Targeting CXCL16 and STAT1 augments immune checkpoint blockade therapy in triple-negative breast cancer - Received and Accepted Article Summary

Sep 24, 2026

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Chemotherapy prior to immune checkpoint blockade (ICB) can improve efficacy, yet resistance remains a clinical challenge linked to highly plastic myeloid cells within the tumor immune microenvironment (TIME). Using CITE-seq single-cell transcriptomics and trajectory analysis, the study shows that neoadjuvant low-dose metronomic chemotherapy drives co-evolution of divergent myeloid subsets in triple-negative breast cancer (TNBC). CXCL16+ myeloid proportions increase and high STAT1 regulon activity marks PD-L1–expressing immature myeloid cells. STAT1 inhibition sensitizes MCT-primed tumors to ICB, supporting STAT1 modulation with anti-PD-1 as a pre-clinical strategy.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages17

Reading Time43 min

AccessFree to download

Introduction

Rationale for systemic interrogation of the tumor ecosystem

Myeloid plasticity and regulation of TIME

Results

MCT improves T-myeloid spatial proximity

Chemotherapy priming and dynamic myeloid homeostasis

STAT1 signaling modulation to enhance anti-PD-1 efficacy

Article [https://doi.org/10.1038/s41467-023-37727-y](https://doi.org/10.1038/s41467-023-37727-y) Targeting CXCL16 and STAT1 augments immune checkpoint blockade therapy in triple-negative breast cancer Received: 25 January 2022 | Accepted: 27 March 2023 | | --- | | | | Check for updates | Bhavana Palakurthi1,2, Shaneann R. Fross1,2, Ian H. Guldner1,2, Emilija Aleksandrovic 1,2, Xiyu Liu1,2, Anna K. Martino 1, Qingfei Wang 1,2, Ryan A. Neff1, Samantha M. Golomb1,2, Cheryl Lewis 3, Yan Peng3, Erin N. Howe1,2 & Siyuan Zhang 1,2,3,4 Chemotherapy prior to immune checkpoint blockade (ICB) treatment appears to improve ICB efﬁcacy but resistance to ICB remains a clinical challenge and is attributed to highly plastic myeloid cells associating with the tumor immune microenvironment (TIME). Here we show by CITE-seq single-cell transcriptomic and trajectory analyses that neoadjuvant low-dose metronomic chemotherapy (MCT) leads to a characteristic co-evolution of divergent myeloid cell subsets in female triple-negative breast cancer (TNBC). Speciﬁcally, we identify that the proportion of CXCL16 + myeloid cells increase and a high STAT1 regulon activity distinguishes Programmed Death Ligand 1 (PD-L1) expressing immature myeloid cells. Chemical inhibition of STAT1 signaling in MCT-primed breast cancer sensitizes TNBC to ICB treatment, which underscores the STAT1’s role in modulating TIME. In summary, we leverage singlecell analyses to dissect the cellular dynamics in the tumor microenvironment (TME) following neoadjuvant chemotherapy and provide a pre-clinical rationale for modulating STAT1 in combination with anti-PD-1 for TNBC patients. Cancer is a heterogeneous disease. As such, a systemic view of cancer as an evolving ecosystem, rather than a singular view of speciﬁc cell type or gene, is essential to guide a more effective and sustained anticancer treatment1. The divergent response to anti-cancer immunotherapy among patients highlighted an urgent need for systemic interrogation of the dynamic tumor ecosystem due to the nature of immune regulation – a dynamic equilibrium, balancing the immunogenic and immunosuppressive/tolerogenic signals1–3. Myeloid cells are prominent regulators of immune equilibrium vital to normal tissue homeostasis and tumor progression2. Their diverse roles in tuning tumor immune microenvironment (TIME) have been increasingly recognized as critical, sometimes decisive factors, for an optimal antitumor immunotherapy response4. Growing literature suggests a perplexing antagonistic/compensatory/redundant phenotypic plasticity among different myeloid cell subsets under various cancer contexts -from the binary M1/M2 paradigm and functionally-deﬁned myeloid-derived suppressor cells (MDSC) to the ever growing characterization of the sub-types of myeloid cells2,5. Myeloid cells are extremely heterogeneous and plastic in response to the cues imposed from TIME and systemic anti-cancer treatment6. For instance, PARP inhibitors (in triple-negative breast cancer (TNBC)) mediate glucose and lipid reprogramming and enhance both anti- and pro-tumorigenic features of macrophages through sterol regulatory element-binding protein-1 pathway7. Similarly, expansion of immunosuppressive M2-like macrophages and contraction of inﬂammatory-macrophages during advanced renal cell 1Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN 46556, USA. 2Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234N. Notre Dame Avenue, South Bend, IN 46617, USA. 3Department of Pathology and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA. 4Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA. e-mail: [Siyuan.Zhang@UTSouthwestern.edu](Siyuan.Zhang@UTSouthwestern.edu) carcinoma leads to decreased T-cell receptor clonality8. It is clear that the coordinated interplay between heteroge

FAQs

What is the main focus of the article in TNBC treatment?

It investigates how targeting CXCL16 and STAT1-related signaling modulates immune checkpoint blockade therapy in triple-negative breast cancer.

How does neoadjuvant low-dose metronomic chemotherapy (MCT) affect myeloid cells?

MCT induces a characteristic co-evolution of divergent myeloid subsets, increasing CXCL16+ myeloid cells and generating high STAT1 regulon activity in PD-L1–expressing immature myeloid cells.

What is the reported impact of inhibiting STAT1 signaling in MCT-primed tumors?

Chemical inhibition of STAT1 sensitizes TNBC to immune checkpoint blockade, highlighting STAT1’s role in shaping the tumor immune microenvironment.

Sep 24, 2026

Uploaded by Hazel