Non-immune targeting of CXCR3 compromises mitochondrial function and suppresses tumor growth in glioblastoma

The Chemokine Receptor CXCR3 is traditionally recognized for its role in immune cell trafficking. However, emerging evidence suggests that its functions may extend beyond the immune system, particularly in Cancer, where its roles remain to be elucidated. In this study, we demonstrated that CXCR3 expression correlates with glioblastoma (GBM) grading, with CXCR3-A isoform being associated with poorer patient prognosis compared to CXCR3-B. Ablation of both CXCR3 isoforms significantly impaired GBM cell proliferation, migration, and tumor growth both in vitro and in immunodeficient mice. To elucidate the mechanistic role of CXCR3, we conducted transcriptomic profiling of tumor xenografts, revealing that CXCR3 depletion would disrupt mitochondrial homeostasis. This was further supported by our findings that CXCR3 would localize to the mitochondrial membrane, and that inhibition of CXCR3 would lead to mitochondrial depolarization and increased Reactive Oxygen Species production. Notably, activation of phosphorylated-STAT3 rescued cell viability in CXCR3-depleted cells, suggesting that CXCR3 may modulate mitochondrial function through a STAT3-dependent mechanism, consistent with the known functional role of STAT3 in maintaining mitochondrial redox balance. Furthermore, treatment with the selective CXCR3 Antagonist AMG487 reduced tumor growth and disrupted mitochondrial function in vitro, in vivo, and in patient-derived GBM stem cells. Our findings reveal CXCR3 as a previously unrecognized regulator of mitochondrial function in Cancer cells, positioning the CXCR3-mitochondrial signaling axis as a promising therapeutic target for GBM. Chemokine receptors are well-established mediators of inflammatory responses, emerging evidence suggests that these receptors may play roles beyond the immune system. In this study, we have demonstrated that CXCR3 would localize to the mitochondrial membrane and exert a previously unrecognized function in regulating Cancer metabolism and mitochondrial function. Figure created using BioRender ( https://biorender.com ).