IL-33 Modulation in Tumor Microenvironment and Cancer Immunity

Interleukin-33 (IL-33) is a dual-function cytokine that resides in the nucleus of epithelial, endothelial and stromal cells but is rapidly released upon cellular stress or necrosis. In the tumour microenvironment (TME), IL-33 engages its receptor ST2 to orchestrate complex immune networks, driving either pro- or antitumour responses depending on local context, concentration and cellular source. Exogenous administration of IL-33 has been shown to enhance dendritic cell antigen presentation and cytotoxic T-cell priming, whereas constitutive endogenous IL-33 often fosters immunosuppressive niches by recruiting regulatory T cells and polarising macrophages towards a protumour M2 phenotype. Beyond immune cell recruitment, IL-33 signalling influences tumour angiogenesis, metastatic dissemination and the efficacy of chemotherapeutic and checkpoint-blockade regimens. Taken together, modulation of the IL-33/ST2 axis holds promise as both a prognostic biomarker and a therapeutic target across diverse malignancies, with strategies ranging from receptor blockade to engineered cytokine delivery under active investigation.

Research from Nature Portfolio

Recent studies have demonstrated that inhibition of the TBK1-IRF3 signalling pathway by pitavastatin prevents IL-33 induction in chronically inflamed tissues, thereby reducing cancer risk in pancreatitis models and suggesting a chemopreventive role for statins via IL-33 suppression. Foundational work has also revealed that pericyte-derived IL-33, upregulated through PDGF-BB-SOX7 activation, drives recruitment of tumour-associated macrophages (TAMs) and promotes metastatic spread, highlighting a stromal cell–immune cell axis in metastasis. In colorectal cancer, overexpression of the soluble ST2 decoy receptor reprogrammes the TME by sequestering IL-33, suppressing tumour angiogenesis, limiting macrophage M2 polarisation and ultimately inhibiting tumour growth and dissemination.

IL-33 Modulation in Tumor Microenvironment and Cancer Immunity publication trend

The graph below shows the total number of articles in il-33 modulation in tumor microenvironment and cancer immunity across all publications each year (not limited to Nature Index journals).

Technical terms

IL-33: A member of the IL-1 cytokine family that functions as an alarmin when released by damaged cells.

ST2: The receptor for IL-33, existing as a membrane-bound form (ST2L) that transduces signals and a soluble decoy form (sST2).

Alarmin: A damage-associated molecular pattern released upon cellular stress to alert and activate the immune system.

Conventional type 1 dendritic cell (cDC1): A dendritic cell subset specialised in cross-presenting antigens to CD8+ T cells and initiating cytotoxic responses.

Tumour-associated macrophage (TAM): A macrophage within the TME that can polarise to antitumour (M1) or protumour (M2) states.

References

1. Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression. Nature Communications (2024).
2. The PDGF-BB-SOX7 axis-modulated IL-33 in pericytes and stromal cells promotes metastasis through tumour-associated macrophages. Nature Communications (2016).
3. Soluble IL-33 receptor sST2 inhibits colorectal cancer malignant growth by modifying the tumour microenvironment. Nature Communications (2016).
4. Discovery of highly immunogenic spleen-resident FCGR3+CD103+ cDC1s differentiated by IL-33-primed ST2+ basophils. Cellular & Molecular Immunology (2023).
5. IL-33/NF-κB/ST2L/Rab37 positive-feedback loop promotes M2 macrophage to limit chemotherapeutic efficacy in lung cancer. Cell Death & Disease (2024).
6. IL-33 and IL-33-derived DC-based tumor immunotherapy. Experimental & Molecular Medicine (2024).