The most provocative of the new findings concerns triple-negative breast cancer, one of the most aggressive and least treatable forms of the disease. For years, drug developers have tried to starve triple-negative tumors by blocking glutamine, the amino acid these cancer cells rely on as their primary fuel. The strategy made elegant biochemical sense, yet it repeatedly stumbled in clinical trials. A team at MSK’s Sloan Kettering Institute, overseen by senior authors Justin Perry and Kayvan Keshari and led by postdoctoral researcher Nancy Santiappillai, has now explained why. Using advanced spatial metabolomics, a technique that maps the chemical activity of tissues with fine resolution, the researchers discovered that tumor-associated macrophages, immune cells that normally patrol and clean up within tumors, quietly sabotage the starvation strategy. Adapted to the oxygen-poor interior of the tumor, these macrophages rewire their own metabolism and release ornithine, an alternative nutrient that triple-negative breast cancer cells happily consume when glutamine runs dry. Even more striking, the macrophages engaged in clearing dead cells from the tumor release additional ornithine, effectively accelerating the very growth they were thought to suppress.

The therapeutic implications are considerable. When the team disrupted macrophage metabolism in mice using a drug called 6-AN, tumor growth slowed significantly in one triple-negative breast cancer model but not in another, a result that captures the humbling diversity of real tumors. In the responsive model, something remarkable happened: the macrophages flipped from a pro-tumor state into an anti-tumor one, and the number of cancer-killing CD8+ T cells inside the tumor rose. Targeting the metabolism of immune cells, in other words, may simultaneously cut off a hidden nutrient supply and awaken the immune system. But the effect was selective. Only tumors whose cells express high levels of two enzymes, OAT and PYCR1, in the proline synthesis pathway were vulnerable. Those enzymes help cancer cells tolerate redox stress, the damaging accumulation of unstable molecules, and enable construction of the extracellular matrix that tumors need to grow. An analysis of two large patient databases reinforced the clinical relevance: triple-negative breast cancer patients with high levels of those enzymes tended to have worse survival outcomes, tying the laboratory mechanism directly to human prognosis.

Elsewhere in the body, MSK researchers tackled one of oncology’s most feared complications: leptomeningeal metastasis, in which cancer spreads into the cerebrospinal fluid bathing the brain and spinal cord. Proton craniospinal irradiation, a form of radiation therapy, offers one of the few treatment options, but many cancers resist it. A team led by neuro-oncologist Adrienne Boire analyzed cerebrospinal fluid from patients both with and without leptomeningeal metastases, before and during radiation. The comparison revealed that cancer cells produce a signaling protein called CXCL1, which is linked to more aggressive disease and poorer responses to radiation. CXCL1 exerts its effects through a receptor called CXCR2, and that receptor became the team’s target. In mouse models, blocking CXCR2 with genetic tools or drugs suppressed the growth of leptomeningeal metastases. The combination of radiation with CXCR2 inhibition outperformed either treatment alone, raising the possibility that patients could receive lower radiation doses and thereby avoid some of the therapy’s most harmful side effects.

The translational pipeline moved with unusual speed. MSK has already opened a clinical trial testing radiation combined with SX-682, a CXCR2 inhibitor, in a collaborative effort among neuro-oncologist Jessica Wilcox, medical oncologist Monica Chen, thoracic medical oncologist Jark Jeng, and radiation oncologist Yao Yu. For a disease that has historically carried a prognosis measured in weeks, the leap from cerebrospinal fluid biomarker to active clinical trial represents the kind of rapid bench-to-bedside movement that precision oncology promises but rarely delivers so cleanly. If the trial confirms the preclinical results, patients with leptomeningeal disease could gain a strategy that sensitizes their tumors to radiation while sparing healthy tissue.

Breast cancer treatment, meanwhile, may be on the verge of its own diagnostic rethink. Trastuzumab deruxtecan, known as T-DXd or Enhertu, is an antibody-drug conjugate that uses an antibody to deliver chemotherapy directly into tumor cells, and it has already transformed outcomes in metastatic breast cancer. Yet its use is currently guided almost entirely by a single measurement: how much HER2 protein is visible on the surface of tumor cells. Approval was first limited to patients with high HER2 levels and later expanded to certain patients with lower levels, largely on the strength of MSK-led research. Now breast medical oncologists Joshua Drago, Nicholas Mai, and Sarat Chandarlapaty have identified a second, hidden indicator of benefit: mutations in the ERBB2 gene, which encodes the HER2 protein. In a study of 272 women with metastatic breast cancer lacking high HER2 levels, roughly 7 percent carried ERBB2 mutations, and those patients benefited from T-DXd for nearly twice as long as those without mutations, an average of 11 months compared with 6.2 months. In Chandarlapaty’s laboratory, cells carrying the mutation took up the drug faster and were killed more efficiently even when the amount of HER2 on the cell surface was identical.

The finding carries a direct message for clinical practice. Standard HER2 testing alone, the study suggests, may miss a group of patients who uniquely benefit from one of the most effective drugs available. Drago argues that genetic testing should be performed on the tumors of all patients with metastatic cancer, a stance that, if widely adopted, could reshape molecular diagnostics for breast cancer and push testing beyond protein-level measurements into the genome itself. It is a reminder that in modern oncology, the answer to whether a drug will work may be hiding in a mutation no one thought to check.

Genomic testing also anchors the fourth study, which offers hope to patients with biliary tract cancers, malignancies of the bile duct and gallbladder that are often diagnosed late and have few effective options once chemotherapy and immunotherapy fail. Gastrointestinal medical oncologist James J. Harding led an analysis of tumors from more than 1,200 patients with previously treated advanced disease, using MSK-IMPACT, a test that detects DNA changes across hundreds of cancer-associated genes. The team found that actionable DNA alterations were common across biliary tract cancer subtypes, identifying therapeutic targets including RAS alterations, MTAP deletion, and amplification of MDM2 and MET. Crucially, patients whose tumors harbored changes susceptible to targeted therapies lived longer without disease progression when matched to a drug aimed at their specific alteration than when treated with chemotherapy alone. By comparing tumor samples taken before treatment and after progression, the researchers also uncovered several mechanisms of resistance, insights that could guide the design of future combination therapies for this hard-to-treat disease.

The fifth study leaves human tumors behind entirely and looks at how a body builds itself. A team at the Sloan Kettering Institute has unveiled an artificial intelligence system called Twin Attention that can identify, track, and analyze individual cells in a developing embryo with striking accuracy. The system works by examining pairs of 3D snapshots of a growing embryo, learning to recognize each cell from its position and its relationships with neighboring cells, and assigning every cell a unique numerical fingerprint that captures not just location but tissue context. Demonstrated in the roundworm C. elegans, Twin Attention identified individual cells with roughly 93 to 97 percent accuracy as the embryo grew from a handful of cells to more than 500. Its most demanding test came in screening hundreds of embryos whose genes had been selectively silenced. A manual analysis of 700 such embryos would have consumed hundreds of hours; the AI system completed the task in a few hours, flagging developmental defects across the majority of genes tested and pinpointing 29 genes whose disruption delayed gastrulation, the pivotal step in which cells migrate into the embryo’s interior. Co-corresponding author Anthony Santella, a senior research scientist specializing in computer vision, says the tool could enable large-scale developmental screens that would otherwise be impossible, with applications in understanding how tissues form and malfunction in human disease. From starving tumors to decoding embryos, the through-line of this research is unmistakable: context is destiny, in biology as in medicine.

Subject of Research: Cancer immunometabolism, targeted therapy biomarkers, and AI-based developmental cell tracking

Article Title: MSK Research Highlights, October 9, 2026

Article References: MSK Research Highlights, October 9, 2026. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: triple-negative breast cancer, tumor-associated macrophages, glutamine metabolism, ornithine, spatial metabolomics, leptomeningeal metastasis, CXCL1, CXCR2 inhibitor, trastuzumab deruxtecan, ERBB2 mutations, biliary tract cancer, MSK-IMPACT

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