---
title: "Immunotherapy Resistance in Esophageal Cancer: Molecular Mechanisms and Therapeutic Strategies (Ar"
id: "frontiers-in-immunology-17-molecular-mechanisms-and-therapeutic-strategies-of-immunotherapy-resistance-in"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-17-molecular-mechanisms-and-therapeutic-strategies-of-immunotherapy-resistance-in"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1973515"
published_at: "2026-10-06T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Immunotherapy Resistance in Esophageal Cancer: Molecular Mechanisms and Therapeutic Strategies (Ar
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- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1973515)
- **Published At:** 2026-10-06T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The source is a review article titled "Molecular mechanisms and therapeutic strategies of immunotherapy resistance in esophageal cancer" published in Frontiers in Immunology. - The document metadata identifies this as a REVIEW article, but the body content of the article was not included in the provided source. - No specific molecular mechanisms, pathways, mutations, or immunologic processes were reported in the supplied text. - No therapeutic strategies, clinical trial data, drug names, combination approaches, or outcome measures were reported in the supplied text. - The supplied source includes journal navigation, section lists, and site headers but lacks the article’s abstract, main text, figures, tables, and references. - Because the core article content was not provided, definitive summaries, data extraction, or clinical recommendations cannot be drawn from the supplied material. - For clinicians and researchers, the available facts are limited to the article title, journal, article type (review), and incomplete date fragment; all substantive details were not reported in the source provided. - Any further clinical or mechanistic interpretation requires access to the full article text; this summary does not infer or invent mechanisms, trial results, or therapeutic recommendations.
## Clinical Analysis & Structured Key Points
Frontiers | Molecular mechanisms and therapeutic strategies of immunotherapy resistance in esophageal cancer REVIEW article Front. Immunol. , 06 October 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1973515 Published in Frontiers in Immunology Cancer Immunity and Immunotherapy 7 impact factor 11.3 citescore Part of a Research Topic Cancer cell immune evasion: epigenetic mechanisms and emerging therapeutic strategies Submission open 3200 views 3 articles Editor & Reviewers Edited by K R Kishu Ranjan Reviewed by J H Jinyang Huang F V Foram Vaidya Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Table 1 Selected clinical trials and registered studies investigating strategies to overcome immunotherapy resistance in esophageal cancer. View in article REVIEW article Front. Immunol. , 06 October 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1973515 Molecular mechanisms and therapeutic strategies of immunotherapy resistance in esophageal cancer Y P Yiqian Pang 1 † P J Panpan Jiang 1 † K L Ke Liu 1 X S Xingyao Suo 1 D Z Dianbao Zhang 1 Y X Yishi Xu 1 Y G Yi Ge 1 Q F Qizhi Fu 1 * S G Shegan Gao 1,2 * 1. Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China 2. Institute of Organoid on Chip and Drug Translation Research, Henan Academy of Sciences, Zhengzhou, China Article metrics View details Abstract Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has transformed the treatment landscape for advanced esophageal cancer (EC). Nevertheless, clinical benefits are constrained by primary and acquired resistance driven by a dynamic immunosuppressive tumor microenvironment (TME), extensive metabolic reprogramming, and epigenetic dysregulation. This review provides a comprehensive analysis of the molecular mechanisms underlying immunotherapy resistance in EC, including TME remodeling by cancer-associated fibroblasts, tumor-associated macrophages, and immunosuppressive cell populations; metabolic reprogramming encompassing glucose, amino acid, and lipid metabolism; epigenetic regulation involving DNA methylation, histone modifications, and non-coding RNAs; and compensatory immune checkpoint upregulation. We further highlight the emerging role of the microbiome and critically evaluate combination strategies designed to overcome resistance, including anti-angiogenic agents, ADCs, and personalized approaches guided by multi-omics and organoid models. 1 Introduction Esophageal cancer ranks as one of the most prevalent and lethal malignant tumors of the digestive tract globally, occupying the eighth position in cancer-related mortality rates ( 1 – 3 ). The two predominant histological subtypes are squamous cell carcinoma (ESCC) and adenocarcinoma (EAC). In China, the predominant histological subtype is ESCC ( 4 , 5 ). Despite considerable advancements in multidisciplinary treatment approaches, encompassing surgery, chemotherapy, and radiotherapy, the prognosis for patients with EC, particularly in advanced stages, remains poor, characterized by a low 5-year survival rate. The high invasiveness of EC, coupled with its propensity for rapid progression and metastasis, highlights the urgent need for more effective and durable therapies ( 6 , 7 ). In recent years, the advent of immunotherapy, particularly the utilization of ICIs, has significantly transformed the landscape of cancer treatment ( 8 ). These groundbreaking agents, including anti-programmed cell death protein 1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) monoclonal antibodies, have shown considerable clinical benefits across various malignant tumors, notably in advanced EC, thereby offering renewed hope to patients. Currently, several immunotherapeutic agents, such as pembrolizumab and nivolumab, have received approval for the treatment of advanced EC ( 9 – 13 ). Nevertheless, despite these advancements, the overall response rate (ORR) among ESCC patients undergoing immunotherapy remains relatively low, with a significant proportion of patients either displaying primary resistance or subsequently developing acquired resistance over time ( 14 – 16 ). This issue of drug resistance poses a substantial challenge to the long-term efficacy of ICIs, underscoring the necessity for a comprehensive understanding of the molecular mechanisms that underpin immune escape and treatment failure in esophageal cancer. Immune escape in ESCC arises from the dynamic interplay between tumor cells, their microenvironment, and intrinsic cellular regulatory networks ( 17 – 19 ). A deeper understanding of these mechanisms is crucial for developing effective combination therapies and predictive biomarkers to improve patient outcomes. This review aims to systematically analyze the fundamental mechanisms of ICI resistance in EC, focusing on TME remodeling, metabolic reprogramming, and the roles of non-coding RNAs and epigenetic regulation. By synthesizing recent insights from single-cell sequencing, multi-omics analyses, and clinical studies, we endeavor to establish a coherent framework for understanding immune resistance. Given the global epidemiological differences, this review primarily focuses on ESCC, which is predominant in East Asia, while also incorporating key findings from EAC where relevant to highlight both shared and distinct resistance mechanisms. We aim to propose innovative combinatorial strategies to overcome this major clinical challenge. Whereas prior reviews have largely addressed individual axes of immunotherapy resistance in esophageal cancer in isolation—such as immune checkpoint signaling or TME composition—the present review is distinguished by an integrative, mechanism-centered framework. Specifically, we position the cross-regulation between metabolic reprogramming and epigenetic modifications as a central organizing principle, incorporate the emerging contribution of the tumor microbiome, and synthesize recent single-cell and multi-omics evidence, thereby connecting each resistance mechanism to mechanism-guided combination strategies. Throughout the review, we further distinguish the mechanisms that predominantly drive primary resistance—such as a pre-existing immunosuppressive TME and intrinsic oncogenic pathway activation—from those more closely associated with acquired resistance, including compensatory immune checkpoint upregulation, metabolic reprogramming, and epigenetic remodeling, while recognizing that several pathways contribute to both. Where relevant, we consistently distinguish direct evidence demonstrated in ESCC from mechanistic insights extrapolated from other tumor types, explicitly flagging the latter as hypotheses that require validation in esophageal cancer ( Figure 1 ). Figure 1 Schematic overview of the major mechanistic axes driving resistance to immune checkpoint inhibitors in esophageal squamous cell carcinoma. The diagram integrates three interconnected axes that cooperatively establish an immunosuppressive tumor microenvironment. Top, CAF axis: CAFs secrete WNT2 and CXCL12, which impair dendritic cell maturation and recruit immunosuppressive MDSCs, leading to reduced priming of T cells. Middle, MDSC/NK axis: MDSCs, often expanded via signals from CD49a + NK cells, produce Arg1 and other suppressive mediators that directly inhibit CD8 + T cell function. Together with TGF-β-driven ECM remodeling, this axis promotes the exclusion of CD8 + T cells from the tumor core. Bottom, Metabolic & epigenetic reprogramming axis: Metabolic alterations and epigenetic regulators upregulate immune-escape genes and enhance the immunosuppressive function of M2-like macrophages and glycosylated MDSCs. These multilayered mechanisms collectively impair the efficacy of anti-PD-1 therapy. Consistent with the framework introduced in the Introduction, the CAF and MDSC/NK axes predominantly reflect a pre-existing immunosuppressive TME that drives primary resistance, whereas metabolic and epigenetic reprogramming is more closely associated with acquired resistance; several of these mechanisms contribute to both. 2 TME remodeling is the main driving factor for immunotherapy resistance TME represents a dynamic and heterogeneous ecosystem that encompasses not only malignant cells but also various stromal cells, immune cells, extracellular matrix components, and soluble factors. Collectively, these elements influence tumor progression and treatment response ( 20 – 22 ). In EC, the TME is pivotal in facilitating immune escape and fostering resistance to immunotherapy, which is a major cause of treatment failure ( 23 , 24 ). The immunosuppressive remodeling of the TME establishes a formidable barrier that impedes effective anti-tumor immune responses, consequently diminishing the efficacy of immune checkpoint blockade ( 25 , 26 ). 2.1 Cellular components and their immunosuppressive effects In the intricate TME of ESCC, various key cellular components play active roles in immunosuppression. Cancer-associated fibroblasts (CAFs) are particularly significant, serving as core coordinators of TME remodeling and immune cell recruitment ( 27 – 29 ). These activated fibroblasts secrete numerous cytokines, chemokines, and extracellular matrix components, thereby fostering the development of an immunosuppressive microenvironment. A critical mechanism by which CAFs enhance drug resistance involves their capacity to recruit and activate other immunosuppressive cell populations, notably tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) ( 30 – 32 ). Epithelial cells activate the NOTCH1 signaling pathway in CAFs through JAG1 ligands, which promotes the secretion of CXCL1 and CXCL8, facilitating the recruitment of immunosuppressive cells and the remodeling of the extracellular matrix (ECM). This interaction creates a “CAF-Epi niche” that impedes T cell infiltration ( 33 ). Regarding immune cell interactions, CCL2 and IL-6 secreted by CAFs attract monocytes and induce their differentiation into SPP1+ macrophages. These macrophages, in turn, activate the TNFRSF4 signaling pathway in Tregs by releasing SPP1 protein, establishing a “SPP1 macrophage-Treg” positive feedback loop that inhibits the function of CD8+ T cells ( 34 ). Additionally, the WNT2 protein secreted by CAFs can suppress the maturation and antigen presentation capabilities of dendritic cells (DCs), further obstructing T cell activation ( 35 ). Furthermore, plasminogen activator inhibitor-1 (PAI-1) secreted by CAFs can trigger the Akt/Erk1/2 pathway ( 36 ) in cancer cells, leading to the stimulation of epithelial-mesenchymal transition (EMT) that boosts tumor cell migration capability and resistance to drugs. TAMs are another key immunosuppressive cell population in the TME of esophageal cancer ( 37 ). Studies have demonstrated that the expression levels of characteristic genes, such as SPP1 and APOE, in the highly infiltrating TREM2+ TAM subpopulation within esophageal squamous cell carcinoma tissues are significantly correlated with resistance to anti-PD-1 treatment ( 38 ). Specific TAM subsets can induce T cell exhaustion through various mechanisms, including lipid metabolic reprogramming ( 39 ). In esophageal squamous cell carcinoma, tumor-cell-secreted cholesterol drives immunosuppressive TAM polarization through a TFEB–PLD3 axis that degrades cytosolic DNA and suppresses TLR9 signaling, thereby impairing T-cell effector functions and promoting a non-responsive or exhausted state. The chemokine CCL22, secreted by TAMs, activates the FAK/AKT/Gli1 signaling pathway in tumor cells. This activation not only induces a stem phenotype in tumor stem cells but also significantly inhibits T cell infiltration ( 40 ). Furthermore, TAMs establish a synergistic network with other immunosuppressive cells, including Tregs and myeloid-derived suppressor cells (MDSCs) ( 37 ). M2-type TAMs recruit Tregs through the secretion of vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGF-β), while also enhancing the immunosuppressive functions of MDSCs, collectively impeding the anti-tumor effects of CD8+ T cells ( 41 ). Nanodelivery systems that target TAMs, such as EA2-PSL-PTX/LUT ( 42 ), can diminish the accumulation of these inhibitory cells, thereby reversing the immunosuppressive microenvironment. Concurrently, TAM aggregation in the tumor core creates a formidable physical obstacle that greatly impedes T cell penetration. Single-cell sequencing data revealed a notable association between TREM2+ TAMs and the fibroblast-enriched phenotype in the TME of non-responders to immunotherapy, leading to inadequate immune cycle activation ( 38 , 43 ). Additionally, research indicates that hypoxia in the TME can trigger the ALCAMhigh phenotype in TAMs, augmenting their immunosuppressive capacity and facilitating immune evasion, a phenomenon yet to be confirmed in esophageal cancer. Tregs significantly contribute to the immune resistance microenvironment in esophageal cancer, playing a crucial role in the development of immunotherapy resistance. They are excessively present in the esophageal cancer microenvironment, promoting immune evasion through direct suppression of effector T cells, secretion of immunosuppressive factors like interleukin-10 (IL-10) and IL-35, and modulation of the ECM. Analysis of single-cell sequencing data revealed a notable rise in Treg levels within esophageal squamous cell carcinoma tumors, constituting over 30% of CD4 + T cells. Moreover, the extent of Treg infiltration positively correlates with unfavorable prognosis and resistance to immunotherapy ( 44 ). The differentiation of Tregs is modulated by CAFs. The CAF-secreted protein PI16 promotes the differentiation of naive CD4 + T cells into T-BET + Tregs by binding to the DOCK2 receptor, which subsequently inhibits the function of CD8 + T cells. Clinical samples have demonstrated that elevated PI16 expression in the interstitium correlates significantly with increased Treg infiltration and a reduced patient survival rate ( 45 ). Additionally, Tregs deplete local ATP through the high expression of molecules such as CD39, leading to the generation of adenosine, which inhibits the activity of effector T cells ( 45 , 46 ). Tregs can sustain a stable immunosuppressive phenotype within the TME via clonal expansion and epigenetic modifications, including the demethylation of the Foxp3 gene ( 34 ). In Tregs from non-responders in ESCC, the expression of TNFRSF4 is upregulated, enhancing its inhibitory function through the activation of the NF-κB signaling pathway. Continuous activation of the STAT3 signaling pathway further promotes stable Foxp3 expression, establishing a self-sustaining regulatory loop. MDSCs represent a heterogeneous population of immature myeloid cells that contribute to immunosuppression and facilitate resistance to immunotherapy within the TME of esophageal cancer through various mechanisms. The expansion of MDSCs significantly promotes tumor progression by directly inhibiting CD8 + T cell function, inducing the differentiation of Tregs, and reshaping the immunosuppressive microenvironment. Studies have demonstrated that MDSCs inhibit T cell proliferation and cytotoxicity through the secretion of molecules such as arginase-1 (Arg-1), reactive oxygen species (ROS), IL-10, and TGF-β. Additionally, MDSCs promote angiogenesis and establish an immunosuppressive microenvironment. Specifically, PKN2 ( 47 ) enhances the transcription of CPT1B by activating STAT3 phosphorylation, which in turn boosts the fatty acid oxidation (FAO) metabolism of MDSCs, increases the expression of inhibitors like Arg-1 and ROS, and diminishes the anti-tumor efficacy of T cells. Conversely, GPR84 ( 48 ) is overexpressed in MDSCs, where it inhibits the lysosomal degradation of PD-L1, thereby sustaining its elevated expression and contributing to resistance against anti-PD-1 therapy. Furthermore, the interaction between MDSCs and other immune cells can contribute to the remodeling of the TME. Exhausted CD49a + NK cells promote MDSC infiltration by secreting granulocyte-macrophage colony-stimulating factor (GM-CSF), a mechanism that may be linked to the poor prognosis observed in early esophageal cancer ( 49 ). Additionally, MDSCs can secrete VEGF to facilitate angiogenesis while simultaneously reinforcing the ECM through collagen deposition, thereby impeding immune cell infiltration ( 47 ). A recent study by the Institute of Biomedical Experiments in Argentina demonstrated that galectin-1 (GAL1) recognizes β [1,6]-branched N-glycans on the surface of myeloid-derived suppressor cells (MDSCs), binds to the CD18/CD11b/CD177 receptor complex, and activates signaling through the signal transducer and activator of transcription 3 (STAT3) pathway. This activation synergistically upregulates immune checkpoints such as PD-L1 and indoleamine 2,3-dioxygenase 1 (IDO1), as well as the secretion of VEGF, thereby enhancing immunosuppressive and pro-angiogenic functions. In patients resistant to immunotherapy, the downregulation of ST6GAL1, which is responsible for α[2,6]-sialylation, in MDSCs results in the exposure of GAL1 binding sites and further enhances the immunosuppressive phenotype ( 50 ). 2.2 Physical and biochemical barriers within the TME In the microenvironment of immunotherapy resistance in ESCC, beyond cellular elements, the physical and biochemical attributes of the TME can impede immune cell infiltration, disrupt immune function, and stimulate the activation of immunosuppressive cells, contributing to immunotherapy failure. The physical barriers in the TME primarily impede immune cell infiltration by causing ECM fibrosis and vascular irregularities. The accumulation of type I collagen, hyaluronic acid (HA), and fibronectin in the TME leads to the formation of a dense structure, elevating tissue rigidity and impeding the entry of CD8 + T cells into the tumor core. In ESCC, the ECM facilitates immune evasion by activating the YAP/TAZ pathway and physically obstructing T cell movement ( 51 ). This process may involve collagen-modifying enzymes like LOX, which bolster ECM integrity, raise interstitial hydraulic pressure, and limit the diffusion of therapeutic agents and immune cells ( 52 ). Notably, the composition and function of the TME can differ significantly between histological subtypes. For example, EAC is often characterized by a higher degree of immune infiltration but also more pronounced T-cell exhaustion compared to ESCC ( 26 , 51 ). Furthermore, distinct CAF populations may predominate in each subtype, leading to different therapeutic vulnerabilities. Abnormal blood vessel formation can elevate interstitial pressure and disrupt blood flow, impeding immune cell transport. Activation of the VEGF pathway by hypoxia-inducible factor-1 α (HIF-1α) stimulates angiogenesis, resulting in the development of an “abnormal vascular network” characterized by heightened vascular permeability and an incomplete basement membrane, thereby impeding immune cell infiltration ( 53 , 54 ). The acidic microenvironment characterizes numerous solid tumors, such as esophageal cancer, due to tumor cells’ heightened reliance on aerobic glycolysis (Warburg effect) and consequent lactic acid generation ( 55 ). This acidity significantly hampers immune cell activities, particularly CD8 + T cells and NK cells, diminishing their cytotoxic functions, cytokine secretion, and replication. Additionally, the low pH levels can modify the expression of immune checkpoints and other suppressive molecules on both tumor and immune cells, thereby advancing immune evasion ( 56 ). Hypoxia is a common characteristic of the TME in esophageal cancer, resulting from rapid t
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