IL-15 Superagonists for Reprogramming the Immunosuppressive Microenvironment in Gastrointestinal Adenocarcinomas.

Authors

Neeraj Choudhary, Md Faiyazuddin, Raj Kamal, Dinesh Kumar, Thomas J Webster

Published in

Cancer letters. Pages 218780. Aug 11, 2026. Epub Aug 11, 2026.

Abstract

Gastrointestinal (GI) adenocarcinomas pose a significant therapeutic challenge due to highly immunosuppressive tumor microenvironments that limit effective antitumor immune responses. Dense stromal fibrosis, immune exclusion and poor responses to immune checkpoint inhibitors are hallmarks of treatment-resistant malignancies, most notably pancreatic ductal adenocarcinoma (PDAC) and subsets of gastric cancer. In this regard, IL-15 superagonists such as N-803, NIZ985, RLI, and NKTR-255 have emerged as promising immunotherapeutic candidates, as they selectively expand natural killer (NK) cells and CD8+ T-cells without the systemic toxicity and regulatory T-cell activation observed with IL-2 therapy. IL-15 superagonists have emerged as more effective therapeutic agents when used in conjunction with local inhibitors of TGF-β and IL-10, stromal remodelling, and vascular normalization. They are supported by increasingly conclusive mechanistic, preclinical and early clinical data. A combination of these interventions circumvents extracellular matrix-provoked immune barriers, reverses VEGF-induced endothelial dysfunction, and enhances the trafficking of lymphocytes into tumor cores. Moreover, several localized therapeutic delivery strategies, such as endoscopic delivery, implantable depots, biomaterial scaffolds, and nanocarriers, can improve intratumoral cytokine retention and reduce systemic inflammatory toxicity. Together, these advances define a new paradigm for cytokine-immunotherapy, with IL-15 superagonists serving as key mediators of reprogramming of the tumor microenvironment. Therapeutic strategies targeting IL-15 have the potential to restore cytotoxic immunity, improve access to immune cells, and promote responsiveness to the checkpoint blockade, making them a promising yet investigational approach to converting immune-cold GI malignancies into more treatment-responsive disease states, though further clinical validation is required.

PMID:
42580433
Bibliographic data and abstract were imported from PubMed on 12 Aug 2026.

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