Molecular, metabolic, and functional CD4 T cell paralysis in the lymph node impedes tumor control

CD4 T cells are central effectors of anti-cancer immunity and immunotherapy, yet the regulation of CD4 tumor-specific T (T_TS) cells is unclear. We demonstrate that CD4 T_TS cells are quickly primed and begin to divide following tumor initiation. However, unlike CD8 T_TS cells or exhaustion programming, CD4 T_TS cell proliferation is rapidly frozen in place by a functional interplay of regulatory T cells and CTLA4. Together these mechanisms paralyze CD4 T_TS cell differentiation, redirecting metabolic circuits, and reducing their accumulation in the tumor. The paralyzed state is actively maintained throughout cancer progression and CD4 T_TS cells rapidly resume proliferation and functional differentiation when the suppressive constraints are alleviated. Overcoming their paralysis established long-term tumor control, demonstrating the importance of rapidly crippling CD4 T_TS cells for tumor progression and their potential restoration as therapeutic targets.