Targeting BCL9/BCL9L enhances CD4+ T cell-mediated Th1 antitumor immunity through activation of STAT1/STAT4 signaling.

Emerging evidence underscores the pivotal role of CD4+ effector T cells in antitumor immunity, yet their full therapeutic potential remains underexplored. This study investigates the impact of targeting the Wnt coactivators B-cell lymphoma 9 and B-cell lymphoma 9-like (BCL9/BCL9L) on CD4+ T cell-mediated antitumor immunity. We demonstrate that either genetic deletion or pharmacological inhibition of BCL9/BCL9L suppresses tumor progression and increases CD4+ T cell activation in the tumor microenvironment (TME). Critically, loss of Bcl9/Bcl9l skews CD4+ T cell differentiation toward a Th1 phenotype at the expense of Th2, Th17, and Treg lineages, thereby establishing a Th1-dominant TME and unleashing a direct cytotoxic program in these Th1 cells. Mechanistically, BCL9/BCL9L inhibition promotes Th1 polarization by suppressing TCF4-mediated regulation of PIAS family genes and enhancing STAT1/STAT4 activation, thereby driving a potent Th1-mediated antitumor response. Collectively, our findings identify BCL9/BCL9L as critical negative regulators of CD4+ T cell antitumor immunity and establish them as promising therapeutic targets for reprogramming the TME toward a Th1-supportive state.