Abstract
The polarization of tumor-associated macrophages (TAMs) toward an M2-like phenotype critically promotes acute myeloid leukemia (AML) progression. Building on the clinical observation that Caspase-1 (CASP1) expression is elevated in AML and correlates with M2 macrophage abundance, we identify a novel signaling axis in AML cells, involving CASP1 and the transcription factor early growth response protein 4 (EGR4), that orchestrates macrophage polarization. Knockdown (KD) of CASP1 in human AML cells (THP-1, MOLM-13) shifted their secretome, which consequently skewed macrophage polarization away from the M2 phenotype at multiple levels. Mechanistically, transcriptomic sequencing revealed that CASP1 KD significantly upregulated EGR4 expression. Crucially, EGR4 interference partially reversed the macrophage-polarizing effects of CASP1 KD, establishing EGR4 as an essential downstream effector. In a xenograft model using NOD/SCID mice—a defined system for studying human AML-macrophage crosstalk—CASP1 KD potently suppressed tumor growth. Immunohistochemical analysis revealed a remodeled microenvironment characterized by reduced proliferation (Ki67), upregulated EGR4, suppression of the M2-associated IL-10/p-STAT3 pathway and CD206, alongside a concomitant increase in M1-associated marker CD86. In conclusion, our integrated analysis delineates a novel AML cell-intrinsic pathway wherein CASP1 represses EGR4, thereby enabling an M2-like macrophage phenotype via the IL-10/p-STAT3 pathway. The identification of this CASP1-EGR4 axis identifies it as a promising therapeutic target for reshaping the immunosuppressive microenvironment in AML.
Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
References
Vago, L. & Gojo, I. Immune escape and immunotherapy of acute myeloid leukemia. J. Clin. Invest. 130 (4), 1552–1564 (2020).
Gale, R. P. Will immune therapy cure acute myeloid leukemia? Blood Sci. 1 (1), 2–3 (2019).
Gale, R. P. Can Immune Therapy Cure Acute Myeloid Leukemia? Curr. Treat. Options Oncol. 24 (5), 381–386 (2023).
Sauerer, T., Velazquez, G. F. & Schmid, C. Relapse of acute myeloid leukemia after allogeneic stem cell transplantation: immune escape mechanisms and current implications for therapy. Mol. Cancer. 22 (1), 180 (2023).
Restelli, C. et al. Recent Advances in Immune-Based Therapies for Acute Myeloid Leukemia. Blood Cancer Discov. 5 (4), 234–248 (2024).
Neaga, A. et al. MicroRNAs Associated With a Good Prognosis of Acute Myeloid Leukemia and Their Effect on Macrophage Polarization. Front. Immunol. 11, 582915 (2020).
Liu, J. et al. Corrigendum to Chenodeoxycholic acid suppresses AML progression through promoting lipid peroxidation via ROS/p38 MAPK/DGAT1 pathway and inhibiting M2 macrophage polarization. Redox Biol. 59, 102566. (2023).
Sharma, B. R. & Kanneganti, T. D. NLRP3 inflammasome in cancer and metabolic diseases. Nat. Immunol. 22 (5), 550–559 (2021).
Wei, X. et al. Role of pyroptosis in inflammation and cancer. Cell. Mol. Immunol. 19 (9), 971–992 (2022).
Niu, Z. et al. Caspase-1 cleaves PPARgamma for potentiating the pro-tumor action of TAMs. Nat. Commun. 8 (1), 766 (2017).
Hwang, H. J. et al. Endothelial cells under therapy-induced senescence secrete CXCL11, which increases aggressiveness of breast cancer cells. Cancer Lett. 490, 100–110 (2020).
Zhang, Y. et al. Schwann cell-derived CXCL2 contributes to cancer pain by modulating macrophage infiltration in a mouse breast cancer model. Brain Behav. Immun. 109, 308–320 (2023).
Wang, R. et al. Exosome microRNA-125a-5p derived from epithelium promotes M1 macrophage polarization by targeting IL1RN in chronic obstructive pulmonary disease. Int. Immunopharmacol. 137, 112466 (2024).
Yang, L. et al. M2 macrophage inhibits the antitumor effects of Lenvatinib on intrahepatic cholangiocarcinoma. Front. Immunol. 14, 1251648 (2023).
Almosailleakh, M. & Schwaller, J. Murine Models of Acute Myeloid Leukaemia. Int. J. Mol. Sci. 20 (2). (2019).
de la Diaz, R. et al. Engraftment characterization of risk-stratified AML in NSGS mice. Blood Adv. 5 (23), 4842–4854 (2021).
Ahmadi Bidakhvidi, N. et al. Comparison of PSMA immunohistochemistry scoring systems to parametric [(18)F]PSMA-1007 PET/MRI in primary prostate cancer. Eur. J. Nucl. Med. Mol. Imaging. 52 (2), 766–778 (2025).
Botelho, L. et al. Somatostatin receptors in pituitary somatotroph adenomas as predictors of response to somatostatin receptor ligands: A pathologist’s perspective. Brain Pathol. 35 (1), e13313 (2025).
Mori, M. et al. CD163(+) Macrophages Induce Endothelial-to-Mesenchymal Transition in Atheroma. Circ. Res. 135 (2), e4–e23 (2024).
Murray, P. J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41 (1), 14–20 (2014).
Chen, Y. et al. EBV promotes TCR-T-cell therapy resistance by inducing CD163 + M2 macrophage polarization and MMP9 secretion. J. Immunother. Cancer 12 (6). (2024).
Kanehisa, M., Furumichi, M., Sato, Y., Kawashima, M. & Ishiguro-Watanabe, M. KEGG for taxonomy-based analysis of pathways and genomes. Nucleic Acids Res. 51 (D1), D587–D592 (2023).
Fan, Y. et al. Senescent-like macrophages mediate angiogenesis for endplate sclerosis via IL-10 secretion in male mice. Nat. Commun. 15 (1), 2939 (2024).
Zheng, W. et al. Crosstalk between GBP2 and M2 macrophage promotes the ccRCC progression. Cancer Sci. 115 (11), 3570–3586 (2024).
Qian, L., Shi, R., Yang, J. & Zhang, J. KIF2C regulates macrophage M2 polarization and DLBCL progression by regulating the STAT3/IL-10 axis. Cell. Signal. 136, 112155 (2025).
Ross, C. et al. Inflammatory Caspases: Toward a Unified Model for Caspase Activation by Inflammasomes. Annu. Rev. Immunol. 40, 249–269 (2022).
Casirati, G. et al. Epitope editing enables targeted immunotherapy of acute myeloid leukaemia. Nature 621 (7978), 404–414 (2023).
Cobaleda, C., Godley, L. A., Nichols, K. E., Wlodarski, M. W. & Sanchez-Garcia, I. Insights into the Molecular Mechanisms of Genetic Predisposition to Hematopoietic Malignancies: The Importance of Gene-Environment Interactions. Cancer Discov. 14 (3), 396–405 (2024).
Pinal-Fernandez, I. et al. Machine learning algorithms reveal unique gene expression profiles in muscle biopsies from patients with different types of myositis. Ann. Rheum. Dis. 79 (9), 1234–1242 (2020).
Turker, F., Brennan, A. & Margolis, S. S. Neuronal membrane proteasome-derived peptides modulate NMDAR-dependent neuronal signaling to promote changes in gene expression. Mol. Biol. Cell. 35 (1), ar6 (2024).
Hua, Y., Wang, H., Ye, Z., Zheng, D. & Zhang, X. An integrated pan-cancer analysis of identifying biomarkers about the EGR family genes in human carcinomas. Comput. Biol. Med. 148, 105889 (2022).
Wang, B. et al. Identification of EGR4 as a prospective target for inhibiting tumor cell proliferation and a novel biomarker in colorectal cancer. Cancer Gene Ther. 31 (6), 871–883 (2024).
Guo, R. et al. Multifaceted regulatory mechanisms of the EGR family in tumours and prospects for therapeutic applications (Review). Int. J. Mol. Med. 56 (1). (2025).
Gong, X. et al. Gramicidin inhibits cholangiocarcinoma cell growth by suppressing EGR4. Artif. Cells Nanomed. Biotechnol. 48 (1), 53–59 (2020).
Mookerjee-Basu, J. et al. Suppression of Ca(2+) signals by EGR4 controls Th1 differentiation and anti-cancer immunity in vivo. EMBO Rep. 21 (5), e48904 (2020).
Samakai, E. et al. Novel STIM1-dependent control of Ca2 + clearance regulates NFAT activity during T-cell activation. FASEB J. 30 (11), 3878–3886 (2016).
Li, Z. J. et al. Artesunate synergizes with sorafenib to induce ferroptosis in hepatocellular carcinoma. Acta Pharmacol. Sin. 42 (2), 301–310 (2021).
Shu, M. et al. Programmed cell death regulates hematopoietic cell homeostasis under radiation conditions. Stem Cell. Res. Ther. 16 (1), 390 (2025).
Funding
This study was supported by the National Natural Science Foundation of China (Grant 82360029); Gansu Province Graduate Student Innovation Star Program (Grant 2025CXZX-211); and Gansu Province Graduate Student Innovation Star Program (Grant 24YFFA046).
Author information
Authors and Affiliations
Contributions
Yi Qian conducted the majority of the experiments, collected the clinical samples and relevant information and wrote the initial manuscript draft. Yue Chen, Zu-Xi Feng, Xiao-Feng Zhu, Li Zhang, Hao Xiong, Xiang-Hui Zhang, Jun Bai, Yan-Hong Li, and Yu-Xian Wang provided occasional assistance with the experimental work. Li-Juan Li and Lian-Sheng Zhang conceived, designed the study and critically revised the manuscript. All authors reviewed and approved the final version for submission.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Qian, Y., Chen, Y., Feng, ZX. et al. The Caspase-1-EGR4 axis regulates macrophage repolarization in acute myeloid leukemia cells. Sci Rep (2026). https://doi.org/10.1038/s41598-026-41381-x
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41598-026-41381-x
