Bhlhe40 Coordinates T Cell Programs with Distinct CD4 and CD8 T Cell Requirements for Anti-PD-1 Versus Anti-CTLA-4.

The transcriptional programs that enable CD4 and CD8 T cells to mediate effective anti-tumor immunity remain incompletely defined. Here, we identify distinct, therapy-specific roles for the transcriptional regulator Bhlhe40 in CD4 and CD8 T cells, revealing divergent requirements during anti-PD-1 versus anti-CTLA-4 immune checkpoint therapy (ICT). Using conditional knockout mice, we show that anti-PD-1 efficacy depends on CD8 T cell-intrinsic Bhlhe40 and may also require its expression in CD4 T cells, whereas anti-CTLA-4 relies primarily on CD4 T cell-intrinsic Bhlhe40 and remains effective without Bhlhe40 in CD8 T cells. Loss of Bhlhe40 skews CD8 T cells toward TCF-1-expressing naïve and progenitor exhausted-like states, particularly in the absence of ICT. Bhlhe40 sustains CD8 effector and exhausted phenotypes, promotes IFN-γ production, and supports glycolytic and mitochondrial programs, with Bhlhe40 deficiency leading to impaired glycolysis under either anti-PD-1 or anti-CTLA-4 ICT, and reduced mitochondrial function primarily during anti-PD-1. In addition, CD8 T cell-intrinsic Bhlhe40 is required for full ICT-induced remodeling of the tumor myeloid compartment from CX3CR1