Targeting tumor-intrinsic BCL9 reverses immunotherapy resistance by eliciting macrophage-mediated phagocytosis and antigen presentation.

Immune checkpoint inhibitors (ICI) benefit some cancer patients but de novo resistance remains poorly understood. Analyzing transcriptional data from two clinical trial cohorts, GO30140 and IMbrave150, we find B cell lymphoma 9 (BCL9), a Wnt/β-catenin co-factor, associated with resistance. We develop a BCL9-targeting peptide, hsBCL9Z96, which suppresses tumor growth in combination with anti-PD-L1 ab in preclinical hepatocellular carcinoma (HCC) mouse models. Multi-omics analyses implicate targeting BCL9 inhibits BMP4 secretion and downregulates CD24 on tumor cells, reprogramming macrophages toward a tumor-suppressive phenotype and promoting macrophage phagocytosis. This in turn rejuvenates T cell immunity via enhanced macrophage-mediated antigen presentation. Our data extend our understanding of how tumor-derived Wnt/β-catenin signaling impedes the innate and adaptive immune responses in the tumor microenvironment and provide preliminary evidence that targeting BCL9 is a promising preclinical strategy to mitigate ICI resistance in HCC.