ArticleJournal for immunotherapy of cancer2026
Reprogramming the melanoma tumor immune microenvironment via combinatorial signal 2/3 gene delivery.
Article in Journal for immunotherapy of cancer, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
introductionAn adaptive immune response to cancer requires three main signals: antigen presentation and recognition ("signal 1"), costimulation ("signal 2"), and secreted immunostimulatory cytokines ("signal 3"). Expression of these signals in tumors via non-viral gene delivery represents a promising strategy to reprogram the tumor microenvironment (TME) and prime antitumor immunity.
methodsWe used modular polymeric poly(beta-amino ester)-based nanoparticles (NPs) to investigate codelivery of plasmids encoding signal 3s (interleukin (IL)-2, IL-12, IL-15, IL-23, IL-35, or granulocyte-macrophage colony-stimulating factor) and signal 2s (4-1BBL, CD80, CD86, or OX40L) to B16F10 melanoma tumors in vivo. Downstream immune responses and impact on the TME were assessed via flow cytometry and spatial proteomics using a 27-marker PhenoCycler panel.
resultsEx vivo flow cytometry and PhenoCycler tissue analysis revealed that multiple signal 2/3 NP combinations led to decreased tumor growth, increased immune-cell infiltration, and skewing of adaptive and innate populations towards immunostimulatory phenotypes with increased CD8
conclusionsThese results demonstrate the utility of a modular NP design for systematic screening of signal 2/3 delivery to melanoma in vivo and highlight the benefit of in-depth profiling via spatial proteomics to evaluate local antitumor immune responses. The results provide insight into the mechanisms underpinning this therapeutic reprogramming strategy, emphasizing the relationship between signal 2/3 NPs and their ability to drive signal 1 for productive antitumor responses in vivo.
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