INTRODUCTION
Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers, often diagnosed late with a poor prognosis. Understanding the molecular mechanisms driving its progression is essential for developing effective therapies. The aryl hydrocarbon receptor (AHR) has recently been recognized as a key factor in the pathogenesis of several cancers, including ESCC. Rahmati et al’s mini-review offers a comprehensive analysis of AHR’s role in ESCC, emphasizing its potential as a therapeutic target[1]. This editorial highlighted the key insights from their work, exploring the implications of AHR dynamics in ESCC and its potential to influence future treatment approaches.
AHR ACTIVATION AND ITS EFFECTS ON GENE EZPRESSION IN ESCC
The activation of the AHR plays a pivotal role in regulating gene expression in ESCC. Upon ligand binding, AHR translocates to the nucleus and binds to xenobiotic response elements in the promoters of target genes. This transcriptional regulation affects several pathways involved in cancer progression, including cell proliferation, migration, and immune evasion. AHR activation notably modulates genes linked to cell proliferation and metastasis. For instance, AHR upregulates cytochrome P450 1A1, a gene involved in xenobiotic detoxification, which is also associated with oxidative stress, DNA damage, and carcinogenesis[1]. This highlights AHR’s dual role in both protecting against environmental toxins and promoting tumor development in contexts such as ESCC. Another key gene influenced by AHR is ATP-binding cassette subfamily G member 2, which contributes to multidrug resistance. Constitutive AHR activation has been shown to increase ATP-binding cassette subfamily G member 2 expression in cisplatin-resistant ESCC cells, enhancing drug efflux and reducing chemotherapy efficacy[2]. This demonstrates AHR’s role not only in tumor progression but also in treatment resistance, underscoring its importance as a therapeutic target. AHR activation also influences genes involved in epithelial-mesenchymal transition, a process critical for cancer invasion and metastasis. Studies have shown that AHR activation can inhibit RhoA/Rho-associated protein kinase 1 signaling, reversing the mesenchymal phenotype and reducing ESCC cell invasiveness[3]. This indicates that AHR plays a nuanced role, balancing tumor suppression and promotion depending on the signaling context. Moreover, AHR activation regulates genes that facilitate immune escape. For example, it promotes the expression of indoleamine 2,3-dioxygenase 1, an enzyme that metabolizes tryptophan into kynurenine, which in turn activates AHR and fosters an immunosuppressive environment. This promotes the recruitment of regulatory T cells (Tregs) and suppresses cytotoxic T cell activity[1]. The kynurenine/sialic acid binding immunoglobulin like lectin 15 (Siglec-15) axis, as identified by Zhang et al[4], further contributes to immune evasion in squamous cell carcinomas, suggesting a similar mechanism in ESCC. By creating an immunosuppressive microenvironment, AHR helps cancer cells evade immune detection. In addition, AHR modulates macrophage polarization within the tumor microenvironment (TME). Activation of AHR drives macrophages toward an M2-like phenotype, which is associated with pro-tumorigenic activities such as angiogenesis and tissue remodeling[5]. These macrophages secrete cytokines that support tumor growth and metastasis, further emphasizing how AHR shapes the TME to favor cancer progression. AHR activation also interacts with molecular chaperones, with ligand specificity influencing these interactions. Narita et al[6] demonstrated that different toxic and non-toxic ligands recruit distinct sets of chaperone proteins to the AHR complex, impacting transcriptional outcomes. This ligand-specific regulation underscores the complexity of AHR’s role in gene expression and presents opportunities for therapeutic intervention by manipulating ligand-AHR interactions. Overall, AHR activation in ESCC leads to the upregulation of genes associated with oxidative stress, drug resistance, immune evasion, and tumor progression. Targeting AHR and its downstream pathways offers a promising strategy for disrupting these mechanisms, potentially improving patient outcomes by inhibiting tumor growth and enhancing immunotherapy efficacy. Continued research into the specific gene networks regulated by AHR in ESCC will be critical for developing more effective AHR-targeted therapies[1,7].
IMMUNE MODULATION BY AHR
The AHR plays a crucial role in shaping immune responses within the TME, creating an immunosuppressive environment that promotes tumor progression. Beyond its direct effects on tumor cells, AHR profoundly influences both the innate and adaptive immune systems, particularly affecting Tregs, dendritic cells, and macrophages. As Rahmati et al[1] note, AHR activation fosters an immune-suppressive microenvironment conducive to tumor growth in ESCC. AHR’s impact on dendritic cells includes the induction of immunosuppressive cytokines such as interleukin 10 and transforming growth factor-β, which impair T cell activation and proliferation, thereby weakening the immune response against tumor cells[1]. Moreover, AHR signaling promotes Tregs, which inhibit effector T cells and reinforce immune suppression in tumors[8]. This dampening of the immune response further compromises the body’s ability to combat cancer effectively. In addition to Tregs, AHR also modulates macrophages within the TME. Activation of AHR polarizes macrophages toward an M2-like phenotype, characterized by tumor-promoting activities such as the secretion of growth factors, angiogenic mediators, and tissue-remodeling enzymes[5]. These M2-like macrophages support metastasis and immune evasion, contributing to tumor progression, as shown in studies across multiple cancers, including ESCC. While AHR’s role in immune suppression and tumor promotion presents challenges, it also offers therapeutic opportunities. AHR-driven immune modulation can hinder immunotherapies by promoting immune tolerance, but targeting AHR could enhance cancer treatments. Blocking AHR may reduce Treg-mediated suppression and reprogram macrophages toward an anti-tumor M1 phenotype, thereby restoring immune surveillance and strengthening the anti-tumor response[7]. Interestingly, AHR’s effects on immune cells appear to be ligand-dependent. Narita et al[6] demonstrated that different AHR ligands, whether toxic or non-toxic, elicit distinct immune responses. This ligand-specific activation suggests that not all forms of AHR engagement lead to immunosuppression, which holds significant implications for developing selective therapies targeting AHR. Furthermore, dietary components such as tryptophan metabolites can activate AHR and influence immune function in non-cancerous contexts, indicating that modulating AHR could have preventative benefits as well[9]. In sum, AHR’s ability to shape the immune landscape in cancer, particularly through its effects on Tregs and macrophages, makes it a compelling target for novel therapeutic strategies. By inhibiting its immunosuppressive actions, we could disrupt the tumor-supportive environment, enhancing immunotherapy efficacy and improving patient outcomes. The growing understanding of AHR’s role in immune regulation underscores the need for therapies that account for its complex, context-dependent effects on various immune cells[10].
THERAPEUTIC POTENTIAL OF TARGETING AHR
The exploration of the AHR as a therapeutic target in ESCC has garnered significant attention, with various studies highlighting its potential to enhance cancer treatment strategies. AHR plays a pivotal role in modulating immune responses and influencing tumor progression, making it an attractive candidate for targeted therapies. The editorial accompanying the mini-review by Rahmati et al[1] emphasizes novel strategies for inhibiting AHR activity in ESCC, including the development of small molecule inhibitors and the exploration of natural compounds to disrupt AHR signaling pathways. Targeting these pathways could inhibit tumor growth and improve patient outcomes. AHR’s immune-modulatory effects are a crucial aspect of its therapeutic potential. AHR activation often leads to an immunosuppressive TME, enabling cancer cells to evade immune detection and proliferate unchecked[1]. Research has shown that inhibiting AHR could reverse these effects, potentially restoring immune surveillance and enhancing the body’s natural ability to combat tumors. This has broad implications for improving the efficacy of existing therapies, especially when AHR inhibitors are combined with conventional treatments like chemotherapy and immunotherapy, which may yield synergistic effects. The study by Malany et al[5] underscores this potential, highlighting how AHR-driven macrophage functions can be modulated to favor anti-tumor responses. Moreover, AHR’s role extends beyond immune modulation to influence tumor progression and metastasis. Helmbrecht et al[7] suggest that the modern human AHR, when ancestralized through genome editing, exhibits higher activity levels. This discovery points to new avenues for therapeutic interventions, as manipulating AHR activity could enhance its effectiveness as a target in cancer treatment. Similarly, Narita et al[6] provide valuable insights into how different ligands, whether toxic or non-toxic, differentially affect the AHR-molecular chaperone complex. This understanding could guide the development of more precise AHR inhibitors that selectively target cancer-promoting activities while minimizing adverse effects. Integrating AHR inhibitors into combination therapies represents another promising strategy for improving treatment outcomes in ESCC. Although AHR has been studied as a drug target in other cancers, including advanced prostate cancer, the challenges and insights from those investigations are equally relevant to ESCC[10]. Overcoming obstacles like drug resistance and improving inhibitor efficacy remain critical. The potential for AHR-targeted therapies to complement other modalities, such as immune checkpoint inhibitors, opens up a multi-faceted approach to cancer treatment that could address both the tumor and its immune microenvironment. Recent studies further support the innovative use of AHR inhibitors in modulating the metabolic landscape of tumors. The kynurenine/Siglec-15 axis has been explored in head and neck squamous cell carcinoma, revealing crucial interactions that may also occur in ESCC[4]. Targeting this axis could potentially prevent immune evasion and enhance the therapeutic efficacy of AHR inhibitors, highlighting a broader scope for AHR-targeted therapies that extend beyond traditional immune modulation to integrate metabolic pathways. In summary, targeting AHR in ESCC presents a multifaceted therapeutic strategy with the potential to improve patient outcomes by directly inhibiting tumor growth and modulating the immune environment. The research reviewed here demonstrates that AHR’s role in both immune suppression and tumor progression makes it a valuable target for developing novel treatments. Continued investigation into AHR inhibitors, their interactions with other therapeutic modalities, and the exploration of specific metabolic pathways will be essential for advancing cancer therapies and improving patient outcomes in ESCC. The integration of AHR-targeted strategies into the current cancer treatment landscape represents a promising direction for future clinical applications.
FUTURE DIRECTIONS IN AHR RESEARCH
Research into the AHR in ESCC has gained significant momentum, presenting opportunities to advance cancer therapy. As discussed by Rahmati et al[1], targeting AHR may modulate immune responses and inhibit tumor progression. However, the mechanisms through which AHR influences tumor biology and immune modulation in ESCC remain incompletely understood, necessitating further investigation. One critical area for future research involves dissecting the molecular pathways by which AHR impacts both oncogenic signaling and immune surveillance in ESCC. Understanding AHR’s role in immune evasion is particularly important, as it may help identify biomarkers for treatment resistance or response. The kynurenine/Siglec-15 axis, highlighted in studies of head and neck squamous cell carcinoma[4], suggests potential parallels in ESCC. Investigating whether similar metabolic interactions occur in ESCC could provide valuable insights for developing more effective therapeutic strategies. The development of AHR inhibitors represents another promising therapeutic approach, though challenges remain. As Helmbrecht et al[7] indicate, modifying AHR to mimic ancestral versions could enhance receptor activity and therapeutic efficacy. This concept raises the possibility of designing inhibitors finely tuned to modulate AHR signaling without compromising physiological functions, thereby reducing off-target effects. Furthermore, Mosa et al[11] emphasize the potential of repurposing clinically approved drugs as AHR modulators, which could expedite the development of new treatment options for ESCC. However, safety concerns related to AHR inhibition must also be addressed. Narita et al[6] explain that the composition of the AHR-chaperone complex varies depending on whether the ligand is toxic or non-toxic, highlighting the need for thorough preclinical testing to mitigate potential adverse effects. Understanding the toxicological profiles of AHR inhibitors is crucial to ensuring their safe application in cancer therapy. As well as Malany et al[5] pointed out, AHR-driven macrophage polarization could lead to unintended immune consequences, necessitating a careful balance between immune modulation and anti-tumor effects. Delivery mechanisms also warrant critical attention in future research. Effective delivery of AHR inhibitors to tumor cells while minimizing systemic exposure is essential for maximizing therapeutic benefit. Targeted delivery systems, potentially employing nanoparticle-based approaches, could enhance drug accumulation in the TME and reduce off-target toxicity - a significant challenge that must be addressed for these therapies to succeed in clinical settings. Moreover, the interplay between AHR and other oncogenic pathways in ESCC deserves further investigation. Recent studies, such as those by Zhang et al[12], suggest that AHR may intersect with pathways like Wnt/β-catenin and mitogen-activated protein kinase, known to drive cancer progression. Targeting these intersections could yield novel combination strategies for treating ESCC, as indicated by similar approaches in other cancers[13]. Finally, clinical trials evaluating AHR inhibitors in combination with standard-of-care therapies, such as chemotherapy or immune checkpoint inhibitors, are essential to determine whether these agents can improve patient outcomes. Optimizing such combinatory regimens could enhance therapeutic efficacy by simultaneously targeting multiple facets of ESCC biology, a strategy currently being explored with other molecular targets[14]. Overall, the work of Rahmati et al[1] lays a foundation for advancing AHR research in ESCC. By addressing these future directions, researchers can develop more effective and safer therapeutic strategies that leverage AHR’s unique role in cancer biology.
CONCLUSION
This editorial emphasizes the significant insights provided by Rahmati et al[1] regarding the AHR and its multifaceted role in ESCC. Their work positions AHR as a promising therapeutic target with the potential to enhance treatment strategies for ESCC. Building on this foundation, Helmbrecht et al[7] suggest that ancestralizing of AHR through genome editing could fine-tune its modulation and lead to more effective therapeutic agents. Also, Zhang et al’s research on the kynurenine/Siglec-15 axis in head and neck squamous cell carcinoma highlights critical metabolic interactions that may offer valuable insights for ESCC, paving the way for targeting immune evasion mechanisms[4]. The development of potent, selective AHR inhibitors remains a key priority as the potential for clinical application increases. However, Narita et al[6] caution that variations in the components of the AHR-molecular chaperone complex - depending on ligand toxicity - necessitate careful evaluation of the safety and efficacy of these inhibitors. Furthermore, research by Malany et al[5] underscores the importance of optimizing AHR modulation to balance macrophage-driven immune responses, further highlighting the therapeutic potential of AHR-targeted strategies. In conclusion, Rahmati et al[1] have established a strong foundation for future research into harnessing AHR as a therapeutic target in ESCC. Continued investigation into its metabolic and immunological mechanisms, alongside the development of safe and effective inhibitors, will be critical for advancing AHR-based therapies and improving patient outcomes in ESCC.
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Medicine, research and experimental
Country of origin: Taiwan
Peer-review report’s classification
Scientific Quality: Grade C
Novelty: Grade B
Creativity or Innovation: Grade B
Scientific Significance: Grade B
P-Reviewer: Zheng Q S-Editor: Wei YF L-Editor: A P-Editor: Yu HG
