IκBζ orchestrates the generation of effector-like CD8+ T cells to sustain antitumor immunity

During tumor progression, CD8⁺ T cells undergo heterogeneous exhaustion, generating the effector-like transitory exhausted (Tex-int) cells that serve as the primary effectors of tumor eradication. These Tex-int cells differentiate from progenitor exhausted (Tex-prog) cells; however, mechanisms governing their generation remain poorly characterized. Here, we identified IκBζ (Nfkbiz) as a pivotal regulator of Tex-int differentiation. Nfkbiz expression was found to escalate progressively from Tex precursor (Tex-pre) cells in tumor-draining lymph nodes (TdLNs) through Tex-prog to Tex-int cells. Genetic ablation of Nfkbiz disrupted this hierarchy, depleting Tex-int population while expanding Tex-pre cells. Mechanistically, IκBζ was verified to directly bind to promoters of Tbx21 (T-bet) and effector genes (Ifng, Gzmb) to potentiate cytotoxic programs. IκBζ deficiency abrogated T-bet expression, impaired IFNγ and GZMB production and attenuated Tex-int cell accumulation, accelerating tumor progression. Strikingly, IL-12 failed to fully restore T-bet and effector function in Nfkbiz-/- CD8⁺ T cells during chronic antigen exposure, underscoring the critical role of IκBζ in integrating inflammatory signals for cytotoxic programming. Our findings reveal IκBζ as a master regulator that licenses effector differentiation across the exhausted CD8⁺ T cell continuum, thereby nominating it as a promising therapeutic target for cancer immunotherapy.