The IL-1R and NFKBIZ pathway mediates immunoregulatory responses and immunotherapy efficacy in anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL), an aggressive T-cell malignancy, is marked by elevated expression of CD30 and the immune checkpoint molecule PD-L1. While CD30-directed chimeric antigen receptor (CAR) therapies have demonstrated clinical promise, therapeutic resistance remains a major hurdle. Here, we conducted integrated genome-wide CRISPR-Cas9 loss-of-function screens using CD30-specific CAR-engineered natural killer (CAR-NK) cells, alongside a complementary PD-L1 regulator screen, and uncovered a critical role for interleukin-1 receptor (IL-1R) signaling in modulating CAR therapy efficacy in both ALK⁺ and ALK⁻ ALCL. Mechanistically, IL-1R signaling drives an NFKBIZ - IL-17F - MAPK axis that sustains PD-L1 expression via an autocrine loop, while simultaneously inducing proinflammatory cytokines and chemokines that reinforce immune evasion and shape an immunosuppressive tumor microenvironment. Notably, NFKBIZ (IκBζ) emerges as a central transcriptional regulator orchestrating this immune suppression program upstream of IL-17F. Importantly, pharmacologic inhibition of IL-1R signaling significantly enhances the antitumor activity of CD30-specific CAR therapies both in vitro and in ALCL xenograft models. Collectively, our findings uncover a novel mechanism of immune resistance and nominate IL-1R blockade as a promising combinatorial strategy to improve CAR-based immunotherapy in ALCL.