGF-β signaling in the tumor microenvironment. Here we focus on the TGF-β signaling in CRC and its interaction with the tumor microenvironment. We summarize the molecular mechanisms of CRC tumorigenesis and progression caused by disruption of TGF-β signaling by cancer epithelial cells and host stromal cells.

PANoptosis, an integrated form of programmed cell death encompassing pyroptosis, apoptosis, and necroptosis, has emerged as a key mechanism at the intersection of inflammation and immunity [1] . Acting through the PANoptosome complex, this multifaceted pathway not only regulates cellular homeostasis but also orchestrates immune activation and tissue remodeling. In the tumor immune microenvironment, PANoptosis plays dual roles: it can amplify anti-tumor immunity or, conversely, induce immune exhaustion and immune escape when dysregulated [2,3] . T cell-based immunotherapy-including immune checkpoint blockade (ICB) and chimeric antigen receptor (CAR) T cell therapy-has transformed the therapeutic landscape of multiple cancers [4] . However, the variability in patient responses underscores the complexity of immune regulation and cell death signaling. Exploring how PANoptosis modulates T cell activity offers new insights into the mechanisms underlying immunotherapy resistance and tumor immune evasion. This Research Topic gathers a series of studies that collectively explore this dynamic interplay from molecular discovery to translational potential.At the molecular level, Wang et al. applied a multi-omics strategy to classify renal cell carcinoma (RCC) into distinct metabolic subtypes. Their findings revealed that metabolic reprogramming tightly associates with PANoptosis-related signaling, defining prognostic subgroups and potential targets for precision immunotherapy. Building on the theme of molecular regulation, Tao et al. investigated cathepsin Z (CTSZ) in prostate cancer and found that its overexpression not only predicts poor clinical outcomes but also shapes an immunosuppressive microenvironment characterized by elevated PD-1 and PD-L1 expression-linking protease signaling to checkpoint regulation and PANoptotic control.Expanding this exploration into other cancer types, Lei et al. developed a programmed cell death (PCD) score model for hepatocellular carcinoma (HCC) that integrates transcriptomic and single-cell analyses. Their identification of UBE2E1 as a key oncogenic driver associated with high PCD scores highlights how cell death dynamics affect T cell exhaustion and tumor aggressiveness. Complementing this, Wu et al. conducted a pancancer analysis of PLAG1 and demonstrated its functional role in promoting tumor proliferation and immune evasion in bladder cancer, further strengthening the connection between PANoptosis and immune modulation.Moving from genomics to the tumor microenvironment, Liao et al. explored the clinical relevance of tumor mutation burden (TMB) across cancers and identified RPLP0 as a predictive biomarker for immunotherapy response. Interestingly, RPLP0 knockdown enhanced anti-PD-L1 efficacy in bladder cancer models, providing a tangible example of how PANoptosis-related translational control may affect therapeutic sensitivity. Similarly, Wan et al. synthesized current findings on immune cell PANoptosis in colorectal cancer, emphasizing that excessive immune cell death can undermine anti-tumor immunity and proposing strategies to restore immune balance through targeted interventions.Beyond oncology, Chen et al. extended the concept of PANoptosis to diabetic retinopathy, identifying several hub genes that regulate inflammation and immune cell infiltration. Their integrative machine-learning approach underscores that PANoptotic signaling has broad implications in immune-related diseases beyond cancer. In parallel, Ma et al. reviewed advances in immunogenic cell death (ICD) and nanomaterial-based therapies, highlighting how nanotechnology can trigger PANoptosis-like mechanisms to promote antigen release and potentiate durable T cell immunity. These findings demonstrate that manipulating cell death pathways can synergize with T cell-based therapies to achieve improved clinical outcomes.Together, the articles in this Research Topic illuminate PANoptosis as a pivotal immunoregulatory hub bridging cell death, metabolism, and immune activation. They reveal how fine-tuning PANoptotic signaling can shape tumor immunogenicity, determine therapeutic response, and open new avenues for combinatorial immunotherapy. Future studies integrating single-cell, spatial, and multi-omics technologies will be essential to define the spatial and temporal coordination of PANoptosis within the tumor microenvironment. By deepening our mechanistic understanding, researchers may unlock strategies to exploit PANoptosis for enhanced T cell function, reinvigorated anti-tumor immunity, and ultimately improved patient survival.