ISX–TWIST1 reprograms CD47–inflammasome signaling to reshape the immune microenvironment in liver cancer

Immunotherapies have shown promise effectiveness in cancer treatment, yet the complex tumor microenvironment poses challenges to their efficacy. The interaction between immune checkpoints in malignant and immune cells is crucial for cancer cells to evade the host’s immune response, but the impact of tumor cell immune checkpoint molecules on disease progression remains incompletely understood. Our study uncovers a significant link between the CD47 signals, inflammasomes and intestine-specific homeobox (ISX), correlating strongly with lesion count, disease stage, and lymph vascular invasion. Elevated CD47 expression activates CD47–SIRPα signaling to promote M2-like macrophage polarization, accompanied by inflammasome activation and cytokine production within the tumor microenvironment and memory T cell differentiation within the hepatic microenvironment, intensifying disease progression. In xenograft and chronic hepatic tumor model featuring a liver-specific ISX mutant, the elimination of M2-like TAM macrophages and TRM cells halts disease advancement. Through transcriptomic analysis and molecular evidence, we unveil the interaction of ISX with TWIST1, triggering CD47-SIRPα and inflammasome activation by binding to specific degenerate sequences (“-GGDWYR-“) in the promoter regions of CD47-SIRPα signals and inflammasome-related genes. These findings underscore the pivotal role of the ISX-CD47 axis in liver disease and tumor progression. They offer promising insights into potential treatments for liver disease, shedding light on new therapeutic strategies with the potential to improve patient outcomes.