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

Leukemia volume 40, pages 152–165 (2026) Cite this article

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Abstract

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.

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Fig. 1: IL-1R signaling supports CD30-directed immunotherapy in ALCL.
The alternative text for this image may have been generated using AI.
Fig. 2: The IL-1R pathway promotes IL-17F production in ALCL.
The alternative text for this image may have been generated using AI.
Fig. 3: The IL-1R pathway contributes to the upregulation of PD-L1 in ALCL.
The alternative text for this image may have been generated using AI.
Fig. 4: Biological role of the NFKBIZ–IL17F axis in ALCL.
The alternative text for this image may have been generated using AI.
Fig. 5: IL-1R signaling promotes immune evasion in ALCL through NFKBIZ.
The alternative text for this image may have been generated using AI.
Fig. 6: Targeting the IL-1R pathway to enhance CD30 CAR therapy efficacy in ALCL.
The alternative text for this image may have been generated using AI.
Fig. 7: IL-1R blockade enhances CD30 CAR efficacy in ALCL xenograft models.
The alternative text for this image may have been generated using AI.

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Data availability

The high-throughput RNA sequencing data from this study have been submitted to the NCBI Sequence Read Archive (SRA) under accession number: SUB15217599.

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Acknowledgements

This research was supported by the NIH R01 CA259188 (YY), R01 CA251674 (YY), a Scholar Award from the Blood Cancer United, formerly The Leukemia & Lymphoma Society (YY), and a Research Scholar Grant from the American Cancer Society (ACS RSG-23-722314, YY). This research was also supported by the JSPS KAKENHI Grant JP21H02775 (MN) and 24K02315 (MN).

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Author notes

  1. These authors contributed equally: Wei Wei, Zhihui Song, Yajun Wang.

Authors and Affiliations

  1. Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center, Philadelphia, PA, USA

    Wei Wei, Zhihui Song, Yajun Wang, Shen Li, Lingli Tan, John Lee, Kerry S. Campbell & Yibin Yang

  2. Histopathology Facility, Fox Chase Cancer Center, Philadelphia, PA, USA

    Kathy Q. Cai

  3. Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USA

    Reza Nejati

  4. Department of Pathology, University of Virginia, Charlottesville, VA, USA

    Marshall E. Kadin

  5. Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan

    Masao Nakagawa

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  1. Wei Wei
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Contributions

YY designed and oversaw the project. WW, ZS, YW, SL, and LT performed experiments and collected data. YY, WW, ZS, YW, SL, and LT analyzed and interpreted the data. KQC performed the IHC analysis. JL, RN, MEK, KSC, and MN provided technical support and critical materials. YY wrote the manuscript.

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Correspondence to Yibin Yang.

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Wei, W., Song, Z., Wang, Y. et al. The IL-1R and NFKBIZ pathway mediates immunoregulatory responses and immunotherapy efficacy in anaplastic large cell lymphoma. Leukemia 40, 152–165 (2026). https://doi.org/10.1038/s41375-025-02809-x

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