One of the most stubborn puzzles in esophageal cancer research has just gained a striking new piece. Myeloid-derived suppressor cells, a family of immature immune cells long known for dampening antitumor T cell responses, appear to do far more than simply shield tumors from immune attack. According to a new open-access study published in Cancer Immunology, Immunotherapy, these cells directly reprogram esophageal squamous cell carcinoma cells into a stem-like state, endowing a subset of them with the self-renewing, treatment-resistant properties of cancer stem cells. The finding, reported by a team at Zhengzhou University led by Yi Zhang, reveals a signaling circuit that operates entirely independently of adaptive immunity, and it points to a therapeutic vulnerability that T cell-focused treatments alone cannot reach.
The research builds on the group’s earlier work showing that myeloid-derived suppressor cells, or MDSCs, accumulate in abundance within human esophageal squamous cell carcinoma, the dominant histological subtype of esophageal cancer worldwide, and that their presence correlates with worse patient outcomes. What remained unclear was whether MDSCs contribute to tumor propagation through mechanisms that go beyond their canonical role of suppressing T cells. To answer that question, the investigators turned to mouse models of esophageal cancer that included both immunocompetent animals and mice lacking T cells altogether. If MDSCs promoted tumor growth only by disarming T cells, their influence should have vanished in the T cell-deficient setting. Instead, the tumors accelerated in both contexts, a result that signaled the existence of an intrinsic, T cell-independent tumor-promoting program driven by these myeloid cells.
Tracking down the molecular machinery behind that program led the team to an unexpected transcription factor. When the researchers depleted MDSCs in tumor-bearing mice using an anti-Gr1 antibody, or when they neutralized the inflammatory cytokine interleukin-1 beta, expression of HNF1A inside the tumor cells dropped. HNF1A, a transcription factor best known for its roles in liver and pancreatic development and metabolism, has more recently been implicated in tumor biology, but its involvement in MDSC-driven esophageal cancer progression had not been established. The new data place it at the center of the circuit: MDSCs, acting through IL-1 beta, appear to switch on HNF1A within the carcinoma cells themselves.
From HNF1A, the signal flows onward to a chemokine. The study showed that HNF1A sustains the activity of the CXCL1 promoter, and that disrupting the upstream inputs, whether by depleting MDSCs or blocking IL-1 beta, blunted CXCL1 promoter activity and reduced CXCL1 output. CXCL1 is a chemokine of the CXC family that signals through the receptor CXCR2 and is well recognized as a mediator of neutrophil recruitment and inflammatory signaling in tumors. In this context, however, its downstream consequences are not primarily inflammatory in the classical sense. Rather, the researchers found that the HNF1A-CXCL1 axis feeds directly into the core stemness machinery of the cancer cells, downregulating or, when the axis is active, sustaining the expression of the transcription factors Oct4, Nanog and Sox9, the canonical guardians of stem-like identity in embryonic and cancer stem cells alike.
The functional consequences of that molecular cascade were tested with rigor. When the team deleted HNF1A specifically in tumor cells, the MDSC-driven expansion of the cancer stem cell population collapsed, and, critically, the ability of the tumors to initiate new growth was abolished. Tumor initiation is the hallmark functional readout of cancer stem cell activity: only cells with genuine self-renewal capacity can seed a new tumor from a limited inoculum. The fact that HNF1A deletion eliminated this capacity demonstrates that the transcription factor is not merely a correlate of stemness but a required licensing factor in this pathway. Conversely, when the researchers supplied exogenous IL-1 beta, the cancer stem cell frequencies rebounded, confirming that the myeloid-cell-derived cytokine sits upstream of the entire axis and is sufficient to re-ignite the stem-like program.
These results reframe the relationship between inflammation and cancer stemness in esophageal cancer. Rather than acting as passive bystanders that merely modulate the immune microenvironment, MDSCs emerge as active instructors of tumor cell identity, delivering an IL-1 beta signal that is transcribed into a heritable, self-reinforcing stem-like state through HNF1A and CXCL1. Because the pathway was operative in T cell-deficient mice, the authors conclude that MDSC-derived IL-1 beta licenses the HNF1A-CXCL1 axis and sustains cancer stem cell properties independently of adaptive immunity. That independence matters clinically. Modern oncology has invested heavily in T cell-directed strategies, from immune checkpoint inhibitors to engineered cell therapies, and esophageal cancer has been among the tumor types to benefit. But a tumor-promoting program that runs beneath the T cell layer provides a reservoir of malignant potential that such therapies would not touch, and it may help explain why responses in esophageal squamous cell carcinoma remain incomplete for many patients.
The therapeutic implication drawn by the authors is that targeting this pathway could complement, rather than replace, T cell-focused treatments. Several points of intervention suggest themselves from the data. MDSC depletion, as achieved with anti-Gr1 in the preclinical setting, removes the source of the signal. IL-1 beta neutralization interrupts the messenger, and IL-1-blocking agents already exist in the clinical arsenal for inflammatory diseases, offering a plausible route to translation. Downstream, the CXCL1-CXCR2 axis is a recognized drug target, with CXCR2 antagonists under investigation in multiple cancers. Each of these strategies was supported, directly or indirectly, by the experimental results: depleting MDSCs or neutralizing IL-1 beta reduced HNF1A expression, dampened CXCL1 promoter activity and lowered stemness factor levels, while restoring IL-1 beta reinstated cancer stem cell frequencies.
The study also carries prognostic weight. The graphical summary accompanying the article emphasizes that the HNF1A-driven CXCL1 program not only licenses stem-like properties in esophageal squamous cell carcinoma but also predicts poor prognosis, consistent with the team’s earlier finding that MDSC abundance in human tumors correlates with adverse outcomes. Cancer stem cells are widely associated with resistance to chemotherapy and radiotherapy, metastatic dissemination and relapse after apparently curative treatment, so a microenvironmental signal that expands this compartment provides a mechanistic bridge between inflammatory infiltration and clinical aggressiveness. For patients with esophageal squamous cell carcinoma, a disease with persistently poor survival statistics in many regions, that bridge may represent one of the more actionable links identified to date.
Methodologically, the work combined genetically defined mouse models, cell-specific deletion of HNF1A, pharmacologic MDSC depletion, cytokine neutralization and supplementation, and molecular readouts of promoter activity and stemness factor expression, an integrated design that allowed the authors to move from correlation to causal mechanism. The study was supported by the National Natural Science Foundation of China, and the MEC25 cell line used in the experiments was provided by the laboratory of Professor Li Fu at Shenzhen University Medical School. The corresponding author, Yi Zhang, holds appointments across the Biotherapy Center and Cancer Center of the First Affiliated Hospital of Zhengzhou University, the State Key Laboratory of Metabolic Dysregulation and Prevention and Treatment of Esophageal Cancer, and related Zhengzhou University institutions, reflecting the translational infrastructure behind the project. The article was received in January 2026, accepted in September 2026 and published on 20 September 2026 under a Creative Commons Attribution license.
As with any preclinical study, the path from mouse models to patient benefit will require validation in human tumor specimens and, ultimately, clinical testing of pathway-targeted interventions. Nevertheless, the conceptual advance is clear and consequential: the immune microenvironment does not merely decide whether the immune system sees a tumor, it can also decide what the tumor is. In esophageal squamous cell carcinoma, myeloid-derived suppressor cells appear to whisper a developmental command into the cancer cells, activating HNF1A, broadcasting CXCL1 and preserving a self-renewing core that survives whatever the immune system or the oncologist throws at it. Silencing that command, whether by removing the myeloid messengers, intercepting their IL-1 beta message or blocking the CXCL1 relay downstream, now stands as a defined and testable strategy to strip esophageal cancer of its stem-like resilience and to make T cell-directed therapies work against a smaller, more vulnerable target.
Subject of Research: How myeloid-derived suppressor cells confer cancer stem cell properties to esophageal squamous cell carcinoma via the HNF1A/CXCL1 signaling axis
Article Title: Myeloid-derived suppressor cells confer stemness to esophageal cancer cells through the HNF1A/CXCL1 signaling axis
Article References: Qin, G., Ma, P., Liu, S., Chen, T., Guo, K., Zhao, Q., Wu, P., Chen, X., & Zhang, Y. (2026). Myeloid-derived suppressor cells confer stemness to esophageal cancer cells through the HNF1A/CXCL1 signaling axis. Cancer Immunology, Immunotherapy. https://doi.org/10.1007/s00262-026-04577-8
Image Credits: AI Generated
DOI: 10.1007/s00262-026-04577-8
Keywords: myeloid-derived suppressor cells, esophageal squamous cell carcinoma, HNF1A, CXCL1, cancer stem cells, interleukin-1 beta, tumor microenvironment, stemness, Oct4, Nanog, Sox9, cancer immunology
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Nathaniel Bowman. (September 20, 2026). Immune Cells Hand Esophageal Cancer Its Stem-Like Edge Through an HNF1A/CXCL1 Circuit. Scienmag. https://scienmag.com/immune-cells-hand-esophageal-cancer-its-stem-like-edge-through-an-hnf1a-cxcl1-circuit/
Nathaniel Bowman. “Immune Cells Hand Esophageal Cancer Its Stem-Like Edge Through an HNF1A/CXCL1 Circuit.” Scienmag, 20 September 2026, https://scienmag.com/immune-cells-hand-esophageal-cancer-its-stem-like-edge-through-an-hnf1a-cxcl1-circuit/. Accessed 20 September 2026.
Nathaniel Bowman. “Immune Cells Hand Esophageal Cancer Its Stem-Like Edge Through an HNF1A/CXCL1 Circuit.” Scienmag. September 20, 2026. https://scienmag.com/immune-cells-hand-esophageal-cancer-its-stem-like-edge-through-an-hnf1a-cxcl1-circuit/
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Tags: Cancer immunologycancer stem cell inductioncancer stem cellscancer stemness and immune modulationCXCL1esophageal squamous cell carcinomaHNF1AHNF1A/CXCL1 signaling pathwayimmune cell reprogrammingimmune cell role beyond T cell suppressionimmune cell-tumor interactionsimmune-mediated tumor reprogramminginterleukin-1 betamyeloid-derived suppressor cellsNanogOct4SOX9stemnesstherapeutic vulnerabilities in esophageal cancertreatment resistance in esophageal cancertumor immune microenvironmenttumor microenvironment
