Abstract
Abstract
Background
Radioresistance remains a major cause of glioma recurrence, highlighting the need for therapeutically actionable radiosensitizing targets. Kinesin family member 18A (KIF18A), a mitotic motor protein essential for the survival of chromosomally unstable tumor cells, has emerged as a promising therapeutic target. However, its role and underlying mechanisms in regulating glioma radiosensitivity remain poorly understood. This study aims to evaluate the therapeutic potential and mechanisms of KIF18A inhibition combined with radiotherapy in glioma.
Methods
Integrated analyses of the Chinese Glioma Genome Atlas, The Cancer Genome Atlas and two public CRISPR/Cas9 screening platforms were performed to identify regulators of glioma radiosensitivity. KIF18A was genetically depleted using shRNA and pharmacologically inhibited with sovilnesib, a selective KIF18A inhibitor. Radiosensitizing effects were evaluated in glioma cell lines, patient-derived glioma stem cells, glioma organoids, and intracranial U251 and U87 xenograft models. To investigate the mechanism, Bulk RNA sequencing, STING inhibition with H151, and STING1 silencing were employed. An immunocompetent GL261 syngeneic glioma model was used to assess antitumor immune responses.
Results
KIF18A was identified as a novel regulator of glioma radiosensitivity, with elevated expression associated with poor survival among patients receiving radiotherapy. KIF18A knockdown enhanced radiosensitivity in U251, U87, and GL261 cells. Consistently, KIF18A knockdown combined with radiotherapy prolonged survival in U251 and U87 xenograft models. Moreover, the KIF18A inhibitor sovilnesib combined with irradiation suppressed proliferation of glioma cell lines and patient-derived primary and recurrent glioma cell lines. In patient-derived glioma organoids, combination treatment increased γH2AX-positive cells and decreased Ki-67-positive cells. It also significantly prolonged survival in U251 orthotopic models. Mechanistically, KIF18A inhibition increased radiation-induced micronuclei formation, leading to cytosolic double-stranded DNA accumulation and subsequent cGAS–STING pathway activation. This activation was accompanied by elevated cleaved caspase-3 levels and increased secretion of inflammatory mediators (TNF, CXCL3, and CXCL8). STING inhibition with H-151 or STING1 silencing attenuated the radiosensitizing effects. Notably, in immunocompetent GL261 models, combination treatment increased CD8
+
T-cell infiltration and promoted M1-like macrophage polarization.
Conclusion
KIF18A inhibition enhances glioma radiosensitivity by increasing DNA damage and activating cGAS–STING signaling. These findings highlight sovilnesib as a promising radiosensitizer for glioma.