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Immune checkpoint blockade (ICB) relieves CD8 +  T-cell exhaustion in most mutated tumors, and TCF-1 is implicated in converting progenitor exhausted cells to functional effector cells. However, identifying mechanisms that can prevent functional senescence and potentiate CD8 +  T-cell persistence for ICB non-responsive and resistant tumors remains elusive. We demonstrate that targeting  Cbx3 /HP1γ in CD8 +  T cells augments transcription initiation and chromatin remodeling leading to increased transcriptional activity at  Lef1  and  Il21r . LEF-1 and IL-21R are necessary for  Cbx3 /HP1γ-deficient CD8 +  effector T cells to persist and control ovarian cancer, melanoma, and neuroblastoma in preclinical models. The enhanced persistence of  Cbx3 /HP1γ-deficient CD8 +  T cells facilitates remodeling of the tumor chemokine/receptor landscape ensuring their optimal invasion at the expense of CD4 +  Tregs. Thus, CD8 +  T cells heightened effector function consequent to  Cbx3 /HP1γ deficiency may be distinct from functional reactivation by ICB, implicating  Cbx3 /HP1γ as a viable cancer T-cell-based therapy target for ICB resistant, non-responsive solid tumors.

Targeting Cbx3/HP1γ Induces LEF-1 and IL-21R to Promote Tumor-Infiltrating CD8 T-Cell Persistence