CCL20–CCR6 Signaling as a Prognostic Biomarker and Therapeutic Target in Temozolomide-Resistant Glioblastoma
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Glioblastoma remains highly lethal, with median survival of ∼15 months. Resistance to temozolomide is ubiquitous, yet its mechanisms are incompletely understood. Here, we identify the CCL20-CCR6 chemokine axis as a stress-responsive survival pathway limiting therapeutic efficacy. Targeting CCL20–CCR6 in combination with temozolomide and cannabidiol was evaluated using clinical datasets, GBM cell lines, tumor organoids, and a syngeneic CT-2A mouse model integrating proteomic and lipidomic profiling. Low CCL20 expression was associated with improved survival, supporting its prognostic relevance. Across models, TMZ alone or with CBD induced CCL20 expression while exerting limited antitumor activity. Targeted disruption of CCL20-CCR6 signaling using dendrimer-delivered shRNA enhanced therapeutic response in murine models and GBM organoids. Multi-omic analyses revealed that CCL20 inhibition reprograms the tumor microenvironment and induces mitochondrial dysfunction, resulting in elevated reactive oxygen species (ROS) and tumor cell death. This effect was accompanied by accumulation of 17-hydroxydocosahexaenoic acid and activation of oxidative stress-associated cytotoxic pathways. Functional assays confirmed that CCL20 blockade selectively amplifies mitochondrial ROS beyond levels induced by TMZ alone potentiating TMZ efficacy by promoting mitochondrial oxidative stress. Targeting this axis represents a promising strategy to overcome chemoresistance and positions CCL20 as both a prognostic biomarker and a therapeutic vulnerability in GBM.
Key Points
CCL20-CCR6 is a clinically relevant adaptive resistance pathway in GBM
Targeting CCL20-CCR6 significantly enhances TMZ-based therapy
Therapeutic benefit is driven by mitochondrial dysfunction and oxidation stress
Importance of this study
Our study identifies a previously underappreciated role for the chemokine CCL20 in regulating metabolism and mitochondrial function in GBM. In addition, we show that targeting the CCL20/CCR6 axis can significantly influence therapeutic outcomes. Prior studies have reported elevated CCL20 expression in glioblastoma relative to normal tissue, as well as its induction following TMZ treatment. Building on these observations, our findings demonstrate that inhibition of CCL20 may act synergistically with TMZ by disrupting redox homeostasis and promoting mitochondrial dysfunction.
These results have important translational implications. Validating CCL20 as a therapeutic target to enhance TMZ efficacy supports further development of small-molecule inhibitors of the CCL20/CCR6 pathway. Moreover, investigating oxidative stress mechanisms downstream of CCL20 may uncover additional strategies to circumvent CCR6-dependent survival pathways, ultimately improving responses to TMZ and advancing GBM treatment.
