The Caspase-1-EGR4 axis drives acute myeloid leukemia progression by orchestrating macrophage repolarization

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 from M2 to M1 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, and elevation of the M1 marker CD86. In conclusion, our integrated analysis delineates a novel AML cell-intrinsic pathway wherein CASP1 promotes disease progression via negative regulation of EGR4, promoting an M2-like macrophage phenotype via the IL-10/p-STAT3 pathway. The identification of the CASP1-EGR4 axis, in addition to explaining the mechanistic link between CASP1 and poor prognosis, highlights a promising therapeutic target for reshaping the innate immune landscape in AML.